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1. Abdel-Salam O.M.E. et al. Cannabis-Induced Impairment of Learning and Memory: Effect of Different Nootropic Drugs // EXCLI J. 2013. Vol. 12. P. 193–214.

Cannabis sativa preparations are the most commonly used illicit drugs worldwide. The present study aimed to investigate the effect of Cannabis sativa extract in the working memory version of the Morris water maze (MWM; Morris, 1984) test and determine the effect of standard memory enhancing drugs. Cannabis sativa was given at doses of 5, 10 or 20 mg/kg (expressed as Delta(9)-tetrahydrocannabinol) alone or co-administered with donepezil (1 mg/kg), piracetam (150 mg/kg), vinpocetine (1.5 mg/kg) or ginkgo biloba (25 mg/kg) once daily subcutaneously (s.c.) for one month. Mice were examined three times weekly for their ability to locate a submerged platform. Mice were euthanized 30 days after starting cannabis injection when biochemical assays were carried out. Malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide, glucose and brain monoamines were determined. Cannabis resulted in a significant increase in the time taken to locate the platform and enhanced the memory impairment produced by scopolamine. This effect of cannabis decreased by memory enhancing drugs with piracetam resulting in the most-shorter latency compared with the cannabis. Biochemically, cannabis altered the oxidative status of the brain with decreased MDA, increased GSH, but decreased nitric oxide and glucose. In cannabis-treated rats, the level of GSH in brain was increased after vinpocetine and donepezil and was markedly elevated after Ginkgo biloba. Piracetam restored the decrease in glucose and nitric oxide by cannabis. Cannabis caused dose-dependent increases of brain serotonin, noradrenaline and dopamine. After cannabis treatment, noradrenaline is restored to its normal value by donepezil, vinpocetine or Ginkgo biloba, but increased by piracetam. The level of dopamine was significantly reduced by piracetam, vinpocetine or Ginkgo biloba. These data indicate that cannabis administration is associated with impaired memory performance which is likely to involve decreased brain glucose availability as well as alterations in brain monoamine neurotransmitter levels. Piracetam is more effective in ameliorating the cognitive impairments than other nootropics by alleviating the alterations in glucose, nitric oxide and dopamine in brain.


2. Afanasieva O.G., Suslov N.I., Shilova I.V. Antidepressant, Psychostimulant, and Nootropic Effects of Major and Trace Element Composition // Bull. Exp. Biol. Med. 2013. Vol. 155, № 2. P. 204–206.

The antidepressant, psychostimulant, and nootropic effects of a composition of major and trace elements including KCl, RbNO3, magnesium sulfate, and zinc sulfate were studied on the models of behavioural despair (Porsolt test) and conditioned passive avoidance test. The preparation was found to shorten the immobilization time in the Porsolt test and promote retention of the conditioned passive avoidance. The most pronounced psychostimulant effect of the substance was observed at a dose of 4.68 mg/kg and the most pronounced antidepressant effect was found at a dose of 18.72 mg/kg. Maximum nootropic activity of the preparation was found at a dose of 93.6 mg/kg.



Oxidative stress appears to be an early event involved in the pathogenesis of Alzheimer's disease. The present study was designed to investigate the neuroprotective effects of isorhamnetin (IRN) against amyloid beta 25-35 (A beta 25-35)-induced memory impairment and oxidative damage in rats. Memory task was assessed using Y-arm maze and it revealed the impairment in spatial memory. The IRN treated rats showed improvement in memory task. A beta 25-35 induced animals also exhibited increase in hydrogen peroxide (H2O2), Monoamine oxidase activity (MAO) and decrease in choline acetyltransferase (ChAT) activity. It also enhanced the expression of inducible nitric oxide synthase (iNOS) and proinflammatory cytokine, IL-beta whereas all these abnormalities were reduced significantly in IRN treated rats showing the neuroprotective effect of IRN against A beta 25-35 induced Alzheimer's disease (AD). Thus, IRN may be a potential therapeutic agent for Alzheimer's disease.


4. Baluchnejadmojarad T. et al. S-allyl cysteine ameliorates cognitive deficits in streptozotocin-diabetic rats via suppression of oxidative stress, inflammation, and acetylcholinesterase // Eur. J. Pharmacol. 2017. Vol. 794. P. 69–76.

Diabetes mellitus (DM) is associated with learning, memory, and cognitive deficits. S-allyl cysteine (SAC) is the main organosulfur bioactive molecule in aged garlic extract with anti-diabetic, antioxidant, anti-inflammatory and nootropic property. This research was conducted to evaluate the efficacy of SAC on alleviation of learning and memory deficits in streptozotocin (STZ)-diabetic rats and to explore involvement of toll-like receptor 4 (TLR4), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), nuclear factor-kappa B (NF-kappa B), and heme oxygenase 1 (HO-1) signaling cascade. Male Wistar rats were divided into control, diabetic, SAC-treated diabetic, and glibenclamide-treated diabetic (positive control) groups. SAC was administered at a dose of 150 mg/kg for seven weeks. Treatment of diabetic rats with SAC lowered serum glucose, improved spatial recognition memory in Y maze, discrimination ratio in novel object recognition task, and restored step-through latency (STL) in passive avoidance paradigm. In addition, SAC reduced acetylcholinesterase activity, lipid peroxidation marker malondialdehyde (MDA) and augmented antioxidant defensive system including superoxide dismutase (SOD), catalase and reduced glutathione (GSH) in hippocampal lysate. Meanwhile, SAC lowered hippocampal NF-kB, TLR4, and TNF alpha and prevented reduction of Nrf2 and heme oxygenase-1 (HO-1) in diabetic rats. Taken together, chronic SAC treatment could ameliorate cognitive deficits in STZ-diabetic rats through modulation of Nrf2/NF-kappa B/TLR4/HO-1, and acetylcholinesterase and attenuation of associated oxidative stress and neuroinflammation.


5. Battisti U.M. et al. An unexpected reversal in the pharmacological stereoselectivity of benzothiadiazine AMPA positive allosteric modulators // MedChemComm. 2016. Vol. 7, № 12. P. 2410–2417.

Benzothiadiazine type compounds (BTDs) have gained great attention for their potential therapeutic activity as nootropic and neuroprotective agents. BTDs, acting as AMPA positive allosteric modulators, potentiate the glutamatergic neurotransmission without the side effects typically associated with direct agonists. Studies regarding the binding mode of racemic BTDs into the receptor binding pocket demonstrated that one enantiomer establishes a more favourable interaction and possesses a higher biological activity with respect to the other one. The S enantiomer was proved to be the eutomer for both IDRA21 and S18986, two of the most studied BTD AMPA positive allosteric modulators. However, recent data highlighted an opposite stereoselectivity for some substituted BTDs (7-chloro-9-(furan-3-yl)-2,3,3a, 4-tetrahydro-1H-benzo[e] pyrrolo[2,1-c].1,2,4] thiadiazine 5,5-dioxide and 7-chloro-2,3,4-trimethyl-3,4-dihydro-2H-benzo[e].1,2,4] thiadiazine 1,1-dioxide) showing unexpected structure-activity relationships. In this work, the synthesis and configuration assignment of the stereoisomers of 7-chloro-5-(3-furanyl)-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide, one of the most active BTDs, are reported. Electrophysiological tests demonstrated that the R form is the eutomer. Docking and molecular dynamics simulations on the AMPA GluA2 binding site revealed new insights into the stereodiscrimination process. Lastly, metabolic studies disclosed a stereoselective hepatic metabolization of this chiral BTD.


6. Battleday R.M., Brem A.-K. Modafinil for cognitive neuroenhancement in healthy non-sleep-deprived subjects: A systematic review // Eur. Neuropsychopharmacol. 2015. Vol. 25, № 11. P. 1865–1881.

Modafinil is an FDA-approved eugeroic that directly increases cortical catecholamine levels, indirectly upregulates cerebral serotonin, glutamate, orexin, and histamine levels, and indirectly decreases cerebral gamma-amino-butrytic acid levels. In addition to its approved use treating excessive somnolence, modafinil is thought to be used widely off-prescription for cognitive enhancement. However, despite this popularity, there has been little consensus on the extent and nature of the cognitive effects of modafinil in healthy, non-sleep-deprived humans. This problem is compounded by methodological discrepancies within the literature, and reliance on psychometric tests designed to detect cognitive effects in ill rather than healthy populations. In order to provide an up-to-date systematic evaluation that addresses these concerns, we searched MEDLINE with the terms "modafinil" and "cognitive", and reviewed all resultant primary studies in English from January 1990 until December 2014 investigating the cognitive actions of modafinil in healthy non-sleep-deprived humans. We found that whilst most studies employing basic testing paradigms show that modafinil intake enhances executive function, only half show improvements in attention and learning and memory, and a few even report impairments in divergent creative thinking. In contrast, when more complex assessments are used, modafinil appears to consistently engender enhancement of attention, executive functions, and learning. Importantly, we did not observe any preponderances for side effects or mood changes. Finally, in light of the methodological discrepancies encountered within this literature, we conclude with a series of recommendations on how to optimally detect valid, robust, and consistent effects in healthy populations that should aid future assessment of neuroenhancement.


7. Bezu M. et al. Repeated application of Modafinil and Levodopa reveals a drug-independent precise timing of spatial working memory modulation // Behav. Brain Res. 2016. Vol. 312. P. 9–13.

Cognition enhancing drugs often target the dopaminergic system, which is involved in learning and memory, including working memory that in turn involves mainly the prefrontal cortex and the hippocampus. In most animal models for modulations of working memory animals are pre-trained to a certain criterion and treated then acutely to test drugs effects on working memory. Thus, little is known regarding sub chronic or chronic application of cognition enhancing drugs and working memory performance. Therefore we trained male rats over six days in a rewarded alternation test in a T-maze. Rats received daily injections of either modafinil or Levodopa (L-Dopa) at a lower and a higher dose 30 min before training. Levodopa but not modafinil increased working memory performance during early training significantly at day 3 when compared to vehicle controls. Both drugs induced dose dependent differences in working memory with significantly better performance at low doses compared to high doses for modafinil, in contrast to L-Dopa where high dose treated rats performed better than low dose rats. Strikingly, these effects appeared only at day 3 for both drugs, followed by a decline in behavioral performance. Thus, a critical drug independent time window for dopaminergic effects upon working memory could be revealed. Evaluating the underlying mechanisms contributes to the understanding of temporal effects of dopamine on working memory performance.


8. Bhanumathy M. et al. Nootropic activity of Celastrus paniculatus seed // Pharm. Biol. 2010. Vol. 48, № 3. P. 324–327.

The effect of Celastrus paniculatus Willd. (Celastraceae) seed aqueous extract on learning and memory was studied using elevated plus maze and passive avoidance test (sodium nitrite induced amnesia rodent model). The aqueous seed extract was administered orally in two different doses to rats (350 and 1050 mg/kg) and to mice (500 and 1500 mg/kg). The results were compared to piracetam (100 mg/kg, p.o.) used as a standard drug. Chemical hypoxia was induced by subcutaneous administration of sodium nitrite (35 mg/kg), immediately after acquisition training. In elevated plus maze and sodium nitrite-induced amnesia model, Celastrus paniculatus extract has showed statistically significant improvement in memory process when compared to control. The estimation of acetylcholinesterase enzyme in rat brain supports the plus maze and passive avoidance test by reducing acetylcholinesterase activity which helps in memory performance. The study reveals that the aqueous extract of Celastrus paniculatus seed has dose-dependent cholinergic activity, thereby improving memory performance. The mechanism by which Celastrus paniculatus enhances cognition may be due to increased acetylcholine level in rat brain.


9. Bhattacharjee A., Shashidhara S.C., Saha S. Nootropic Activity of Crataeva Nurvala Buch-Ham Against Scopolamine Induced Cognitive Impairment // EXCLI J. 2015. Vol. 14. P. 335–345.

Loss of cognition is one of the age related mental problems and a characteristic symptom of neurodegenerative disorders like Alzheimer's. Crataeva nurvala Buch-Ham, a well explored traditional Indian medicinal plant of Westernghats, is routinely used as folkloric medicine to treat various ailments in particular urolithiasis and neurological disorders associated with cognitive dysfunction. The objective of the study was to evaluate the nootropic activity of Crataeva nurvala Buch-Ham stem bark in different learning and memory paradigm viz. Elevated plus maze and Y-maze against scopolamine induced cognitive impairment. Moreover, to elucidate possible mechanism, we studied the influence of Crataeva nurvala ethanolic extract on central cholinergic activity via estimating the whole brain acetyl cholinesterase enzyme. Ethanolic extracts of Crataeva nurvala (100, 200 and 400 mg/kg body weight) were administered to adult Wistar rats for successive seven days and the acquisition, retention and retrieval of spatial recognition memory was determined against scopolamine (1 mg/kg, i.p.) induced amnesia through exteroceptive behavioral models viz. Elevated plus maze and Y-maze models. Further, whole brain acetyl cholinesterase enzyme was estimated through Ellman's method. Pretreatment with Crataeva nurvala ethanolic extract significantly improved spatial learning and memory against scopolamine induced amnesia. Moreover, Crataeva nurvala extract decreased rat brain acetyl cholinesterase activity in a dose dependent manner and comparable to the standard drug Piracetam. The results indicate that ethanolic extract of Crataeva nurvala might be a useful as nootropic agent to delay the onset and reduce the severity of symptoms associated with dementia and Alzheimer's disease. The underlying mechanism of action of its nootropic potentiality might be attributed to its anticholinesterase property.


10. Birks J., McGuinness B., Craig D. Rivastigmine for vascular cognitive impairment // Cochrane Database Syst Rev. 2013. № 5. P. CD004744.

Background Vascular dementia represents the second most common type of dementia after Alzheimer's disease. In older patients, in particular, the combination of vascular dementia and Alzheimer's disease is common, and is referred to as mixed dementia. The classification of vascular dementia broadly follows three clinico-pathological processes: multi-infarct dementia, single strategic infarct dementia and subcortical dementia. Not all victims fulfil strict criteria for dementia and may be significantly cognitively impaired without memory loss, when the term vascular cognitive impairment (VCI) is more useful. Currently, no established standard treatment for VCI exists. Reductions in acetylcholine and acetyltransferase activity are common to both Alzheimer's disease and VCI, raising the possibility that cholinesterase inhibitors - such as rivastigmine - which are beneficial in Alzheimer's disease, may also be beneficial for VCI. Objectives To assess the efficacy of rivastigmine compared with placebo in the treatment of people with vascular cognitive impairment (VCI), vascular dementia or mixed dementia. Search methods We searched ALOIS (the Cochrane Dementia and Cognitive Improvement Group's Specialized Register) on 12 February 2013 using the terms: rivastigmine, exelon, "SDZ ENA 713". ALOIS contains records of clinical trials identified from monthly searches of a number of major healthcare databases (The Cochrane Library, MEDLINE, EMBASE, CINAHL, PsycINFO, LILACS), numerous trial registries and grey literature sources. Selection criteria All unconfounded randomized double-blind trials comparing rivastigmine with placebo in the treatment of people with VCI, vascular dementia or mixed dementia were eligible for inclusion. Data collection and analysis Two reviewers extracted and assessed data independently, and agreement was reached after discussion. They noted results concerning adverse effects. Main results Three trials, with a total of 800 participants, were identified for inclusion. The participants in one trial did not have dementia, while the other two studies included participants with dementia of different severities. The dose of rivastigmine was different in each study. No pooling of study results was attempted because of these differences between the studies. One trial included 40 participants with subcortical vascular dementia (age range 40 to 90 years) with a mean mini-mental state examination (MMSE) score of 13.0 and 13.4 in the rivastigmine and placebo arms, respectively. Treatment over 26 weeks was limited to 3 mg rivastigmine twice daily, or placebo. No significant difference was found on any outcome measure relevant to cognition, neuropsychiatric symptoms, function or global rating, or in the number of withdrawals before the end of treatment. Another trial included 710 participants with vascular dementia, including subcortical and cortical forms (age range 50 to 85 years). Over 24 weeks, a mean dose of rivastigmine of 9.4 mg/day was achieved versus placebo. Baseline MMSE was identical for both groups, at 19.1. Statistically significant advantage in cognitive response (but not with global impression of change or non-cognitive measures) was seen with rivastigmine treatment at 24 weeks (MMSE change from baseline MD 0.6, 95% CI 0.11 to 1.09, P value 0.02; Vascular Dementia Assessment Scale (VaDAS) change from baseline MD -1.3, 95% CI-2.62 to 0.02, P value 0.05). Significantly higher rates of vomiting, nausea, diarrhoea and anorexia and withdrawals from treatment were noted in the participants randomized to rivastigmine compared with placebo (withdrawals rivastigmine 90/365, placebo 48/345, OR 2.02, 95% CI 1.38 to 2.98) (withdrawals due to an adverse event rivastigmine 49/365, placebo 19/345, OR 2.66, 95% CI 1.53 to 4.62, P value 0.0005). The third study included 50 participants (age range 48 to 84 years) with mean MMSE scores of 23.7 and 23.9 in the rivastigmine and placebo arms, respectively. Over a 24-week period, par


11. Blokland A. et al. Why an M1 Antagonist Could Be a More Selective Model for Memory impairment than Scopolamine // Front. Neurol. 2016. Vol. 7. P. 167 (article number)

In summary, although scopolamine is being used to induce memory impairments in human subjects some aspects of this drug may caution the use of this drug to specifically impair memory performance. M1 antagonism can impair memory more specifically and M1 agonism (more specifically, PAMs) can improve memory. This strongly supports the notion that the M1 receptor is highly relevant and specific for memory. The use of M1 antagonist may offer a good alternative but more data are needed to support this claim.


12. Bogachouk A.P. et al. Comparative study of the neuroprotective and nootropic activities of the carboxylate and amide forms of the HLDF-6 peptide in animal models of Alzheimer’s disease // J. Psychopharmacol. 2016. Vol. 30, № 1. P. 78–92.

A comparative study of the neuroprotective and nootropic activities of two pharmaceutical substances, the HLDF-6 peptide (HLDF-6-OH) and its amide form (HLDF-6-NH2), was conducted. The study was performed in male rats using two models of a neurodegenerative disorder. Cognitive deficit in rats was induced by injection of the beta-amyloid fragment 25-35 (A 25-35) into the giant-cell nucleus basalis of Meynert or by coinjection of A 25-35 and ibotenic acid into the hippocampus. To evaluate cognitive functions in animals, three tests were used: the novel object recognition test, the conditioned passive avoidance task and the Morris maze. Comparative analysis of the data demonstrated that the neuroprotective activity of HLDF-6-NH2, evaluated by improvement of cognitive functions in animals, surpassed that of the native HLDF-6-OH peptide. The greater cognitive/ behavioral effects can be attributed to improved kinetic properties of the amide form of the peptide, such as the character of biodegradation and the half-life time. The effects of HLDF-6-NH2 are comparable to, or exceed, those of the reference compounds. Importantly, HLDF-6-NH2 exerts its effects at much lower doses than the reference compounds.


13. Broad L.M. et al. Identification and pharmacological profile of a new class of selective nicotinic acetylcholine receptor potentiators // J. Pharmacol. Exp. Ther. 2006. Vol. 318, № 3. P. 1108–1117.

Here we report the discovery, by high-throughput screening, of three novel (2-amino-5-keto) thiazole compounds that act as selective potentiators of nicotinic acetylcholine receptors. Compound selectivity was assessed at seven human nicotinic acetylcholine receptors (alpha 1 beta 1 gamma delta, alpha 2 beta 4, alpha 3 beta 2, alpha 3 beta 4, alpha 4 beta 2, alpha 4 beta 4, and alpha 7) expressed in mammalian cells or Xenopus oocytes. alpha 4 beta 4, alpha 4 beta 2, alpha 4 beta 4, and alpha 7, but not alpha 1 beta 1 gamma delta, alpha 3 beta 2, or alpha 3 beta 4, submaximal responses to nicotinic agonists were potentiated in a concentration-dependent manner by all compounds. At similar concentrations, no potentiation of 5-hydroxytryptamine, alpha-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid, GABA(A), and N-methyl-D-aspartate receptors or voltage-gated Na+ and Ca2+ channels was observed. Furthermore, these compounds did not inhibit acetylcholine esterase. Further profiling revealed that these compounds enhanced the potency and maximal efficacy of a range of nicotinic agonists at alpha 4 beta 2 nicotinic acetylcholine receptors, a profile typical of allosteric potentiators. At concentrations required for potentiation, the compounds did not displace [H-3] epibatidine from the agonist-binding site, and potentiation was observed at all agonist concentrations, suggesting a noncompetitive mechanism of action. Blockade of common second messenger systems did not affect potentiation. At concentrations higher then required for potentiation the compounds also displayed intrinsic agonist activity, which was blocked by competitive and noncompetitive nicotinic acetylcholine receptor (nAChR) antagonists. These novel selective nicotinic receptor potentiators should help in clarifying the potential therapeutic utility of selective nAChR modulation for the treatment of central nervous system disorders.


14. Cai Z.-L. et al. Effects of cordycepin on Y-maze learning task in mice // Eur. J. Pharmacol. 2013. Vol. 714, № 1–3. P. 249–253.

Cordycepin (3'-deoxyadenosine) is the major bioactive component of Cordyceps militaris that has been widely used in oriental countries as a Traditional Chinese Medicine and healthy food for preventing early aging, improving physical performance and increasing lifespan. Cordyceps militaris extracts other than cordycepin have been reported to improve cognitive function. Although cordycepin is one of the most utilized Cordyceps militaris components, it remains unknown whether cordycepin could improve learning and memory. Here we investigated effects of cordycepin on learning and memory in healthy and ischemic mice using Y-maze test. We found that oral cordycepin administration at dose of 10 mg/kg significantly improved Y-maze learning performance both in healthy and ischemic mice. However, cordycepin at dose of 5 mg/kg enhanced Y-maze learning only in ischemic mice but not healthy mice. In this study, simultaneously, we found that orally administrated cordycepin significantly decreased the neuronal loss induced by ischemia in hippocampal CA1 and CA3 regions. Collectively, our results can provide valuable evidence that cordycepin may act as a nootropic product or potential clinical application in improving cognitive function of patients with ischemic stroke in the future.


15. Canter P.H., Ernst E. Ginkgo biloba is not a smart drug: an updated systematic review of randomised clinical trials testing the nootropic effects of G-biloba extracts in healthy people // Hum. Psychopharmacol.-Clin. Exp. 2007. Vol. 22, № 5. P. 265–278.

Here, we update our earlier systematic review of 2001, which critically evaluated the data from clinical trials to determine whether Ginkgo biloba enhances cognitive function in healthy subjects. Literatures searches of six computerised databases, updated to January 2007, were made for randomised, placebo-controlled, double-blind clinical trials of the effects of standardised Ginkgo biloba (G. biloba) extracts on cognitive function in healthy subjects under the age of 60 years. Trials published in any language were included, and data were extracted independently by the two authors following a standardised protocol. We include 15 randomised clinical trials of which 7 are single-dose studies and 8 are longer term studies with treatment periods ranging from 2 days to 13 weeks. Three single dose studies and 4 longer term studies are newly included. Several of the studies have methodological flaws. A number of the acute studies used multiple outcomes and report positive effects on one or more of these at particular time points with particular doses but these findings are either not replicated, or are directly contradicted by other studies. The evidence from longer term studies is largely negative. Of those studies which measured subjective effects, only one of five acute studies and one of six longer term studies reported any significant positive results. Overall, and in line with our previous conclusions, we have found no convincing evidence from randomised clinical trials for a robust positive effect of G. biloba ingestion upon any aspect of cognitive function in healthy young people, after either acute or longer term administration.


16. Chiang K., Koo E.H. Emerging Therapeutics for Alzheimer’s Disease // Annual Review of Pharmacology and Toxicology, Vol 54 / ed. Insel P.A. Palo Alto: Annual Reviews, 2014. Vol. 54. P. 381–405.

Despite decades of intense research, therapeutics for Alzheimer's disease (AD) are still limited to symptomatic treatments that possess only short-term efficacy. Recently, several large-scale Phase III trials targeting amyloid-beta production or clearance have failed to show efficacy, leading to a reexamination of the amyloid hypothesis as well as highlighting the need to explore alternatives in both clinical testing strategies and drug discovery targets. In this review, we discuss therapeutics currently being tested in clinical trials and up-and-coming interventions that have shown promise in animal models, devoting attention to the mechanisms that may underlie their ability to influence disease progression and placing particular emphasis on tau therapeutics.


17. Chu S. et al. The anti-dementia drug candidate, (-)-clausenamide, improves memory impairment through its multi-target effect // Pharmacol. Ther. 2016. Vol. 162. P. 179–187.

Multi-target drugs, such as the cocktail therapy used for treating AIDS, often show stronger efficacy than single target drugs in treating complicated diseases. This review will focus on clausenamide (clau), a small molecule compound originally isolated from the traditional Chinese herbal medicine, Clausenalansium. The finding of four chiral centers in clau molecules predicted the presence of 16 clau enantiomers, including (-)-dau and (+)-clau. All of the predicted enantiomers have been successfully synthesized via innovative chemical approaches, and pharmacological studies have demonstrated (-)-clau as a eutomer and (+)-clau as a distomer in improving cognitive function in both normal physiological and pathological conditions. Mechanistically, the nootropic effect of (-)-clau is mediated by its multi-target actions, which include mild elevation of intracellular Ca2+ concentrations, modulation of the cholinergic system, regulation of synaptic plasticity, and activation of cellular and molecular signaling pathways involved in learning and memory. Furthermore, (-)-clau suppresses the pathogenesis of Alzheimer's disease by inhibiting multiple etiological processes: (1) beta amyloid protein-induced intracellular Ca2+ overload and apoptosis and (2) tau hyperphosphorylation and neurodegeneration. In conclusion, the nature of the multi-target actions of (-)-clau substantiates it as a promising chiral drug candidate for enhancing human cognition in normal conditions and treating memory impairment in neurodegenerative diseases.


18. Connolly J.J. et al. Attention-Deficit Hyperactivity Disorder and PharmacotherapyPast, Present, and Future: A Review of the Changing Landscape of Drug Therapy // Ther. Innov. Regul. Sci. 2015. Vol. 49, № 5. P. 632–642.

Attention-deficit hyperactivity disorder (ADHD) is the most common neurobiological disorder in children. Efficacy of pharmacotherapy in treating ADHD symptoms has generally been considerable with at least three-fourths of individuals benefiting from pharmacotherapy, typically in the form of stimulants. In this review, we begin by briefly reviewing the history of pharmacotherapy in relation to ADHD, before focusing (primarily) on the state of the field on themes such as biophysiology, pharmacokinetics, and pharmacogenomics. We conclude with a summary of emerging clinical and research studies, particularly the potential role for precision therapy in matching ADHD patients and drug types.


19. Dearden J.C. et al. QSAR Investigation of New Cognition Enhancers // QSAR Comb. Sci. 2009. Vol. 28, № 10. P. 1123–1129.

Increasing longevity means that there is an increased likelihood of loss of cognitive functions and of incidence of dementias. There is thus a greater demand for cognition-enhancing (nootropic) drugs. Some such drugs are already available, but many display serious side-effects. We have designed, synthesized and tested a number of novel chemical entities that are predicted by the PASS software to be potential nootropic agents. The results have been subjected to QSAR (quantitative structure-activity relationship) analysis, and good QSAR correlations, with external validation, have been obtained, which can be used predictively to guide design of additional potential cognition-enhancers.


20. Dowling G. et al. Outsmarted by nootropics? An investigation into the thermal degradation of modafinil, modafinic acid, adrafinil, CRL-40,940 and CRL-40,941 in the GC injector: formation of 1,1,2,2-tetraphenylethane and its tetra fluoro analog // Drug Test. Anal. 2017. Vol. 9, № 3. P. 518–528.

2-[(Diphenylmethyl)sulfinyl]acetamide (modafinil) is commonly prescribed for the treatment of narcolepsy. Increasing popularity and off-label use as a cognitive enhancer has resulted in a reputation as an intelligence boosting wonder drug'. Common alternatives available from online shops and other retail outlets include 2-[(diphenylmethyl)sulfinyl]-N-hydroxyacetamide (adrafinil), 2-{[bis(4-fluorophenyl)methyl]sulfinyl}acetamide (CRL-40,940), 2-{[bis(4-fluorophenyl)methyl]sulfinyl}-N-hydroxyacetamide (CRL-40,941), and N-methyl-4,4-difluoro-modafinil (modafiendz), respectively. Gas chromatography-mass spectrometry (GC-MS) is a common tool used in forensic and clinical analysis but there is a potential for inducing analysis-related ambiguities. This study reports on the thermal degradation of modafinil, modafinic acid, adrafinil, CRL-40,940, and CRL-40,941 due to exposure to the heated GC injection port dissolved in a variety of solvents. Key degradation products common to modafinil, modafinic acid, and adrafinil analysis included diphenylmethanol and 1,1,2,2-tetraphenylethane (TPE), the latter of which was verified by its synthesis and characterization by x-ray crystallography. The investigated compounds were also characterized by H-1 and C-13 NMR. Diphenylmethane and thiobenzophenone were also identified in some instances. TPE formation was suggested to involve the generation of a benzhydrylium ion and its reaction with the sulfoxide oxygen of the parent compound to give an oxysulfonium intermediate. Correspondingly, the fluorinated TPE analogue was formed during heat-induced degradation of modafiendz, CRL-40,940 and CRL-40,941, respectively. When a mixture of modafinil (non-fluorinated) and modafiendz (fluorinated) were subjected to GC analysis, 4,4'-(2,2-diphenylethane-1,1-diyl)bis(fluorobenzene) was detected as a third cross reaction product in addition to the two expected TPE analogues. These observations served as a reminder that the seemingly straightforward implementation of GC-MS analysis can lead to challenges during routine analysis.


21. Downey L.A. et al. An Acute, Double-Blind, Placebo-Controlled Crossover Study of 320mg and 640mg Doses of a Special Extract of Bacopa monnieri (CDRI 08) on Sustained Cognitive Performance // Phytother. Res. 2013. Vol. 27, № 9. P. 1407–1413.

Standardized extracts of the traditional Ayurvedic medicine Bacopa monnieri (BM) (Brahmi) have been recently shown to have cognitive enhancing effects in chronic administration studies. Pre-clinical work has also identified a number of acute anxiolytic, nootropic, and cardiovascular effects of BM. There has, however, been little research on the acute effects of BM on cognitive function. The current study aimed to assess the acute effects of a specific extract of BM (KeenMind (R) - CDRI 08) in a double-blind, placebo-controlled study in normal healthy participants who completed a cognitively demanding series of tests. Twenty-four healthy volunteers completed six repetitions of the Cognitive Demand Battery (CDB) after consuming a placebo, 320mg BM or 640mg of BM in a cross-over design and provided cardiovascular and mood assessments before and after treatment. Change from baseline scores indicated that the 320mg dose of BM improved performance at the first, second, and fourth repetition post-dosing on the CDB, and the treatments had no effect upon cardiovascular activity or in attenuating task-induced ratings of stress and fatigue. It was concluded that assessment of an earlier pharmacological window and use of less memory-specific cognitive tests together with more temporally sensitive measures of brain activity may improve our understanding of the acute neurocognitive properties of BM.


22. Draghici B. et al. Ethylene bis-imidazoles are highly potent and selective activators for isozymes VA and VII of carbonic anhydrase, with a potential nootropic effect // Chem. Commun. 2014. Vol. 50, № 45. P. 5980–5983.

A series of ethylene bis-imidazoles was synthesized via a novel microwave-mediated synthesis. Biological testing on eight isozymes of carbonic anhydrase (CA) present in the human brain revealed compounds with nanomolar potency against CA VA and CA VII, also displaying excellent selectivity against other CA isozymes present in this organ.


23. Fandy T.E. et al. In vitro characterization of transport and metabolism of the alkaloids: vincamine, vinpocetine and eburnamonine // Cancer Chemother. Pharmacol. 2016. Vol. 77, № 2. P. 259–267.

Vincamine, vinpocetine and eburnamonine are alkaloids known for their neuroprotective attributes, enhancement of cerebrovascular blood flow and antitumor effect of their derivatives. However, the relative metabolic stability of these alkaloids and their extrusion by the drug efflux transporters expressed at the blood-brain barrier (BBB) are not clear. In this study, we developed rapid and sensitive methods for the detection of these alkaloids and investigated their relative metabolic stability and their interaction with drug efflux transporters. UPLC methods were developed to analyze metabolic in vitro samples. Intrinsic clearance was determined using rat liver microsomal enzymes. Drug-stimulated transporter activity was estimated by measuring inorganic phosphate released from ATP spectrophotometrically. The UPLC methods quantification level ranged from 0.02 to 0.025 A mu g/mL, indicating high sensitivity. The intrinsic clearance of eburnamonine was significantly less than both vincamine and vinpocetine. Different concentrations of the three drugs (4, 20 and 100 A mu M) induced minimal stimulation of the ATPase activity of the Bcrp and Pgp membrane transporters. The developed simple, sensitive and reliable UPLC analysis methods can be utilized in future in vitro and in vivo studies. The three alkaloids demonstrated minimal interaction with the drug efflux transporters Pgp and Bcrp, concordant with the ability of these alkaloids to cross the BBB. The relative metabolic stability of eburnamonine compared to the other alkaloids suggests the use of eburnamonine or its derivatives as lead compounds for the development of antitumor and nootropic agents that need to cross the BBB and produce their pharmacological effects in the CNS.


24. Fariello R.G. et al. Broad spectrum and prolonged efficacy of dimiracetam in models of neuropathic pain // Neuropharmacology. 2014. Vol. 81. P. 85–94.

Dimiracetam, a bicyclic 2-pyrrolidinone derivative originally developed as cognition enhancer, is a member of the nootropic family for which anecdotal efficacy in models of neuropathic pain has been reported. Its antineuropathic activity was evaluated in established models of neuropathic pain induced by nerve injury, chemotherapy or MIA-induced osteoarthritis. Acutely, dimiracetam was very effective in models of antiretroviral drug induced painful neuropathy, oxaliplatin-induced hyperalgesia and in the MIA-osteoarthritis. Chronic dimiracetam dosing in the MIA and ART- induced models completely reverted hyperalgesia back to the level of healthy controls. Once reached, the maximal effect was maintained despite dose diminution and increased inter-dose interval. The effect of the last dose outlasted dimiracetam half-life longer than 12 times. In synaptosomal preparations, dimiracetam counteracted the NMDA-induced release of glutamate with highest potency in the spinal cord, possibly via NMDA receptor isoforms containing pH-sensitive GluN1 and G1uN2A subunits. Dimiracetam appears to be a promising and safe treatment for neuropathic pain conditions for which there are very limited therapeutic options.


25. Farina C. et al. Synthesis and biological evaluation of novel dimiracetam derivatives useful for the treatment of neuropathic pain // Bioorg. Med. Chem. 2008. Vol. 16, № 6. P. 3224–3232.

Chemical modifications of dimiracetam, a bicyclic analogue of the nootropic drug piracetam, afforded a small set of novel derivatives that were investigated in in vivo models of neuropathic pain. Compounds 5, 7 and 8 displayed a very promising antihyperalgesic profile in rat models of neuropathic pain induced by both chronic constriction injury of the sciatic nerve and streptozotocin. The compounds completely reverted the reduction of pain threshold evaluated by the paw pressure test. Importantly these derivatives did not induce any behavioural impairment as evaluated by the rotarod test. These results suggest that compounds 5, 7 and 8 might represent novel and well-tolerated therapeutic agents for the relief of neuropathic pain.


26. Gawande D.Y., Goel R.K. Pharmacological validation of in-silico guided novel nootropic potential of Achyranthes aspera L. // J. Ethnopharmacol. 2015. Vol. 175. P. 324–334.

Ethnopharmacological relevance: Achyranthes aspera (A. aspera) has been used as a brain tonic in folk medicine. Although, ethnic use of medicinal plant has been basis for drug discovery from medicinal plants, but the available in-silico tools can be useful to find novel pharmacological uses of medicinal plants beyond their ethnic use. Aim of the study: To validate in-silico prediction for novel nootropic effect of A. aspera by employing battery of tests in mice. Material and methods: Phytoconstituents of A. aspera reported in Dictionary of Natural Product were subjected to in-silico prediction using PASS and Pharmaexpert. The nootropic activity predicted for A. aspera was assessed using radial arm maze, passive shock avoidance and novel object recognition tests in mice. After behavioral evaluation animals were decapitated and their brains were collected and stored for estimation of glutamate levels and acetylcholinesterase activity. Results: In-silico activity spectrum for majority of A. aspera phytoconstituents exhibited excellent prediction score for nootropic activity of this plant. A. aspera extract treatment significantly improved the learning and memory as evident by decreased working memory errors, reference memory errors and latency time in radial arm maze, step through latency in passive shock avoidance and increased recognition index in novel object recognition were observed, moreover significantly enhanced glutamate levels and reduced acetylcholinesterase activity in hippocampus and cortex were observed as compared to the saline treated group. Conclusion: In-silico and in-vivo results suggest that A. aspera plant may improve the learning and memory by modulating the brain glutamatergic and cholinergic neurotransmission.



Docking of a series of methanepyrido[1,2-a][1,5]diazocin[(-)-cytisine derivatives to the active center of the nicotinic acetylcholine receptor was used to generate a set of potential substances for the treatment of cognitive dysfunction. The results from these studies led to the conclusion that six of the 21 structures were potential inhibitors of the nicotinic acetylcholine receptor. Experimental testing confirmed that the study compounds had nootropic actions and allowed the most active of these to be selected for further investigation.


28. Ghosh B. et al. Dissecting structure-activity-relationships of crebinostat: Brain penetrant HDAC inhibitors for neuroepigenetic regulation // Bioorg. Med. Chem. Lett. 2016. Vol. 26, № 4. P. 1265–1271.

Targeting chromatin-mediated epigenetic regulation has emerged as a potential avenue for developing novel therapeutics for a wide range of central nervous system disorders, including cognitive disorders and depression. Histone deacetylase (HDAC) inhibitors have been pursued as cognitive enhancers that impact the regulation of gene expression and other mechanisms integral to neuroplasticity. Through systematic modification of the structure of crebinostat, a previously discovered cognitive enhancer that affects genes critical to memory and enhances synaptogenesis, combined with biochemical and neuronal cell-based screening, we identified a novel hydroxamate-based HDAC inhibitor, here named neurinostat, with increased potency compared to crebinostat in inducing neuronal histone acetylation. In addition, neurinostat was found to have a pharmacokinetic profile in mouse brain modestly improved over that of crebinostat. This discovery of neurinostat and demonstration of its effects on neuronal HDACs adds to the available pharmacological toolkit for dissecting the molecular and cellular mechanisms of neuroepigenetic regulation in health and disease.


29. Ghumatkar P.J. et al. Nootropic, neuroprotective and neurotrophic effects of phloretin in scopolamine induced amnesia in mice // Pharmacol. Biochem. Behav. 2015. Vol. 135. P. 182–191.

Phloretin (PHL), a dihydrochalcone flavonoid usually present in the roots and leaves of apple tree. In vitro study on GT1-7 immortalized hypothalamic neurons exposed to amyloid beta (25-35), demonstrated that PHL significantly influenced membrane fluidity and potential. PHL also significantly decreased excitotoxicity by restoring the calcium homeostasis in the same. Thus, PHL proves to be a promising therapeutic moiety which should be further screened in the treatment of Alzheimer's disease. The objective of the present study was to evaluate the nootropic, neuroprotective and neurotrophic roles of PHL in the subacute scopolamine induced amnesia in mice. In this study, mice were pretreated with PHL 2.5 mg/kg, 5 mg/kg, 10 mg/kg and Donepezil (DON) 1 mg/kg intraperitoneally (i.p) for 14 days. The last 7 days of treatment regimen included daily injection of SCP 1.5 mg/kg to induce cognitive deficits. Mice were subjected to behavioral analysis. Biochemical estimation of the brain homogenates for acetylcholinesterase and oxidative stress biomarkers were conducted. Furthermore, immunohistochemical analysis for the brain derived neurotrophic factor (BDNF) was carried out particularly in the hippocampus. PHL was found to significantly improve the performance of mice in Morris water maze test (P < 0.001) and significantly decreased the acetylcholinesterase activity (P < 0.001) at all doses compared to SCP treated mice. Also, PHL significantly elevated the activity of antioxidant enzymes viz. superoxide dismutase, catalase, reduced glutathione levels (P < 0.001) and decreased malonaldehyde levels (P < 0.001) in comparison with the SCP group. Immunohistochemistry revealed that PHL treatment dose dependently improved BDNF levels in the hippocampus which were found to be significantly depleted (P < 0.001) in the SCP group. Additionally, PHL (10 mg/kg) significantly enhanced the spatial memory formation (P < 0.05) and neurotrophicity (P < 0.001) compared to DON (1 mg/kg). The aforementioned research findings suggested that PHL has nootropic, neuroprotective and neurotrophic activities in SCP induced memory impaired mice and hence, is a promising therapeutic moiety in the treatment of AD.


30. Gualtieri F. Unifi nootropics from the lab to the web: a story of academic (and industrial) shortcomings // J. Enzym. Inhib. Med. Chem. 2016. Vol. 31, № 2. P. 187–194.

This paper is a review of the work of my former academic group of research in the past 15 years, in the field of cognition enhancers (also called nootropics) that identified two very potent molecules: Unifiram and Sunifiram that for a variety of reasons were not protected by a patent. Some 12 years after their disclosure (2000) I casually found that on the web, there were dozens of sites offering Unifiram and Sunifiram as drugs that improve cognition in healthy individuals even if only few preclinical studies were done and their long-term toxicity was unknown.


31. Guandalini L. et al. Influence of ring size on the cognition-enhancing activity of DM235 and MN19, two potent nootropic drugs // Bioorg. Med. Chem. Lett. 2012. Vol. 22, № 5. P. 1936–1939.

A series of analogs of DM235 and MN19, characterized by rings with different size, have been prepared and evaluated for their nootropic activity in the mouse passive-avoidance test. It was found that the optimal ring size for the analogs of DM235, showing endocyclic both amidic groups, is 6 or 7 atoms. For the compounds structurally related to MN19, carrying an exocyclic amide group, the piperidine ring is the moiety which gives the most interesting compounds.


32. Guandalini L. et al. Substituted piperazines as nootropic agents: 2-or 3-phenyl derivatives structurally related to the cognition-enhancer DM235 // Bioorg. Med. Chem. Lett. 2015. Vol. 25, № 8. P. 1700–1704.

A series of 2-phenyl- or 3-phenyl piperazines, structurally related to DM235 and DM232, two potent nootropic agents, have been prepared and tested in the mouse passive-avoidance test, to assess their ability to revert scopolamine-induced amnesia. Although the newly synthesized molecules were less potent than the parent compounds, some useful information has been obtained from structure-activity relationships. A small but significant enantioselectivity has been found for the most potent compound 5a.


33. Gudasheva T.A. et al. N-Phenylacetylglycyl-L-Proline Ethyl Ester Converts into Cyclo-L-Prolylglycine Showing a Similar Spectrum of Neuropsychotropic Activity // Pharm. Chem. J. 2017. Vol. 50, № 11. P. 705–710.

Previously designed cyclo-L-prolylglycine (CPG), a peptide prototype of piracetam, was discovered as an endogenous compound in rat brain and exhibited nootropic and anxiolytic properties. N-Phenylacetylglycyl-L-proline ethyl ester (GZK-111) was synthesized in the present work. It was established that GZK-111 converted to CPG and possessed nootropic, anxiolytic, and antihypoxic activities typical of CPG at doses of 0.1 - 1.5 mg/kg (i.p.). The effects of both GZK-111 and CPG were stereoselective with only the L-enantiomers being active. GZK-111 could be considered as a prodrug that enhanced cognitive functioning with an anxiolytic component.


34. Habibyar A.F., Sharma N., Khurana N. PASS assisted prediction and pharmacological evaluation of hesperidin against scopolamine induced amnesia in mice // Eur. J. Pharmacol. 2016. Vol. 789. P. 385–394.

Alzheimer's disease (AD) is a neurodegenerative disorder that leads to memory impairment. However, the exact etiology of AD is not clear but cholinergic dysfunction and oxidative stress are considered to play an important role in its pathogenesis. Because of this reason, antioxidant compounds are expected to play potential beneficial role in this disease. Among number of antioxidant compounds, hesperidin (HSD) was selected for this study on the basis of its reported antioxidant and neuroprotective effects. Moreover, it has shown higher probable activity value for scavenging free radical along with anti-dementia effects, predicted by PASS online computer program. Current study was designed to evaluate the nootropic and antioxidant effects of HSD. The different groups of animals received scopolamine (2 mg/kg) along with co-treamtment of HSD (100, 200 mg/kg) and donepezil HCl (3 mg/kg) i.p. for consecutive 10 days. Behavioral tests were carried out, 30 min after respective treatment on 2nd, 5th and 9th day for memory evaluation. On 10th day of treatment, the animals were sacrificed and the homogenates of brain hippocampus and cortex were used for biochemical estimation. Co-treatment with HSD at both doses significantly reversed the changes in memory and biochemical alterations, induced by scopolamine administration. It can be concluded that HSD has strong memory enhancing and anti-oxidant effects, therefore, it can be considered as a potential candidate for its further pharmacological evaluation for AD induced dementia.


35. Hannan M.A. et al. Moringa oleifera with promising neuronal survival and neurite outgrowth promoting potentials // J. Ethnopharmacol. 2014. Vol. 152, № 1. P. 142–150.

Ethnopharmacological relevance: Moringa oleifera Lam. (Moringaceae) by virtue of its high nutritional as well as ethnomedical values has been gaining profound interest both in nutrition and medicinal research. The leaf of this plant is used in ayurvedic medicine to treat paralysis, nervous debility and other nerve disorders. In addition, research evidence also suggests the nootropic as well as neuroprotective roles of Moringa oleifera leaf in animal models. The aim of the present study was to evaluate the effect of Moringa oleifera leaf in the primary hippocampal neurons regarding its neurotrophic and neuroprotective properties. Materials and methods: The primary culture of embryonic hippocampal neurons was incubated with the ethanol extract of Moringa oleifera leaf (MOE). After an indicated time, cultures were either stained directly with a lipophilic dye, DiO, or fixed and immunolabeled to visualize the neuronal morphology. Morphometric analyses for neurite maturation and synaptogenesis were performed using Image J software. Neuronal viability was evaluated using trypan blue exclusion and lactate dehydrogenase assays. Results: MOE promoted neurite outgrowth in a concentration-dependent manner with an optimal concentration of 30 mu g/mL. As a very initial effect, MOE significantly promoted the earlier stages of neuronal differentiation. Subsequently, MOE significantly increased the number and length of dendrites, the length of axon, and the number and length of both dendrite and axonal branches, and eventually facilitated synaptogenesis. The beta-carotene, one major compound of MOE, promoted neuritogensis, but the increase was not comparable with the effect of MOE. In addition, MOE supported neuronal survival by protecting neurons from naturally occurring cell death in vitro. Conclusions: Our findings indicate that MOE promotes axodendritic maturation as well as provides neuroprotection suggesting a promising pharmacological importance of this nutritionally and ethnomedically important plant for the well-being of nervous system.


36. He D. et al. Pharmacological treatment for memory disorder in multiple sclerosis // Cochrane Database Syst Rev. 2013. № 12. P. CD008876.

Background This is an update of the Cochrane review "Pharmacologic treatment for memory disorder in multiple sclerosis" (first published in The Cochrane Library 2011, Issue 10). Multiple sclerosis (MS) is a chronic immune-mediated, inflammatory, demyelinating, neurodegenerative disorder of the central nervous system (CNS) and can cause both neurological and neuropsychological disability. Both demyelination and axonal and neuronal loss are believed to contribute to MS-related cognitive impairment. Memory disorder is one of the most frequent cognitive dysfunctions and presents a considerable burden to people with MS and to society due to the negative impact on function. A number of pharmacological agents have been evaluated in many existing randomised controlled trials for their efficacy on memory disorder in people with MS but the results were not consistent. Objectives To assess the absolute and comparative efficacy, tolerability and safety of pharmacological treatments for memory disorder in adults with MS. Search methods We searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Trials Register (24 July 2013), PsycINFO (January 1980 to 26 June 2013) and CBMdisc (1978 to 24 June 2013), and checked reference lists of identified articles, searched some relevant journals manually, registers of clinical trials and published abstracts of conference proceedings. Selection criteria All double-blind, randomised controlled parallel trials on pharmacological treatment versus placebo or one or more pharmacological treatments in adults with MS who had at least mild memory impairment (at 0.5 standard deviations below age-and sex-based normative data on a validated memory scale). We placed no restrictions regarding dose, route of administration and frequency; however, we only included trials with an administration duration of 12 weeks or greater. Data collection and analysis Two review authors independently assessed trial quality and extracted data. We discussed disagreements and resolved them by consensus among review authors. We contacted principal investigators of included studies for additional data or confirmation. Main results We included seven randomised controlled trials (RCTs) involving 625 people mostly with relapsing-remitting, secondary-progressive and primary-progressive MS, evaluating the absolute efficacy of donepezil, ginkgo biloba, memantine and rivastigmine versus placebo in improving memory performance with diverse assessment scales. Overall, clinical and methodological heterogeneities existed across these studies. Moreover, most of them had methodological limitations on non-specific selections of targeted sample, non-matched variables at baseline or incomplete outcome data (high attrition bias). Only the two studies on donepezil had clinical and methodological homogeneity and relatively low risks for bias. One RCT evaluating estriol versus placebo is currently ongoing. We could not carry out a meta-analysis due to the heterogeneities across studies and the high attrition bias. A subgroup analysis for donepezil versus placebo showed no treatment effects on total recall on the Selective Reminding Test (mean difference (MD) 1.68; 95% confidence interval (CI) -2.21 to 5.58), total correct scores on the 10/36 Spatial Recall Test (MD -0.93; 95% CI -3.18 to 1.32), the Symbol Digit Modalities Test (MD -1.27; 95% CI -3.15 to 0.61) and the Paced Auditory Serial Addition Test (2+3 sec) (MD 2.23; 95% CI -1.87 to 6.33). Concerning safety, the main adverse events were: diarrhoea (risk ratio (RR) 3.88; 95% CI 1.66 to 9.05), nausea (RR 1.71; 95% CI 0.93 to 3.18) and abnormal dreams (RR 2.91; 95% CI 1.38 to 6.14). However, the results in both studies were subjected to a serious imprecision resulting from the small sample sizes and the low power of test (lower than 80%), which contributed to a moderate quality of the evidence. No serious adverse events were attributed to the treatments in all experi


37. Hegedus N. et al. Scopolamine provocation-based pharmacological MRI model for testing procognitive agents // J. Psychopharmacol. 2015. Vol. 29, № 4. P. 447–455.

There is a huge unmet need to understand and treat pathological cognitive impairment. The development of disease modifying cognitive enhancers is hindered by the lack of correct pathomechanism and suitable animal models. Most animal models to study cognition and pathology do not fulfil either the predictive validity, face validity or construct validity criteria, and also outcome measures greatly differ from those of human trials. Fortunately, some pharmacological agents such as scopolamine evoke similar effects on cognition and cerebral circulation in rodents and humans and functional MRI enables us to compare cognitive agents directly in different species. In this paper we report the validation of a scopolamine based rodent pharmacological MRI provocation model. The effects of deemed procognitive agents (donepezil, vinpocetine, piracetam, alpha 7 selective cholinergic compounds EVP-6124, PNU-120596) were compared on the blood-oxygen-level dependent responses and also linked to rodent cognitive models. These drugs revealed significant effect on scopolamine induced blood-oxygen-level dependent change except for piracetam. In the water labyrinth test only PNU-120596 did not show a significant effect. This provocational model is suitable for testing procognitive compounds. These functional MR imaging experiments can be paralleled with human studies, which may help reduce the number of false cognitive clinical trials.


38. Kamkaew N. et al. Bacopa monnieri Increases Cerebral Blood Flow in Rat Independent of Blood Pressure // Phytother. Res. 2013. Vol. 27, № 1. P. 135–138.

Bacopa monnieri (L.) Wettst. (Brahmi in India and Thailand) is an ayurvedic dementia treatment, but its effect on cerebral blood flow (CBF) is still unknown. We sought to test its chronic and acute effects on CBF compared with Ginkgo biloba and donepezil. CBF was measured by laser Doppler from rat cerebral cortex after 8 weeks of daily oral dosing of these drugs. Systolic blood pressure was also measured using the tail cuff method or via arterial cannulation. In rats treated with B. monnieri (40 mg/kg), CBF was 25% increased [2927 +/- 123 perfusion units, (PU)] compared with shams (2337 +/- 217PU, p < 0.05, nine rats). G. biloba (60 mg/kg) also increased CBF (by 29% to 3019 +/- 208 PU, p < 0.05, nine rats). No clear effect was obtained with donepezil (1 mg/kg). Chronic administration of the preparations had no effect on blood pressure. In contrast, intravenous acute infusion of these herbals (2060 mg/kg) had marked dose-dependent hypotensive actions (diastolic similar to 31 mmHg lower with 40 mg/kg of either extract), which correspondingly reduced CBF by similar to 15%. Likewise, CBF fell slightly with acute intravenous sodium nitroprusside and rose with noradrenaline. Donepezil (1 mg/kg) was slightly hypotensive without affecting CBF. Increased CBF with B. monnieri may account for its reported procognitive effect, and its further exploration as an alternative nootropic drug is worthwhile.


39. Khurana N. et al. PASS assisted prediction and pharmacological evaluation of novel nicotinic analogs for nootropic activity in mice // Eur. J. Pharmacol. 2011. Vol. 662, № 1–3. P. 22–30.

The aim of present study is to predict the probable nootropic activity of novel nicotine analogues with the help of computer program, PASS (prediction of activity spectra for substances) and evaluate the same. Two compounds from differently substituted pyridines were selected for synthesis and evaluation of nootropic activity based on their high probable activity (Pa) value predicted by PASS computer program. Evaluation of nootropic activity of compounds after acute and chronic treatment was done with transfer latency (TL) and step down latency (SDL) methods which showed significant nootropic activity. The effect on scopolamine induced amnesia was also observed along with their acetylcholine esterase inhibitory activity which also showed positive results which strengthened their efficacy as nootropic agents through involvement of cholinergic system. This nootropic effect was similar to the effect of nicotine and donepezil used as standard drugs. Muscle coordination and locomotor activity along with their addiction liability, safety and tolerability studies were also evaluated. These studies showed that these compounds are well tolerable and safe over a wide range of doses tested along with the absence of withdrawal effect which is present in nicotine due to its addiction liability. The study showed that these compounds are true nicotine analogs with desirable efficacy and safety profile for their use as effective nootropic agents.


40. Krauze A. et al. Synthesis of 3-alkoxycarbonyl-6-alkylsulfanyl-4-[2-(difluoromethoxy)phenyl]-1,4-dihyd ropyridines and related derivatives as analogs of cognition enhancer cerebrocrast // Chem. Heterocycl. Compds. 2013. Vol. 49, № 4. P. 566–573.

4-[2-(Difluoromethoxy)phenyl]-substituted 3-alkoxycarbonyl-6-alkylsulfanyl-3-cyano-2-methyl-1,4-di-hydropyridines and related pyridine and 4,7-dihydrothieno[2,3-b]pyridine derivatives have been prepared, their memory-improving activity has been studied using the passive avoidance responses in the acquisition test, and their calcium overload-preventing activity in SH-SY5Y neuroblastoma cell line in the presence of the agonist carbachol has been examined. 1,4-Dihydropyridine derivatives bearing the 2-propoxyethoxycarbonyl group in position 3 and having weak influence on calcium overload in neuronal cells show high activity comparable with that of cerebrocrast.


41. Kryzhanovskii S.A. et al. Nootropic Action of Some Antihypertensive Drugs: Computer Predicting and Experimental Testing // Pharm. Chem. J. 2012. Vol. 45, № 10. P. 605–611.

Several antihypertensive drugs belonging to the group of ACE inhibitors have been selected for testing their nootropic activity based on a computer-aided prediction of their biological activity spectra using the PASS computer program package. Experiments were conducted on mice by the spontaneous orientation test (patrolling behavior) in a cross-maze. It was found that perindopril at a dose of 1 mg/kg in addition to quinapril and monopril at a dose of 10 mg/kg improved the patrolling behavior in the cross-maze test. This effect is similar to the effects of the standard nootropic drugs piracetam and meclofenoxate (at doses of 300 and 120 mg/kg, respectively). The observed nootropic effect of some ACE inhibitors is likely to be unrelated to their antihypertensive effect since the nootropic action took place only at relatively low doses of perindopril, quinapril, and monopril and was not observed with further increase of the dose. The identification of nootropic action of antihypertensive drugs that are commonly used in clinical practice leads to their new clinical applications with allowance for the relevant idiosyncrasies of patients.


42. Kumar T.V. et al. Evaluation of antibacterial, antioxidant and nootropic activities of Tiliacora racemosa Colebr. leaves: In vitro and in vivo approach // Biomed. Pharmacother. 2017. Vol. 86. P. 662–668.

The antibacterial and antioxidant potential of Tiliacora racemosa leaf extracts in various solvents (methanolic, hexane, chloroform and ethyl acetate) was determined. Additionally, the presence of bisbenzylisoquinoline alkaloids in the plant prompted us to evaluate the nootropic activity of the methanolic extract in mice. Further, we seek to verify the nootropic effect by examining the anticholinesterase inhibition potential of the methanolic extract. The leaf extracts in various solvents were evaluated for their antibacterial and antioxidant activity by agar diffusion technique and alpha, alpha-diphenyl-beta-picrylhydrazyl (DPPH) free radical scavenging method, respectively. The ex vivo acetylcholine esterase inhibitory activity of the methanolic extract was carried out by Ellman's method in male Wistar rats. The nootropic capacity of the methanolic extract was examined in Swiss albino mice by utilizing the diazepam induced acute amnesic model. The chloroform/n-hexane and ethyl acetate fraction showed promising antioxidant and antibacterial (Gram positive and Gram negative bacteria) property, respectively. The methanolic extract was able to diminish the amnesic effect induced by diazepam (1 mg/kg i.p.) in mice. The extract also showed significant acetyl cholinesterase inhibition in rats. The findings prove that the memory enhancing capability is due to increased acetyl choline level at the nerve endings. The strong antioxidant nature and potential nootropic activity shown by the extract suggests its future usage in the treatment of neurodegenerative disorders such as dementia and Alzheimer.


43. Lanni C. et al. Cognition enhancers between treating and doping the mind // Pharmacol. Res. 2008. Vol. 57, № 3. P. 196–213.

Memory, attention and creativity represent three different cognitive domains, which are interconnected and contribute the "mental performance" of an individual. Modern neuroscience has investigated some of the neuronal circuits and of the neurotransmitters and molecular events underlying the above-mentioned cognitive functions. Within this renewed reference context, some of the properties of the components of the remedies to increase mental performance have been studied and validated in experimental models and, to date, these substances are named "smart drugs", "memory enhancing drugs" or "nootropic drugs" (from the Greek root noos for mind and tropein for toward). Recently pharmaceutical industries are increasingly focusing on the research for potential substances in this field: several "smart drugs" are in clinical trials and could be on the market in few years. Furthermore, a quick survey from Internet highlights the presence of a great variety of both approved and non-approved drugs, with some of them addressing to only medical and others to performance-oriented use, opening room to some reflections or speculations from scientific and ethical points of view. In order to point out the effect of nootropic drugs on cognition of healthy people, we reviewed the literature on drug enhancement of various cognitive functions, including memory, attention and creativity. As their simplest, memory is regarded as the ability to remember events or learned material, attention is the cognitive process of selectively concentrating on one aspect while ignoring distracters and creativity could be described as the ability to create products or ideas which are original and which possess a social usefulness. Reports from literature reveal that some medications currently available to patients with memory disorders may also increase performances in healthy people and that drugs designed for psychiatric disorders can also be used to enhance certain mental functions. However, the long-term effects of these drugs are unknown, but their apparent effectiveness allows room to their use and misuse. At variance with these literature data showing scientific, even if poor, evidence of the effect of smart drugs in the field of memory and attention, only indirect information on creativity can be obtained by studies of the effects of diseases and drugs on the artistic productivity of classic painters and famous authors, offering a link to understand the neuronal basis of this cognitive function and a cue to understand how drugs (used to correct the illness) may affect the function. On the basis of these cues, in this review we will discuss some critical aspects of the different cerebral circuits and molecular events regulating memory, attention and creativity in order to outline the neurobiological bases of the effects of "smart drugs" on cognitive functions, and to evaluate their putative pharmaceutical development.


44. Li X. et al. Studies on the synthesis and biological evaluation of the metabolite of clausenamide CM2 and its stereoisomers // Eur. J. Med. Chem. 2014. Vol. 74. P. 736–741.

The synthesis and biological evaluation of 5-hydroxy clausenamide (CM2), one of the major metabolites of clausenamide, and its stereoisomers have been carried out. The absolute configurations of (-)- and (+)-CM2 were assigned as 3S,4S,5S,6S and 3R,4R,5R,6R respectively based on H-1 NMR spectroscopic investigation and their chemical correlation to (-)- and (+)-clausenamidone (3). Electrophysiological assay showed that compound (+)-CM2 and its C-6 epimer (+)-8a had significant effects on synaptic transmission and thus induced the long-term potentiation of the dentate gyrus.


45. Li X. et al. Traditional Chinese Nootropic Medicine Radix Polygalae and Its Active Constituent Onjisaponin B Reduce beta-Amyloid Production and Improve Cognitive Impairments // PLoS One. 2016. Vol. 11, № 3. P. e0151147.

Decline of cognitive function is the hallmark of Alzheimer's disease (AD), regardless of the pathological mechanism. Traditional Chinese medicine has been used to combat cognitive impairments and has been shown to improve learning and memory. Radix Polygalae (RAPO) is a typical and widely used herbal medicine. In this study, we aimed to follow the beta-amyloid (A beta) reduction activity to identify active constituent(s) of RAPO. We found that Onjisaponin B of RAPO functioned as RAPO to suppress A beta production without direct inhibition of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) and gamma-secretase activities. Our mechanistic study showed that Onjisaponin B promoted the degradation of amyloid precursor protein (APP). Further, oral administration of Onjisaponin B ameliorated A beta pathology and behavioral defects in APP/PS1 mice. Taken together, our results indicate that Onjisaponin B is effective against AD, providing a new therapeutic agent for further drug discovery.


46. Ling I. et al. A novel GABA(A) alpha 5 receptor inhibitor with therapeutic potential // Eur. J. Pharmacol. 2015. Vol. 764. P. 497–507.

Novel 2,3-benzodiazepine and related isoquinoline derivatives, substituted at position 1 with a 2-benzothiophenyl moiety, were synthesized to produce compounds that potently inhibited the action of GABA on heterologously expressed GABA(A) receptors containing the alpha 5 subunit (GABA(A) alpha(5)), with no apparent affinity for the benzodiazepine site. Substitutions of the benzothiophene moiety at position 4 led to compounds with drug-like properties that were putative inhibitors of extra-synaptic GABA(A) alpha(5) receptors and had substantial blood-brain barrier permeability. Initial characterization in vivo showed that 8-methyl-5-[4-(trifluoromethyl)-1-benzothiophen-2-yl]-1,9-dihydro-2H-[1,3]oxazolo[4,5-h][2,3] benzodiazepin-2-one was devoid of sedative, pro-convulsive or motor side-effects, and enhanced the performance of rats in the object recognition test. In summary, we have discovered a first-in-class GABA-site inhibitor of extra-synaptic GABA(A) alpha(5) receptors that has promising drug-like properties and warrants further development.


47. Lu X.-C.M. et al. Nefiracetam attenuates post-ischemic nonconvulsive seizures in rats and protects neuronal cell death induced by veratridine and glutamate // Life Sci. 2013. Vol. 92, № 22. P. 1055–1063.

Aims: Stroke patients are at a high risk of developing post-ischemic seizures and cognitive impairment. Nefiracetam (NEF), a pyrrolidone derivative, has been shown to possess both anti-epileptic and cognitive-enhancing properties. In this study the anti-seizure effects of NEF were evaluated in a rat model of post-ischemic nonconvulsive seizures (NCSs). Its potential mechanisms were investigated in neuronal cell culture assays of neurotoxicity associated with ischemic brain injury and epileptogenesis. Main methods: In the in vivo study, rats received 24 h permanent middle cerebral artery occlusion. NEF was administered intravenously either at 15 min post-injury but prior to the first NCS event (30 mg/kg, pre-NCS treatment) or immediately after the first NCS occurred (30 or 60 mg/kg, post-NCS treatment). In the in vitro study, neuronal cell cultures were exposed to veratridine or glutamate and treated with NEF (1-500 nM). Key findings: The NEF pre-NCS treatment significantly reduced the NCS frequency and duration, whereas the higher NEF dose (60 mg/kg) was required to achieve similar effects when given after NCS occurred. The NEF treatment also dose-dependently (5-500 nM) protected against neuronal cell death induced by veratridine as measured by MTT cell viability assay, but higher doses (250-500 nM) were required against glutamate toxicity. Significance: The anti-seizure property of NEF was demonstrated in a clinically relevant rat model of post-ischemic NCS. The preferential effects of NEF against in vitro veratridine toxicity suggest the involvement of its modulation of sodium channel malfunction. Future studies are warranted to study the mechanisms of NEF against ischemic brain injury and post-ischemic seizures.


48. Maheswari J.U., Muthu S., Sundius T. Molecular docking, spectroscopic studies and quantum calculations on nootropic drug // Spectroc. Acta Pt. A-Molec. Biomolec. Spectr. 2014. Vol. 123. P. 503–510.

A systematic vibrational spectroscopic assignment and analysis of piracetam [(2-oxo-1-pyrrolidineacetamide)] have been carried out using FT-IR and FT-Raman spectral data. The vibrational analysis was aided by an electronic structure calculation based on the hybrid density functional method B3LYP using a 6-311G++(d,p) basis set. Molecular equilibrium geometries, electronic energies, IR and Raman intensities, and harmonic vibrational frequencies have been computed. The assignments are based on the experimental IR and Raman spectra, and a complete assignment of the observed spectra has been proposed. The UV-visible spectrum of the compound was recorded and the electronic properties, such as HOMO and LUMO energies and the maximum absorption wavelengths lambda(max) were determined by the time-dependent DFT (TD-DFT) method. The geometrical parameters, vibrational frequencies and absorption wavelengths were compared with the experimental data. The complete vibrational assignments are performed on the basis of the potential energy distributions (PED) of the vibrational modes in terms of natural internal coordinates. The simulated FT-IR, FT-Raman, and UV spectra of the title compound have been constructed. Molecular docking studies have been carried out in the active site of piracetam by using Argus Lab. In addition, the potential energy surface, HOMO and LUMO energies, first-order hyperpolarizability and the molecular electrostatic potential have been computed.


49. Maino B. et al. Drug target identification at the crossroad of neuronal apoptosis and survival // Expert. Opin. Drug Discov. 2017. Vol. 12, № 3. P. 249–259.

Introduction: Inappropriate activation of apoptosis may contribute to neurodegeneration, a multifaceted process that results in various chronic disorders, including Alzheimer's and Parkinson's diseases. Several in vitro and in vivo studies demonstrated that neuronal apoptosis is a multi-pathway cell-death program that requires RNA synthesis. Thus, transcriptionally activated genes whose products induce cell death can be triggered by different stimuli and antagonized by neurotrophic factors. Systems biology is now unveiling the series of intracellular signaling pathways and key drug targets at the intersection of neuronal apoptosis and survival. Areas covered: This review introduces a genomic approach that can be used to elucidate the systems biology of neuronal apoptosis and survival, and to rationally select drug targets, no longer oriented to emulate the action of growth factors at the membrane receptor level, but rather to modulate their downstream signals. Expert opinion: The advent of genomics is offering an unprecedented opportunity to explore how the delicate balance between apoptosis and survival-inducing signals triggers a transcriptional program. Characterization of this program can be useful to identify potential pharmacological targets for existing drugs. Such knowledge might pave the way towards an innovative pharmacology.


50. Makara N.S. et al. New (-)-Cytisine Derivatives with Nootropic Activity // Pharm. Chem. J. 2015. Vol. 49, № 5. P. 301–303.

The mnestic and antihypoxic effects of new derivatives of the quinolizidine alkaloid (-)-cytisine on acquisition of a conditioned passive avoidance reflex (CPAR) were studied in rats; effects on normobaric (jar) hypoxia were studied in mice. Screening studies showed that the benzamide and the N-(12-methylcytidin-3-yl)-N'-phenylurea not only improved learning and memory, but also increased the resistance of the brain to hypoxia.


51. Malkova L., Kozikowski A.P., Gale K. The effects of huperzine A and IDRA 21 on visual recognition memory in young macaques // Neuropharmacology. 2011. Vol. 60, № 7–8. P. 1262–1268.

Nootropic agents or cognitive enhancers are purported to improve mental functions such as cognition, memory, or attention. The aim of our study was to determine the effects of two possible cognitive enhancers, huperzine A and IDRA 21, in normal young adult monkeys performing a visual memory task of varying degrees of difficulty. Huperzine A is a reversible acetylcholinesterase (AChE) inhibitor, its administration results in regionally specific increases in acetylcholine levels in the brain. In human clinical trials, Huperzine A resulted in cognitive improvement in patients with mild to moderate form of Alzheimer's disease (AD) showing its potential as a palliative agent in the treatment of AD. IDRA 21 is a positive allosteric modulator of glutamate AMPA receptors. It increases excitatory synaptic strength by attenuating rapid desensitization of AMPA receptors and may thus have beneficial therapeutic effects to ameliorate memory deficits in patients with cognitive impairments, including AD. The present study evaluated the effects of the two drugs in normal, intact, young adult monkeys to determine whether they can result in cognitive enhancement in a system that is presumably functioning optimally. Six young pigtail macaques (Macaca nemestrina) were trained on delayed non-matching-to-sample task, a measure of visual recognition memory, up to criterion of 90% correct responses on each of the four delays (10 s, 30s, 60 s, and 90 s). They were then tested on two versions of the task: Task 1 included the four delays intermixed within a session and the monkeys performed it with the accuracy of 90%. Task 2 included, in each of 24 trials, a list of six objects presented in succession. Two objects from the list were then presented for choice paired with novel objects and following two of the four delays intermixed within a session. This task with a higher mnemonic demand yielded an average performance of 64% correct. Oral administration of huperzine A did not significantly affect the monkeys' performance on either task. However, a significant negative correlation was found between the baseline performance on each delay and the change in performance under huperzine A, suggesting that under conditions in which the subjects were performing poorly (55-69%), the drug resulted in improved performance, whereas no improvement was obtained when the baseline was close to 90%. In fact, when the subjects were performing very well, huperzine A tended to reduce the performance accuracy, indicating that in a system that functions optimally, the increased availability of acetylcholine does not improve performance or memory, especially when the animals are close to the maximum performance. In contrast, oral administration of IDRA 21 significantly improved performance on Task 2, especially on the longest delay. This finding supports the potential use of this drug in treatment of cognitive and memory disorders.


52. Malykh A.G., Sadaie M.R. Piracetam and Piracetam-Like Drugs From Basic Science to Novel Clinical Applications to CNS Disorders // Drugs. 2010. Vol. 70, № 3. P. 287–312.

There is an increasing interest in nootropic drugs for the treatment of CNS disorders. Since the last meta-analysis of the clinical efficacy of piracetam, more information has accumulated. The primary objective of this systematic survey is to evaluate the clinical outcomes as well as the scientific literature relating to the pharmacology, pharmacokinetics/pharmacodynamics, mechanism of action, dosing, toxicology and adverse effects of marketed and investigational drugs. The major focus of the literature search was on articles demonstrating evidence-based clinical investigations during the past 10 years for the following therapeutic categories of CNS disorders: (i) cognition/memory; (ii) epilepsy and seizure; (iii) neurodegenerative diseases; (iv) stroke/ischaemia; and (v) stress and anxiety. In this article, piracetam-like compounds are divided into three subgroups based on their chemical structures, known efficacy and intended clinical uses. Subgroup I drugs include piracetam, oxiracetam, aniracetam, pramiracetam and phenylpiracetam, which have been used in humans and some of which are available as dietary supplements. Of these, oxiracetam and aniracetam are no longer in clinical use. Pramiracetam reportedly improved cognitive deficits associated with traumatic brain injuries. Although piracetam exhibited no long-term benefits for the treatment of mild cognitive impairments, recent studies demonstrated its neuroprotective effect when used during coronary bypass surgery. It was also effective in the treatment of cognitive disorders of cerebrovascular and traumatic origins; however, its overall effect on lowering depression and anxiety was higher than improving memory. As add-on therapy, it appears to benefit individuals with myoclonus epilepsy and tardive dyskinesia. Phenylpiracetam is more potent than piracetam and is used for a wider range of indications. In combination with a vasodilator drug, piracetam appeared to have an additive beneficial effect on various cognitive disabilities. Subgroup 2 drugs include levetiracetam, seletracetam and brivaracetam, which demonstrate antiepileptic activity, although their cognitive effects are unclear. Subgroup 3 includes piracetam derivatives with unknown clinical efficacies, and of these nefiracetam failed to improve cognition in post-stroke patients and rolipram is currently in clinical trials as an antidepressant. The remaining compounds of this subgroup are at various preclinical stages of research. The modes of action of piracetam and most of its derivatives remain an enigma. Differential effects on subtypes of glutamate receptors, but not the GABAergic actions, have been implicated. Piracetam seems to activate calcium influx into neuronal cells; however, this function is questionable in the light of findings that a persistent calcium inflow may have deleterious impact on neuronal cells. Although subgroup 2 compounds act via binding to another neuronal receptor (synaptic vesicle 2A), some of the subgroup 3 compounds, such as nefiracetam, are similar to those of subgroup 1. Based on calculations of the efficacy rates, our assessments indicate notable improvements in clinical outcomes with some of these agents.


53. Martini E. et al. Design, synthesis and nootropic activity of new analogues of sunifiram and sapunifiram, two potent cognition-enhancers // Bioorg. Med. Chem. 2009. Vol. 17, № 21. P. 7606–7614.

A series of amides and sulfonamides, structurally related to DM235 (sunifiram) and MN19 (sapunifiram), derived by ring expansion or contraction, or by inversion of the exocyclic amide function, have been synthesized and tested for cognition-enhancing activity in the mouse passive-avoidance test. Some of the compounds display good antiamnesic and procognitive activity, with higher potency than piracetam, and with a potency similar to the parent compounds.


54. Martini E. et al. Synthesis and Biological Evaluation of 3,7-Diazabicyclo[4.3.0]nonan-8-ones as Potential Nootropic and Analgesic Drugs // J. Med. Chem. 2011. Vol. 54, № 7. P. 2512–2516.

A series of cis and trans 3,7-diazabicyclo[4.3.0]nonan-8-ones has been synthesized and tested for their ability to revert scopolamine-induced amnesia in the mouse passive-avoidance test. The racemates of the most potent compounds 4 and 7 were separated and tested, but no enantioselectivity was found for the nootropic activity. Compounds 4 and 7 and their enantiomers displayed interesting antihyperalgesic activity in two models of neuropathic pain (streptozotocin-induced and oxalilplatin-induced neuropathy) in comparison with pregabalin.


55. Martino M.V. et al. Piperazines as nootropic agents: New derivatives of the potent cognition-enhancer DM235 carrying hydrophilic substituents // Bioorg. Med. Chem. 2017. Vol. 25, № 6. P. 1795–1803.

The piperazine ring of the potent nootropic drug DM235 has been decorated with H-bond donor and acceptor groups (CH2OH, CH2OMe, CH2OCOMe, COOEt); the aim was to insert new functional groups, suitable for further chemical manipulation. The influence of these modifications on nootropic activity was assessed by means of the mouse passive avoidance test; some of the newly synthesized molecules (alcohol 7b, acetate 8b and ester 10d) showed interesting in vivo potency. This makes it possible to use these functional groups for adding other residues, in order to increase molecular diversity, or for anchoring a biotin group, to obtain compounds useful to capture the biological target. Moreover, the new compounds will improve our knowledge of structure activity relationships of this family of drugs.


56. Meador K.J. et al. Neurocognitive effects of brivaracetam, levetiracetam, and lorazepam // Epilepsia. 2011. Vol. 52, № 2. P. 264–272.

Brivaracetam (BRV) is a new anticonvulsant under development. Although BRV is an analog of levetiracetam (LEV), in addition to being an SV2A ligand, it also inhibits sodium channels in a voltage-dependent manner. The cognitive effects of BRV are uncertain. Methods: A randomized, double-blind, placebo-controlled, four-way cross-over design was employed in 16 healthy volunteers comparing acute dosing (i.e., two doses) of BRV 10 mg, LEV 500 mg, lorazepam (LZP) 2 mg, and placebo. The primary outcome was the summary score from the cognitive neurophysiologic test (CNT), which combines electrophysiologic and performance measures. Secondary outcomes included CNT cognitive and electrophysiologic subscores, traditional neuropsychological measures, and treatment-emergent adverse events (TEAEs). Results: Compared to BRV, LEV, and placebo, LZP adver-sely affected the CNT summary score and the majority of CNT subscores and neuropsychological measures. In contrast, BRV did not differ from placebo or LEV on any measure. More TEAEs occurred with LZP compared to each of the other treatment conditions. Discussion: The differential pattern of drug effects was consistent across multiple electrophysiologic, cognitive, and subjective measures. The profile of cognitive, subjective, and electrophysiologic effects for BRV was similar to the analog compound LEV and to placebo. The findings suggest that BRV should be tolerated well from a neuropsychological perspective, but additional studies are needed.


57. Mehdi B.J. et al. Nootropic and anti-stress effects of rice bran oil in male rats // J. Food Sci. Technol.-Mysore. 2015. Vol. 52, № 7. P. 4544–4550.

Rice bran oil (RBO) is an important product of rice bran. It is considered to be one of the most important nutritious oil due to its favorable fatty acid composition and unique composition of naturally occurring biologically active antioxidant compounds. This study was designed to monitor the effects of oral intake of RBO on stress response in rats. RBO was extracted using hexane. Rats were divided into Control and test (RBO-treated). RBO-treated rats were given 0.2 ml/day RBO for 6 weeks. Food intake and body weight changes were monitored weekly. After 6 weeks open field activity and Morris Water Maze (MWM) test were performed. Results showed that weekly cumulative food intake but not body weight were lower in RBO-treated rats during 1st to 5th week of treatment, which were normalized at the end of treatment. Exploratory activity of RBO-treated rats in an open field was increased. Spatial memory in Morris water maze was enhanced in RBO-treated than control rats. An episode of 2 h restraint stress decreased the 24 h food intake of both control and RBO-treated animals. Behavioral deficits were lower in RBO-treated rats. Exposure of 2 h restraint stress increased brain serotonin (5-hydroxytryptamine: 5-HT) metabolism. These increases were lower in RBO-treated restrained than their respective control animals. Serotonergic neurotransmitter mechanism is implicated in stress. The findings of the study show beneficial effects of RBO in learning and memory functions. Moreover, the study also highlights the attenuating effect of RBO on stress induced behavioral and neurochemical effects in rats.


58. Mendes G.D. et al. Assessment of pharmacokinetic interaction between piracetam and I-carnitine in healthy subjects // Biomed. Chromatogr. 2016. Vol. 30, № 4. P. 536–542.

A rapid, sensitive and specific method for quantifying piracetam in human plasma using Piracetam d-8 as the internal standard (IS) is described. The analyte and the IS were extracted from plasma by one-step precipitation of protein using an acetonitrile (100%). The extracts were analyzed by high-performance liquid chromatography coupled with electrospray tandem mass spectrometry (HPLC-MS/MS). The method had a chromatographic run time of 3.8 min and a linear calibration curve over the range 0.5-50 mu g/mL (r > 0.99). This LC-MS-MS procedure was used to assess the bioavailability of two piracetam formulations: piracetam + l-carnitine (Piracar (R); 270/330 mg tablet) and piracetam (Nootropil (R); 800 mg tablet) in healthy volunteers of both sexes. The geometric means with corresponding 90% confidence interval (CI) for test/reference percentage ratios were 88.49% (90% CI = 81.19 - 96.46) for peak concentration/dose and 102.55% (90% CI = 100.62 - 104.51) for AUC(inf)/dose. The limit of quantitation of 0.5 mu g/mL is well suited for pharmacokinetic studies in healthy volunteers. It was concluded that piracetam (Piracar (R); 270/330 mg tablet) has a bioavailability equivalent to the piracetam (Nootropil (R); 800 mg tablet) formulation with regard to both the rate and the extent of absorption.


59. Mihalik B. et al. Loop-F of the alpha-subunit determines the pharmacologic profile of novel competitive inhibitors of GABA(A) receptors // Eur. J. Pharmacol. 2017. Vol. 798. P. 129–136.

The neurotransmitter gamma-amino butyric acid (GABA) has a fundamental role in CNS function and ionotropic (GABA(A)) receptors that mediate many of the actions of GABA are important therapeutic targets. This study reports the mechanism of action of novel GABA(A) antagonists based on a tricyclic oxazolo-2,3-benzodiazepine scaffold. These compounds are orthosteric antagonists of GABA on heteropentameric GABA(A) receptors of alpha x beta 2 gamma 2 configuration expressed in HEK293 cells. In silico modelling predicted that the test compounds docked in the GABA binding-pocket and would interact with amino-acid residues in the alpha- and beta-subunit interface that are known to be important for the binding of GABA. Intriguingly, optimal docking also required an interaction with the non-conserved amino-terminal segment of Loop-F of the alpha-subunit. Testing of a compound with altered regiochemistry of the oxazolone moiety supported the model with respect to the conserved GABA-interacting residues in vitro as well as in vivo. The prediction regarding, loop-F was examined by replacing the amino-terminal variable segment of loop-F of the alpha 5-subunit with the corresponding residues in the alpha 1- and alpha 2 subunits. When tested with the novel inhibitors, the receptors formed by the modified alpha 5-subunits displayed the pharmacologic phenotype of the source of loop-F. In summary, these data show that the variable amino terminal segment of loop-F of the alpha-subunit determines the pharmacologic selectivity of the novel tricyclic inhibitors of GABA(A) receptors.


60. Moriguchi S. et al. Nefiracetam potentiates N-methyl-D-aspartate (NMDA) receptor function via protein kinase C activation and reduces magnesium block of NMDA receptor // Mol. Pharmacol. 2007. Vol. 71, № 2. P. 580–587.

Nicotinic acetylcholine receptors and N- methyl- D- aspartate ( NMDA) receptors are known to be down- regulated in the brain of Alzheimer's disease patients. We have previously demonstrated that the nootropic drug nefiracetam potentiates the activity of both nicotinic acetylcholine and NMDA receptors and that nefiracetam modulates the glycine binding site of the NMDA receptor. Because the NMDA receptor is also modulated by Mg2+ and protein kinases, we studied their roles in nefiracetam action on the NMDA receptor by the whole- cell patch- clamp technique and immunoblotting analysis using rat cortical or hippocampal neurons in primary culture. The nefiracetam potentiation of NMDA currents was inhibited by the protein kinase C ( PKC) inhibitor chelerythrine, but not by the protein kinase A ( PKA) inhibitor N-[ 2-( 4- bromocinnamylamino) ethyl]- 5- isoquinoline ( H89). In immunoblotting analysis, nefiracetam treatment increased the PKC alpha activity with a bell- shaped dose-response relationship peaking at 10 nM, thereby increasing phosphorylation of PKC substrate and NMDA receptor. Such an increase in PKC alpha-mediated phosphorylation was prevented by chelerythine. Nefiracetam treatment did not affect the PKA activity. Analysis of the current-voltage relationships revealed that nefiracetam at 10 nM largely eliminated voltage- dependent Mg2+ block and that this action of nefiracetam was sensitive to PKC inhibition. It was concluded that nefiracetam potentiated NMDA currents not by acting as a partial agonist but by interacting with PKC, allosterically enhancing glycine binding, and attenuating voltage- dependent Mg2+ block.


61. Moriguchi S. et al. Novel Nootropic Drug Sunifiram Enhances Hippocampal Synaptic Efficacy via Glycine-Binding Site of N-Methyl-D-aspartate Receptor // Hippocampus. 2013. Vol. 23, № 10. P. 942–951.

Sunifiram is a novel pyrrolidone nootropic drug structurally related to piracetam, which was developed for neurodegenerative disorder like Alzheimer's disease. Sunifiram is known to enhance cognitive function in some behavioral experiments such as Morris water maze task. To address question whether sunifiram affects N-methyl-D-aspartate receptor (NMDAR)-dependent synaptic function in the hippocampal CA1 region, we assessed the effects of sunifiram on NMDAR-dependent long-term potentiation (LTP) by electrophysiology and on phosphorylation of synaptic proteins by immunoblotting analysis. In mouse hippocampal slices, sunifiram at 10-100 nM significantly enhanced LTP in a bell-shaped dose-response relationship which peaked at 10 nM. The enhancement of LTP by sunifiram treatment was inhibited by 7-chloro-kynurenic acid (7-ClKN), an antagonist for glycine-binding site of NMDAR, but not by ifenprodil, an inhibitor for polyamine site of NMDAR. The enhancement of LTP by sunifilam was associated with an increase in phosphorylation of -amino-3-hydroxy-5-methylisozazole-4-propionate receptor (AMPAR) through activation of calcium/calmodulin-dependent protein kinase II (CaMKII) and an increase in phosphorylation of NMDAR through activation of protein kinase C (PKC). Sunifiram treatments at 1-1000 nM increased the slope of field excitatory postsynaptic potentials (fEPSPs) in a dose-dependent manner. The enhancement was associated with an increase in phosphorylation of AMPAR receptor through activation of CaMKII. Interestingly, under the basal condition, sunifiram treatments increased PKC (Ser-657) and Src family (Tyr-416) activities with the same bell-shaped dose-response curve as that of LTP peaking at 10 nM. The increase in phosphorylation of PKC (Ser-657) and Src (Tyr-416) induced by sunifiram was inhibited by 7-ClKN treatment. The LTP enhancement by sunifiram was significantly inhibited by PP2, a Src family inhibitor. Finally, when pretreated with a high concentration of glycine (300 M), sunifiram treatments failed to potentiate LTP in the CA1 region. Taken together, sunifiram stimulates the glycine-binding site of NMDAR with concomitant PKC activation through Src kinase. Enhancement of PKC activity triggers to potentiate hippocampal LTP through CaMKII activation.


62. Moriguchi S. et al. Novel nootropic drug sunifiram improves cognitive deficits via CaM kinase II and protein kinase C activation in olfactory bulbectomized mice // Behav. Brain Res. 2013. Vol. 242. P. 150–157.

Alzheimer's disease (AD) shows degeneration of the cholinergic system in the medial septum, thereby eliciting down-regulation of the olfactory function in patients. We have previously reported that olfactory bulbectomized (OBX) mice show hippocampus-dependent memory impairment as assessed by memory-related behavioral tasks and hippocampal long-term potentiation (LTP). In the present study, we focused whether novel pyrrolidone nootropic drug sunifiram improves both memory impairment And depression observed in OBX mice. OBX mice were administered once a day for 7-12 days with sunifiram (0.01-1.0 mg/kg p.o.) from 10 days after operation with or without gavestinel (10 mg/kg i.p.), which is glycine-binding site inhibitor of N-methyl-D-aspartate receptor (NMDAR). The spatial reference memory assessed by Y-maze and short-term memory assessed by novel object recognition task were significantly improved by sunifiram treatment in OBX mice. Sunifiram also restored hippocampal LTP injured in OBX mice without treatment with gavestinel. By contrast, sunifiram treatment did not ameliorate the depressive behaviors assessed by tail suspension task in OBX mice. Notably, sunifiram treatment restored CaMKII alpha (Thr-286) autophosphorylation and GluR1 (Ser-831) phosphorylation in the hippocampal CM region from OBX mice to the levels of control mice. Likewise, sunifiram treatment improved PKC alpha (Ser-657) autophosphorylation and NR1 (Ser-896) phosphorylation to the control levels. Stimulation of CaMKII and PKC autophosphorylation by sunifiram was significantly inhibited by pre-treatment with gavestinel. However, sunifiram treatment did not affect the phosphorylation of CaMKIV (Thr-196) and ERK. Taken together, sunifiram ameliorates OBX-induced deficits of memory-related behaviors and impaired LTP in the hippocampal CA1 region via stimulation of glycine-binding site of NMDAR


63. Nagpal K., Singh S.K., Mishra D.N. Formulation, Optimization, in Vivo Pharmacokinetic, Behavioral and Biochemical Estimations of Minocycline Loaded Chitosan Nanoparticles for Enhanced Brain Uptake // Chem. Pharm. Bull. 2013. Vol. 61, № 3. P. 258–272.

The minocycline hydrochloride (MH), at higher doses, is useful in the treatment of neurodegenerative disorders and owing to its antioxidant potential, it may have nootropic effects. MH loaded nanoparticles (MHNP) were coated with tween 80 (cMHNP) to improve its brain uptake followed by their optimization employing two factor-three level (3(2)) central composite design (CCD) in order to minimize particle size and maximize drug entrapment efficiency (DEE) and validated. The optimized formulations were further subjected to in vitro drug release study; in vivo biodistribution studies in male wistar rats. The pharmacodynamic study was carried out using elevated plus maze (EPM) and Morris water maze (MWM) behavioral models for nootropic activity in swiss albino mice; and biochemical estimations (acetylcholine esterase, reduced glutathione, malondialdehyde and brain nitrite level). After intravenous (i.v.) administration, the concentration of MH in brain of cMHNP (6.21+/-0.64 mu g/mL) treated rats was significantly higher with MH solution treated (0.70+/-0.06 mu g/mL) as well as MHNP (1.03+/-0.12 mu g/mL) treated animals. Pharmacodynamic studies revealed a significant improvement in memory of MH, MHNP and cMHNP treated swiss albino mice than saline treated control group. However, cMHNP revealed maximum decrease in transfer latency (TL) in EPM and maximum increase in time spent in target quadrant (TSTQ) in MWM. Although cMHNP did not produce significant change in brain acetylcholinesterase, but, significantly increased reduced glutathione, malondialdehyde and reduced brain nitrite level as compared to saline, MH solution and MHNP treated groups. The results suggest that cMHNP is a promising candidate for improved brain uptake of MH with better nootropic effect.


64. Navarrete A. et al. Study on Action Mechanism of 1-(4-Methoxy-2-Methylphenyl)Piperazine (MMPP) in Acquisition, Formation, and Consolidation of Memory in Mice // Drug Dev. Res. 2014. Vol. 75, № 2. P. 59–67.

In the present study, the mechanism of action of MMPP (1-(4-methoxy-2-methylphenyl) piperazine) in the acquisition (pretraining administration), formation (posttraining administration), and consolidation (pretest administration) of memory was assessed in the passive avoidance test using a short- and long-term memory protocol in mice. MMPP modified avoidance in the acquisition and formation of memory protocols but not in the consolidation protocol. Scopolamine (0.1 mg/kg i.p.), dizocilpine (0.003 mg/kg i.p.), and buspirone (0.1 mg/kg i.p.) completely inhibited MMPP-induced effects on memory acquisition and partially inhibited memory formation in the short-term but not long-term paradigm. This suggested that cholinergic, N-methyl-D-aspartate (NMDA) and 5-hydroxytryptamine-1A (5-HT1A) receptors were implicated in the MMPP-induced improvements in memory. The sedative, anxiolytic, motor impairment, myorelaxant, and anticonvulsive (pentylenetetrazole-induced seizures) properties of MMPP were also assessed with the compound only showing a nondose-dependent myorelaxation. These results suggest that MMPP can enhance acquisition and formation, but not consolidation, of memory in short-term and long-term protocol via cholinergic, NMDA-glutamatergic, and 5-HT1A receptors.


65. Navarro S.A. et al. Analgesic activity of piracetam: Effect on cytokine production and oxidative stress // Pharmacol. Biochem. Behav. 2013. Vol. 105. P. 183–192.

Piracetam is a prototype of nootropic drugs used to improve cognitive impairment. However, recent studies suggest that piracetam can have analgesic and anti-inflammatory effects. Inflammatory pain is the result of a process that depends on neutrophil migration, cytokines and prostanoids release and oxidative stress. We analyze whether piracetam has anti-nociceptive effects and its mechanisms. Per oral pretreatment with piracetam reduced in a dose-dependent manner the overt pain-like behavior induced by acetic acid, phenyl-p-benzoquinone, formalin and complete Freund's adjuvant. Piracetam also diminished carrageenin-induced mechanical and thermal hyperalgesia, myeloperoxidase activity, and TNF-alpha-induced mechanical hyperalgesia. Piracetam presented analgesic effects as post-treatment and local paw treatment. The analgesic mechanisms of piracetam were related to inhibition of carrageenin- and TNF-alpha-induced production of IL-1 beta as Well as prevention of carrageenin-induced decrease of reduced glutathione, ferric reducing ability and free radical scavenging ability in the paw. These results demonstrate that piracetam presents analgesic activity upon a variety of inflammatory stimuli by a mechanism dependent on inhibition of cytokine production and oxidative stress. Considering its safety and clinical use for cognitive function, it is possible that piracetam represents a novel perspective of analgesic.


66. Neale C. et al. Cognitive effects of two nutraceuticals Ginseng and Bacopa benchmarked against modafinil: a review and comparison of effect sizes // Br. J. Clin. Pharmacol. 2013. Vol. 75, № 3. P. 728–737.

Over recent years there has been increasing research into both pharmaceutical and nutraceutical cognition enhancers. Here we aimed to calculate the effect sizes of positive cognitive effect of the pharmaceutical modafinil in order to benchmark the effect of two widely used nutraceuticals Ginseng and Bacopa (which have consistent acute and chronic cognitive effects, respectively). A search strategy was implemented to capture clinical studies into the neurocognitive effects of modafinil, Ginseng and Bacopa. Studies undertaken on healthy human subjects using a double-blind, placebo-controlled design were included. For each study where appropriate data were included, effect sizes (Cohen's d) were calculated for measures showing significant positive and negative effects of treatment over placebo. The highest effect sizes for cognitive outcomes were 0.77 for modafinil (visuospatial memory accuracy), 0.86 for Ginseng (simple reaction time) and 0.95 for Bacopa (delayed word recall). These data confirm that neurocognitive enhancement from well characterized nutraceuticals can produce cognition enhancing effects of similar magnitude to those from pharmaceutical interventions. Future research should compare these effects directly in clinical trials.


67. Nemetchek M.D. et al. The Ayurvedic plant Bacopa monnieri inhibits inflammatory pathways in the brain // J. Ethnopharmacol. 2017. Vol. 197. P. 92–100.

Ethnopharmacological relevance: Bacopa monnieri (L) Wettst (common name, bacopa) is a medicinal plant used in Ayurveda, the traditional system of medicine of India, as a nootropic. It is considered to be a "medhya rasayana", an herb that sharpens the mind and the intellect. Bacopa is an important ingredient in many Ayurvedic herbal formulations designed to treat conditions such as memory loss, anxiety, poor cognition and loss of concentration. It has also been used in Ayurveda to treat inflammatory conditions such as arthritis. In modern biomedical studies, bacopa has been shown in animal models to inhibit the release of the pro-inflammatory cytokines TNE-alpha and IL-6. However, less is known regarding the antiinflammatory activity of Bacopa in the brain. Aim of the study: The current study examines the ability of Bacopa to inhibit the release of pro-inflammatory cytokines from microglial cells, the immune cells of the brain that participate in inflammation in the CNS. The effect of Bacopa on signaling enzymes associated with CNS inflammatory pathways was also studied . Materials and methods: Various extracts of Bacopa were prepared and examined in the N9 microglial cell line in order to determine if they inhibited the release of the proinflammatory cytokines TNF-alpha and IL-6. Extracts were also tested in cell free assays as inhibitors of caspase-1 and matrix metalloproteinase-3 (enzymes associated with inflammation) and caspase-3, which has been shown to cleave protein Tau, an early event in the development of Alzheimer's disease. Results: The tea, infusion, and alkaloid extracts of bacopa, as well as Bacoside A significantly inhibited the release of TNF-alpha and IL-6 from activated N9 microglial cells in vitro. In addition, the tea, infusion, and alkaloid extracts of Bacopa effectively inhibited caspase 1 and 3, and matrix metalloproteinase-3 in the cell free assay. Conclusions: Bacopa inhibits the release of inflammatory cytokines from microglial cells and inhibits enzymes associated with inflammation in the brain. Thus, Bacopa can limit inflammation in the CNS, and offers a promising source of novel therapeutics for the treatment of many CNS disorders.


68. Omotuyi O.I., Ueda H. Molecular dynamics study-based mechanism of nefiracetam-induced NMDA receptor potentiation // Comput. Biol. Chem. 2015. Vol. 55. P. 14–22.

Plastic changes in the brain required for memory formation and long-term learning are dependent on N-methyl-D-aspartic acid (NMDA) receptor signaling. Nefiracetam reportedly boosts NMDA receptor functions as a basis for its nootropic properties. Previous studies suggest that nefiracetam potentiates the NMDA receptor activation, as a more potent co-agonist for glycine binding site than glycine, though the underlying mechanisms remain elusive. Here, using BSP-SLIM method, a novel binding site within the core of spiral beta-strands-1-5 of LBD-GLUN1 has been predicted in glycine-bound GLUN1 conformation in addition to the glycine pocket in Apo-GLUN1. Within the core of spiral beta-strands-1-5 of LBD-GLUN1 pocket, all-atom molecular dynamics simulation revealed that nefiracetam disrupts Arg523-glycine-Asp732 interaction resulting in open GLUN1 conformation and ultimate diffusion of glycine out of the clamshell cleft. Open GLUN1 conformation coerces other intra-chain domains and proximal inter-chain domains to sample inactivate conformations resulting in closure of the transmembrane gate via a novel gauche trap on threonine 647 (chi-1 dihedral (X1) = -45 degrees instead of +45 degrees). Docking of nefiracetam into the glycine pocket reversed the gauche trap and meditates partial opening of the TMD gate within a time-scale of 100 ns as observed in glycine-only state. All these results suggest that nefiracetam can favorably complete with glycine for GLUN1-LBD in a two-step process, first by binding to a novel site of GLUN1-LBD-NMDA receptor followed by disruption of glycine-binding dynamics then replacing glycine in the GLUN1-LBD cleft.


69. Ostrovskaya R.U. et al. Neuroprotective effect of novel cognitive enhancer noopept on AD-related cellular model involves the attenuation of apoptosis and tau hyperphosphorylation // J. Biomed. Sci. 2014. Vol. 21. P. 74.

Background: Noopept (N-phenyl-acetyl-L-prolylglycine ethyl ester) was constructed as a dipeptide analog of the standard cognition enhancer, piracetam. Our previous experiments have demonstrated the cognition restoring effect of noopept in several animal models of Alzheimer disease (AD). Noopept was also shown to prevent ionic disbalance, excitotoxicity, free radicals and pro-inflammatory cytokines accumulation, and neurotrophine deficit typical for different kinds of brain damages, including AD. In this study, we investigated the neuroprotective action of noopept on cellular model of AD, A beta(25-35)-induced toxicity in PC12 cells and revealed the underlying mechanisms. Results: The neuroprotective effect of noopept (added to the medium at 10 mu M concentration, 72 hours before A beta(25-35)) was studied on A beta(25-35)-induced injury (5 M for 24 h) in PC12 cells. The ability of drug to protect the impairments of cell viability, calcium homeostasis, ROS level, mitochondrial function, tau phosphorylation and neurite outgrowth caused by A beta(25-35) were evaluated. Following the exposure of PC12 cells to A beta(25-35) an increase of the level of ROS, intracellular calcium, and tau phosphorylation at Ser396 were observed; these changes were accompanied by a decrease in cell viability and an increase of apoptosis. Noopept treatment before the amyloid-beta exposure improved PC12 cells viability, reduced the number of early and late apoptotic cells, the levels of intracellular reactive oxygen species and calcium and enhanced the mitochondrial membrane potential. In addition, pretreatment of PC12 cell with noopept significantly attenuated tau hyperphosphorylation at Ser396 and ameliorated the alterations of neurite outgrowth evoked by A beta(25-35). Conclusions: Taken together, these data provide evidence that novel cognitive enhancer noopept protects PC12 cell against deleterious actions of A beta through inhibiting the oxidative damage and calcium overload as well as suppressing the mitochondrial apoptotic pathway. Moreover, neuroprotective properties of noopept likely include its ability to decrease tau phosphorylation and to restore the altered morphology of PC12 cells. Therefore, this nootropic dipeptide is able to positively affect not only common pathogenic pathways but also disease-specific mechanisms underlying A beta-related pathology.


70. Pahwa P., Goel R.K. Asparagus adscendens root extract enhances cognition and protects against scopolamine induced amnesia: An in-silico and in-vivo studies // Chem.-Biol. Interact. 2016. Vol. 260. P. 208–218.

Asparagus adscendens Roxb. commonly known as safed musli and belonging to the Liliaceae family is cultivated mainly in Asian countries. In traditional medicine, safed musli is recommended as nerve tonic and remedy for memory impairment. The present study was aimed to evaluate nootropic and anti amnesic activities of Asparagus adscendens extract (AAE) using in silico and in vivo approach. Phytoconstituents of A. adscendens root reported in literature were subjected to in silica prediction using PASS and Pharmaexpert. The radial arm maze and passive shock avoidance paradigm were employed to evaluate nootropic activity. Subsequently, the anti-amnesic activity was evaluated in scopolamine induced amnesia model. To elucidate the mechanism of nootropic activity, the effect of AAE on the activities of acetylcholinesterase and antioxidant enzymes in the cortex and hippocampus of mice were also evaluated. In silica activity spectrum for all of A. adscendens phytoconstituents exhibited excellent prediction score for nootropic activity. Pretreatment with AAE (50, 100 & 200 mg/kg, i.p.) for 15 days showed significant decrease in working memory error, reference memory error and retrieval latency in radial arm maze and decrease in step down latency in passive shock avoidance paradigm were observed. Further, AAE significantly reduced acetylcholinesterase and oxidative stress parameters in cortex and hippocampus of mice. Thus, in silica and in vivo results suggest that A. adscendens root may exert its nootropic activity through both anti-acetylcholinesterase and antioxidant activities.


71. Pirzada A.M. et al. Cyperus rotundus L.: Traditional uses, phytochemistry, and pharmacological activities // J. Ethnopharmacol. 2015. Vol. 174. P. 540–560.

Ethno-pharmacological relevance: Cyperus rotundus L. (Cyperaceae) is a medicinal herb traditionally used to treat various clinical conditions at home such as diarrhea, diabetes, pyresis, inflammation, malaria, and stomach and bowel disorders. Currently, it is one of the most widespread, problematic, and economically damaging agronomic weeds, growing wildly in various tropical and subtropical regions of the world. The present paper summarizes the available information that will aid in future medicine preparation by identifying active ingredients and their mode of action for a specific therapeutic activity using the latest technologies. Material and method: This review article is based on the information available on the phytochemical, toxicological, and pharmacological studies on and traditional uses of C. rotundus. The present paper covers the literature available particularly from 2000 to 2015 online (Google Scholar, PubMed, ScienceDirect, Scopus, SpringerLink, and Web of Science) and in books on phytochemistry, ethnopharmacology, and botany of this plant. Results: Phytochemical and pharmacological studies revealed the significance of C. rotundus as an anti-androgenic, antibacterial, anticancerous, anticonvulsant, antidiabetic, antidiarrheal, antigenotoxic, antiinflammatory, antilipidemic, antimalarial, antimutagenic, antiobesity, antioxidant, anti-uropathogenic, hepatoprotective, cardioprotective, neuroprotective, and nootropic agent. This is the most investigated,plant worldwide due to the higher concentration of active ingredients in the form of essential oils, phenolic acids, ascorbic acids, and flavonoids in the tuber and rhizomes. Unfortunately, this significant plant species has not been assessed under improved cultivation conditions with the aim of conservation in natural habitats and high quality. Conclusion: Reports can be found on the ehtnobotanical use of C. rotundus in atherosclerosis, aging, apoptosis, cancer, cystitis, epilepsy, hirsutism, nociception, prostatitis, and genotoxicity disorders. The phytochemical and pharmacological activities of C. rotundus have supported its traditional as well as prospective uses as a valuable Ayurvedic plant. Previous researches focuses on the phytochemistry, biological properties and clinical application of rhizomes and tubers of C. rotundus. However, such studies on the other parts of this medicinally important plant are still quest to be investigate. Furthermore, future study should aim at confirming the clinical activities and safety of this plant before being used for the development of new therapeutic agent in human subjects.


72. Povarov I.S. et al. Nootropic Dipeptide Noopept Enhances Inhibitory Synaptic Transmission in the Hippocampus // Bull. Exp. Biol. Med. 2015. Vol. 158, № 3. P. 349–351.

Application of nootropic agent Noopept on hippocampal slices from Wistar rats enhanced the inhibitory component of total current induced by stimulation of Shaffer collaterals in CA1 pyramidal neurons, but did not affect the excitatory component. A direct correlation between the increase in the amplitude of inhibitory current and agent concentration was found. The substance did not affect the release of inhibitory transmitters from terminals in the pyramidal neurons, which indicated changes in GABAergic interneurons.


73. Rogawski M.A. Brivaracetam: a rational drug discovery success story // Br. J. Pharmacol. 2008. Vol. 154, № 8. P. 1555–1557.

Levetiracetam, the alpha-ethyl analogue of the nootropic piracetam, is a widely used antiepileptic drug (AED) that provides protection against partial seizures and is also effective in the treatment of primary generalized seizure syndromes including juvenile myoclonic epilepsy. Levetiracetam was discovered in 1992 through screening in audiogenic seizure susceptible mice and, 3 years later, was reported to exhibit saturable, stereospecific binding in brain to similar to 90 kDa protein, later identified as the ubiquitous synaptic vesicle glycoprotein SV2A. A large-scale screening effort to optimize binding affinity identified the 4-n-propyl analogue, brivaracetam, as having greater potency and a broadened spectrum of activity in animal seizure models. Recent phase II clinical trials demonstrating that brivaracetam is efficacious and well tolerated in the treatment of partial onset seizures have validated the strategy of the discovery programme. Brivaracetam is among the first clinically effective AEDs to be discovered by optimization of pharmacodynamic activity at a molecular target.


74. Romanelli M.N. et al. Pharmacological characterization of DM232 (Unifiram) and DM235 (Sunifiram), new potent cognition enhancers // CNS Drug Rev. 2006. Vol. 12, № 1. P. 39–52.

DM232 (unifiram) and DM235 (sunifiram) are potent cognition-enhancers, which are four order of magnitude more potent than piracetam. These compounds, although not showing affinity in binding studies for the most important central receptors or channels, are able to prevent amnesia induced by modulation of several neurotransmission systems. These compounds are able to increase the release of acetylcholine from rat cerebral cortex, and, as far as unifiram is concerned, to increase the amplitude of fEPSP in rat hippocampal slices. In vitro experiments, performed on hippocampal slices, also supported the hypothesis of a role of the AMPA receptors for the cognition-enhancing properties of unifiram and sunifiram.


75. Rudolph U., Moehler H. GABA(A) Receptor Subtypes: Therapeutic Potential in Down Syndrome, Affective Disorders, Schizophrenia, and Autism // Annual Review of Pharmacology and Toxicology, Vol 54 / ed. Insel P.A. Palo Alto: Annual Reviews, 2014. Vol. 54. P. 483–507.

The gamma-aminobutyric acid (GABA) system plays a pivotal role in orchestrating the synchronicity of local networks and the functional coupling of different brain regions. Here we review the impact of the GABA(A) receptor subtypes on cognitive and emotional behavior, paying particular attention to five disease states: cognitive dysfunction and Down syndrome, anxiety disorders, depression, schizophrenia, and autism. Through the bidirectional modulation of tonic inhibition, alpha(5)-subunit-containing GABA(A) receptors permit the bidirectional modulation of cognitive processes, and a partial inverse agonist acting at the alpha(5)-subunit-containing GABA(A) receptor is in a clinical trial in individuals with Down syndrome. With regard to anxiety disorders, the viability of nonsedative anxiolytics based on the modulation of alpha(2)- and alpha(3)-subunit-containing GABA(A) receptors has been established in clinical proof-of-concept trials. Regarding the remaining three disease states, the GABA hypothesis of depression offers new options for antidepressant drug development; cognitive symptoms in schizophrenia are attributed to a cortical GABAergic deficit, and dysfunctional GABAergic inhibition is increasingly understood to contribute to the pathophysiology of autism spectrum disorders.


76. Ruiz-Miyazawa K.W. et al. Vinpocetine reduces lipopolysaccharide-induced inflammatory pain and neutrophil recruitment in mice by targeting oxidative stress, cytokines and NF-kappa B // Chem.-Biol. Interact. 2015. Vol. 237. P. 9–17.

In response to lipopolysaccharide (LPS), tissue resident macrophages and recruited neutrophils produce inflammatory mediators through activation of Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-kappa B) signaling pathway. These mediators include inflammatory cytokines and reactive oxygen species that, in turn, sensitize nociceptors and lead to inflammatory pain. Vinpocetine is a nootropic drug widely used to treat cognitive and neurovascular disorders, and more recently its anti-inflammatory properties through inhibition of NF-kappa B activation have been described. In the present study, we used the intraplantar and intraperitoneal LPS stimulus in mice to investigate the effects of vinpocetine pre-treatment (3, 10, or 30 mg/kg by gavage) in hyperalgesia, leukocyte recruitment, oxidative stress, and pro-inflammatory cytokine production (TNF-alpha, IL-1 beta, and IL-33). LPS-induced NF-kappa B activation and cytokine production were investigated using RAW 264.7 macrophage cell in vitro. Vinpocetine (30 mg/kg) significantly reduces hyperalgesia to mechanical and thermal stimuli, and myeloperoxidase (MPO) activity (a neutrophil marker) in the plantar paw skin, and also inhibits neutrophil and mononuclear cell recruitment, superoxide anion and nitric oxide production, oxidative stress, and cytokine production (TNF-alpha, IL-1 beta and IL-33) in the peritoneal cavity. At least in part, these effects seem to be mediated by direct effects of vinpocetine on macrophages, since it inhibited the production of the same cytokines (TNF-alpha, IL-1 beta and IL-33) and the NF-kappa B activation in LPS-stimulated RAW 264.7 macrophages. Our results suggest that vinpocetine represents an important therapeutic approach to treat inflammation and pain induced by a gram-negative bacterial component by targeting NF-kappa B activation and NE-kappa B-related cytokine production in macrophages.


77. Savai J. et al. Investigation of CYP3A4 and CYP2D6 Interactions of Withania somnifera and Centella asiatica in Human Liver Microsomes // Phytother. Res. 2015. Vol. 29, № 5. P. 785–790.

Withania somnifera is commonly used as a rejuvenator, whereas Centella asiatica is well known for its anxiolytic and nootropic effects. The present study aims at investigating the effect of crude extracts and principal phytoconstituents of both the medicinal plants with CYP3A4 and CYP2D6 enzyme activity in human liver microsomes (HLM). Phytoconstituents were quantified in the crude extracts of both the medicinal plants using reverse phase HPLC. Crude extracts and phytoconstituents of W.somnifera showed no significant interaction with both CYP3A4 and CYP2D6 enzymes in HLM. Of the crude extracts of C.asiatica screened in vitro, methanolic extract showed potent noncompetitive inhibition of only CYP3A4 enzyme (Ki64.36 +/- 1.82 mu g/mL), whereas ethanol solution extract showed potent noncompetitive inhibition of only CYP2D6 enzyme (Ki36.3 +/- 0.44 mu g/mL). The flavonoids, quercetin, and kaempferol showed potent (IC50 values less than 100M) inhibition of CYP3A4 activity, whereas quercetin alone showed potent inhibition of CYP2D6 activity in HLM. Because methanolic extract of C.asiatica showed a relatively high percentage content of quercetin and kaempferol than ethanol solution extract, the inhibitory effect of methanolic extract on CYP3A4 enzyme activity could be attributed to the flavonoids. Thus, co-administration of the alcoholic extracts of C.asiatica with drugs that are substrates of CYP3A4 and CYP2D6 enzymes may lead to undesirable herb-drug interactions in humans.


78. Schmitt K.C., Rothman R.B., Reith M.E.A. Nonclassical Pharmacology of the Dopamine Transporter: Atypical Inhibitors, Allosteric Modulators, and Partial Substrates // J. Pharmacol. Exp. Ther. 2013. Vol. 346, № 1. P. 2–10.

The dopamine transporter (DAT) is a sodium-coupled symporter protein responsible for modulating the concentration of extraneuronal dopamine in the brain. The DAT is a principle target of various psychostimulant, nootropic, and antidepressant drugs, as well as certain drugs used recreationally, including the notoriously addictive stimulant cocaine. DAT ligands have traditionally been divided into two categories: cocaine-like inhibitors and amphetamine-like substrates. Whereas inhibitors block monoamine uptake by the DAT but are not translocated across the membrane, substrates are actively translocated and trigger DAT-mediated release of dopamine by reversal of the translocation cycle. Because both inhibitors and substrates increase extraneuronal dopamine levels, it is often assumed that all DAT ligands possess an addictive liability equivalent to that of cocaine. However, certain recently developed ligands, such as atypical benztropine-like DAT inhibitors with reduced or even a complete lack of cocaine-like rewarding effects, suggest that addictiveness is not a constant property of DAT-affecting compounds. These atypical ligands do not conform to the classic preconception that all DAT inhibitors (or substrates) are functionally and mechanistically alike. Instead, they suggest the possibility that the DAT exhibits some of the ligand-specific pleiotropic functional qualities inherent to G-protein-coupled receptors. That is, ligands with different chemical structures induce specific conformational changes in the transporter protein that can be differentially transduced by the cell, ultimately eliciting unique behavioral and psychological effects. The present overview discusses compounds with conformation-specific activity, useful not only as tools for studying the mechanics of dopamine transport, but also as leads for medication development in addictive disorders.


79. Semina I.I. et al. Synthesis and pharmacological activity of (2-chloroethoxy-4’-dimethylaminophenyl)phosphorylacetic acid hydrazide (CAPAH) and its metabolite (N-acetyl derivative) // Pharm. Chem. J. 2013. Vol. 47, № 1. P. 28–30.

The new compound (2-chloroethoxy-4'-dimethylaminophenyl)phosphorylacetic acid N-acetylhydrazide (II) was synthesized. Compound II was proposed as a metabolite of (2-chloroethoxy-4'-dimethylaminophenyl)phosphorylacetic acid hydrazide (CAPAH, I), a drug possessing nootropic activity. The psychotropic and antiarrhythmic properties of II were compared with those of I. It was established that II did not possess nootropic and antidepressant activities although its antiarrhythmic properties were more pronounced. It was suggested that the C(O)CH3 fragment, being a substituent on the hydrazide in II, decreased penetration of the compound through the blood-brain barrier, which could explain the absence of psychotropic activity.


80. Sendrowski K. et al. Study of the protective effects of nootropic agents against neuronal damage induced by amyloid-beta (fragment 25-35) in cultured hippocampal neurons // Pharmacol. Rep. 2015. Vol. 67, № 2. P. 326–331.

Background: Alzheimer's disease (AD) is a common neurodegenerative disorder, in which progressive neuron loss, mainly in the hippocampus, is observed. The critical events in the pathogenesis of AD are associated with accumulation of beta-amyloid (A beta) peptides in the brain. Deposits of A beta initiate a neurotoxic "cascade" leading to apoptotic death of neurons. Aim of this study was to assess a putative neuroprotective effects of two nootropic drugs: piracetam (PIR) and levetiracetam (LEV) on A beta-injured hippocampal neurons in culture. Methods: Primary cultures of rat's hippocampal neurons at 7 day in vitro were exposed to A beta(25-35) in the presence or absence of nootropics in varied concentrations. Flow cytometry with Annexin V/PI staining was used for counting and establishing neurons as viable, necrotic or apoptotic. Additionally, release of lactate dehydrogenase (LDH) to the culture medium, as a marker of cell death, was evaluated. Results: A beta(25-35) caused concentration-dependent death of about one third number of hippocampal neurons, mainly through an apoptotic pathway. In drugs-containing cultures, number of neurons injured with 20 mu M A beta(25-35) was about one-third lesser for PIR and almost two-fold lesser for LEV. When 40 mu M A beta(25-35) was used, only LEV exerted beneficial neuroprotective action, while PIR was ineffective. Conclusions: Our results suggest the protective potential of both studied nootropics against A beta-induced death of cultured hippocampal neurons with more powerful neuroprotective effects of LEV.


81. Shashidhar M.G. et al. Bioactive principles from Cordyceps sinensis: A potent food supplement - A review // J. Funct. Food. 2013. Vol. 5, № 3. P. 1013–1030.

Cordyceps sinensis (CS) is a well-known entamophagus fungus, naturally distributed in the Tibetan Plateau of Asia and Himalayas. Recently this synonym is transferred to Ophiocordyceps by both scientific and non-scientific communities. It is widely used as a tonic and medicinal food in traditional Chinese medicine (TCM), as it possess wonderful health benefits. To support its functional attributes, various investigations have been carried out to find out its adaptogenic, aphrodisiac, anti-oxidant, anti-aging, neuroprotective, nootropic, immunomodulatory, anti-cancer and hepatoprotective role. Its fruiting portion as well as the larvae possesses potent bio-active fractions and their composition almost found to be similar in both. The bioactive principles are nucleosides, exo-polysaccharides, sterols and, proteins, among others. Among nucleosides, adenosine and cordycepin are the major biochemical markers. Further, different types of solvent extracts and their mixtures exhibit wide range of pharmacological activities, while the water and methanol extracts with the richest sources of nucleosides and polysaccharides also show wide range of pharmacological activities. This review gives a panoramic view of potential health benefits of various classes of bio-active fractions along with the need for sustainable management of CS for human wellness.


82. Shilova I.V. et al. Studies of the Lipophilic Components of a Dense Extract of the Herb Alfredia Cernua and its Nootropic Properties // Pharm. Chem. J. 2014. Vol. 48, № 3. P. 181–185

Chromato-mass spectrometry (GC/MS) studies of the chemical composition of a dense extract of the herb Alfredia cernua (L.) Cass. prepared by processing raw material with 95 % ethanol identified 31 aliphatic, including 2-hydroxy- and dicarboxylic, acids, three phenolcarboxylic acids, one di- and two triterpenoic acids, and 16 neutral lipophilic components. A total of 40 compounds were detected in Alfredia cernua for the first time. T maze experiments showed that the plant extract promoted changes in the motivational domain in normal animals, activating appetitive and consumatory behavior due to nootropic and anxiolytic actions, which were greater than those of piracetam.


83. Shilova I.V., Suslov N.I. Nootropic Effect of Meadowsweet (Filipendula vulgaris) Extracts // Bull. Exp. Biol. Med. 2015. Vol. 158, № 5. P. 659–663.

The effects of the extracts of the aboveground parts of Filipendula vulgaris Moench on the behavior and memory of mice after hypoxic injury and their physical performance in the open-field test were studied using the models of hypoxia in a sealed volume, conditioned passive avoidance response (CPAR), and forced swimming with a load. The extracts improved animal resistance to hypoxia, normalized orientation and exploration activities, promoted CPAR retention after hypoxic injury, and increased physical performance. Aqueous extract of meadowsweet had the most pronounced effect that corresponded to the effect of the reference drug piracetam. These effects were probably caused by modulation of hippocampal activity.


84. Shilova I.V., Suslov N.I., Amelchenko V.P. Nootropic Effects of Filipendula Vulgaris Moench Water Extract Fractions // Bull. Exp. Biol. Med. 2015. Vol. 159, № 3. P. 376–379.

Nootropic activity of water extract fractions from aerial parts of Filipendula vulgaris Moench was demonstrated on the models of hermetic volume hypoxia, conditioned passive avoidance response, open field test, and forced swimming with a load. The fractions stimulated hypoxic resistance, normalized orientation and exploratory behavior, improved conditioned response reproduction during testing after hypoxic injury, and increased exercise tolerance. Fractionation of the extract led to dissociation of the effect components, which suggests that individual constituents have specifi c characteristics. Ethylacetate fraction exhibited most pronounced nootropic activity and was superior to plant extract by some characteristics. The detected effects seemed to be caused by modulation of the hippocampus activity the under the effects of phenol and triterpene compounds.


85. Shrivastava S.K. et al. Design, synthesis and evaluation of some N-methylenebenzenamine derivatives as selective acetylcholinesterase (AChE) inhibitor and antioxidant to enhance learning and memory // Bioorg. Med. Chem. 2017. Vol. 25, № 4. P. 1471–1480.

Series of some 3,5-dimethoxy-N-methylenebenzenamine and 4-(methyleneamino)benzoic acid derivatives comprising of N-methylenebenzenamine nucleus were designed, synthesized, characterized, and assessed for their acetylcholinesterase (AChE), butyrylcholinesterase (BChE) inhibitory, and antioxidant activity thereby improving learning and memory in rats. The IC50 values of all the compound along with standard were determined on AChE and BChE enzyme. The free radical scavenging activity was also assessed by in vitro DPPH (2,2-diphenyl-1-picryl-hydrazyl) and hydrogen peroxide radical scavenging assay. The selective inhibitions of all compounds were observed against AChE in comparison with standard donepezil. The enzyme kinetic study of the most active compound 4 indicated uncompetitive AChE inhibition. The docking studies of compound 4 exhibited the worthy interaction on active-site gorge residues Phe330 and Trp279 responsible for its high affinity towards AChE, whereas lacking of the BChE inhibition was observed due to a wider gorge binding site and absence of important aromatic amino acids interactions. The ex vivo study confirmed AChE inhibition abilities of compound 4 at brain site. Further, a considerable decrease in escape latency period of the compound was observed in comparison with standard donepezil through in vivo Spatial Reference Memory (SRM) and Spatial Working Memory (SWM) models which showed the cognition-enhancing potential of compound 4. The in vivo reduced glutathione (GSH) estimation on rat brain tissue homogenate was also performed to evaluate free radical scavenging activity substantiated the antioxidant activity in learning and memory.


86. Sinha S.K., Shrivastava S.K. Design, synthesis and evaluation of some new 4-aminopyridine derivatives in learning and memory // Bioorg. Med. Chem. Lett. 2013. Vol. 23, № 10. P. 2984–2989.

Some new anilide and imide derivatives of 4-aminopyridine (4AP) were synthesized and evaluated against antiamnesic, cognition enhancing and anticholinesterase activity through their respective in vitro and in vivo models. These newly synthesized derivatives have illustrated an enhanced cognition effect on elevated plus maze model and also demonstrated a significant reversal in scopolamine-induced amnesia in same model. The IC50 value of synthesized compounds showed maximum activity of 4APMb compared to standard drug donepezil and other derivatives, whereas its enzyme kinetic study revealed a non-competitive inhibition of acetycholinesterase (AChE) and a competetive inhibition of butyrylcholinesterase (BChE). Significant inhibitions in AChE activity by all the synthesized compounds were found in specific brain regions that is prefrontal cortex, hippocampus and hypothalamus. The docking study confirmed their consensual interaction with AChE, showed an affinity and binding with the key peripheral anionic site residues Trp-286, Tyr-124 and Tyr-341 of AChE.


87. Sinha S.K., Shrivastava S.K. Synthesis and evaluation of some new 4-aminopyridine derivatives as a potent antiamnesic and cognition enhancing drugs // Med. Chem. Res. 2012. Vol. 21, № 12. P. 4395–4402.

4-Aminopyridine (4AP) potentiates acetylcholine (ACh) release by blocking potassium channel in axon terminal and can be used in the treatment of Alzheimer's type of dementia and cognitive disorder. It is reported that ACh is well related with memory and learning. On the basis of these fact, we decided to synthesis and evaluate some new Schiff bases of 4AP (SBAPs) for their putative cognition enhancing, antiamnesic, and anticholinesterase activity. The synthesized and purified SBAPs were characterized by elemental analysis, UV, FTIR, H-1-, and C-13-NMR. SBAPs facilitated the learning on elevated plus maze model and they also significantly reversed the scopolamine-induced amnesia on the same model. The effect of SBAPs on learning and memory was qualitatively similar to standard nootropic drug piracetam used. The SBAPs were found to inhibit acetylcholinesterase enzyme significantly in specific brain regions prefrontal cortex, hippocampus, and hypothalamus. Thus, SBAPs derivatives showed cognitive and antiamnesic activities in the model tested and these effects may probably be due to their anticholinesterase activity.


88. Sinha S.K., Shrivastava S.K. Synthesis, evaluation and molecular dynamics study of some new 4-aminopyridine semicarbazones as an antiamnesic and cognition enhancing agents // Bioorg. Med. Chem. 2013. Vol. 21, № 17. P. 5451–5460.

Some new semicarbazones of 4-aminopyridine were synthesized and evaluated for antiamnesic, cognition enhancing and anticholinesterase activities. The results illustrated a significant cognition enhancing effect on elevated plus maze model with a significant reversal of scopolamine-induced amnesia. A significant inhibition in acetycholinesterase (AChE) activity by all the synthesized compounds in specific brain regions that is, prefrontal cortex, hippocampus and hypothalamus was observed. Compound 4APi exhibited significant antiamnesic and cognition enhancing activity which was comparable with standard drug donepezil. Its enzyme kinetic study revealed a non-competitive inhibition of AChE and a competitive inhibition of butyrylcholinesterase (BChE). Docking studies predicted the binding modes of these compounds in AChE active site, which were further processed for molecular dynamics simulation for calculating binding free energies using Molecular Mechanics-Generalized Born Surface Area (MM/GBSA). All the computational study confirmed their consensual interaction with AChE justifying the experimental outcome.


89. Solomon T.M. et al. A randomized, double-blind, placebo controlled, parallel group, efficacy study of alpha BRAIN (R) administered orally // Hum. Psychopharmacol.-Clin. Exp. 2016. Vol. 31, № 2. P. 135–143.

ObjectiveAlpha BRAIN (R) is a nootropic supplement that purports to enhance cognitive functioning in healthy adults. The goal of this study was to investigate the efficacy of this self-described cognitive enhancing nootropic on cognitive functioning in a group of healthy adults by utilizing a randomized, double blind, placebo-controlled design. MethodsA total of 63-treatment naive individuals between 18 and 35years of age completed the randomized, double-blind, placebo controlled trial. All participants completed a 2-week placebo run in before receiving active product, Alpha BRAIN (R) or new placebo, for 6weeks. Participants undertook a battery of neuropsychological tests at randomization and at study completion. Primary outcome measures included a battery of neuropsychological tests and measures of sleep. ResultsCompared with placebo, Alpha BRAIN (R) significantly improved on tasks of delayed verbal recall and executive functioning. Results also indicated significant time-by-group interaction in delayed verbal recall for the Alpha BRAIN (R) group. ConclusionsThe use of Alpha BRAIN (R) for 6weeks significantly improved recent verbal memory when compared with controls, in a group of healthy adults. While the outcome of the study is encouraging, this is the first randomized controlled trial of Alpha BRAIN (R), and the results merit further study.


90. Stough C. et al. Examining the Nootropic Effects of a special extract of Bacopa monniera on Human Cognitive Functioning: 90 day Double-Blind Placebo-Controlled Randomized Trial // Phytother. Res. 2008. Vol. 22, № 12. P. 1629–1634.

While Ayurvedic medicine has touted the cognitive enhancing effects of Bacopa monniera for centuries, there is a need for double-blind placebo-controlled investigations. One hundred and seven healthy participants were recruited for this double-blind placebo-controlled independent group design investigation. Sixty-two participants completed the study with 80% treatment compliance. Neuropsychological testing using the Cognitive Drug Research cognitive assessment system was conducted at baseline and after 90 days of treatment with a special extract of Bacopa monniera (2 x 150 mg KeenMind) or placebo. The Bacopa monniera product significantly improved performance on the 'Working Memory' factor, more specifically spatial working memory accuracy. The number of false-positives recorded in the Rapid visual information processing task was also reduced for the Bacopa monniera group following the treatment period. The current study provides support for the two other published studies reporting cognitive enhancing effects in healthy humans after a 90 day administration of the Bacopa monniera extract. Further studies are required to ascertain the effective dosage range, the time required to attain therapeutic levels and the effects over a longer term of administration.


91. Strub D.J. et al. The anxiolytic-like activity of a novel N-cycloalkyl-N-benzoylpiperazine derivative // Pharmacol. Rep. 2016. Vol. 68, № 1. P. 62–65.

Background: Anxiety-related disorders are among the most common mental illnesses in the world for which benzodiazepines, buspirone and antidepressant drugs remain the first-line treatment. These drugs have good efficacy but they have numerous disadvantages, such as drug abuse potential, delayed onset of action or tolerance. A literature review reveals that a variety of piperazine derivatives may exhibit interesting pharmacological properties, including anxiolytic-like, antidepressant, nootropic and antinociceptive activities demonstrated in animal models, as well as an antioxidant capacity shown in some in vitro tests. Hence, the aim of this study was the synthesis and preliminary pharmacological in vivo evaluation of a novel N-cycloalkyl-N-benzoylpiperazine derivative, compound 9. Methods: The test compound 9 was synthesized from a cyclic ketone 6,6-dimethylbicyclo[3.1.0]hexan-3-one (compound 7) and N-benzoylpiperazine. The final product was evaluated in vivo for its anxiolytic-like and antinociceptive activity after intraperitoneal (ip) administration. Its impact on animals' locomotor activity and motor performance was also evaluated. Results: At the dose of 50 mg/kg the test compound 9 showed statistically significant (p < 0.01) anxiolytic-like activity in the four plate test. This effect was completely abolished by pretreatment with naloxone hydrochloride (1 mg/kg; ip). Compound 9 did not influence animals' locomotor activity or motor coordination. No antinociceptive effect was demonstrated in the hot plate test. Conclusions: The anxiolytic-like properties of N-bicyclo-[3.1.0]hexyl derivative (9) in the four plate test are mediated by the opioid system. The results obtained make this compound a promising lead structure for further development of anxiolytic drugs.


92. Suliman N.A. et al. Establishing Natural Nootropics: Recent Molecular Enhancement Influenced by Natural Nootropic // Evid.-based Complement Altern. Med. 2016. P. 4391375.

Nootropics or smart drugs are well-known compounds or supplements that enhance the cognitive performance. They work by increasing the mental function such as memory, creativity, motivation, and attention. Recent researches were focused on establishing a new potential nootropic derived from synthetic and natural products. The influence of nootropic in the brain has been studied widely. The nootropic affects the brain performances through number of mechanisms or pathways, for example, dopaminergic pathway. Previous researches have reported the influence of nootropics on treating memory disorders, such as Alzheimer's, Parkinson's, and Huntington's diseases. Those disorders are observed to impair the same pathways of the nootropics. Thus, recent established nootropics are designed sensitively and effectively towards the pathways. Natural nootropics such as Ginkgo biloba have been widely studied to support the beneficial effects of the compounds. Present review is concentrated on the main pathways, namely, dopaminergic and cholinergic system, and the involvement of amyloid precursor protein and secondary messenger in improving the cognitive performance.


93. Thorley E. et al. Varsity Medical Ethics Debate 2015: should nootropic drugs be available under prescription on the NHS? // Philos. Ethics Humanit. Med. 2016. Vol. 11. P. 6.

The 2015 Varsity Medical Ethics debate convened upon the motion: "This house believes nootropic drugs should be available under prescription". This annual debate between students from the Universities of Oxford and Cambridge, now in its seventh year, provided the starting point for arguments on the subject. The present article brings together and extends many of the arguments put forward during the debate. We explore the current usage of nootropic drugs, their safety and whether it would be beneficial to individuals and society as a whole for them to be available under prescription. The Varsity Medical Debate was first held in 2008 with the aim of allowing students to engage in discussion about ethics and policy within healthcare. The event is held annually and it is hoped that this will allow future leaders to voice a perspective on the arguments behind topics that will feature heavily in future healthcare and science policy. This year the Oxford University Medical Society at the Oxford Union hosted the debate.


94. Toscani S. et al. Stability hierarchy between Piracetam forms I, II, and III from experimental pressure-temperature diagrams and topological inferences // Int. J. Pharm. 2016. Vol. 497, № 1–2. P. 96–105.

The trimorphism of the active pharmaceutical ingredient piracetam is a famous case of polymorphism that has been frequently revisited by many researchers. The phase relationships between forms I, II, and III were ambiguous because they seemed to depend on the heating rate of the DSC and on the history of the samples or they have not been observed at all (equilibrium II-III). In the present paper, piezo-thermal analysis and high-pressure differential thermal analysis have been used to elucidate the positions of the different solid-solid and solid-liquid equilibria. The phase diagram, involving the three solid phases, the liquid phase and the vapor phase, has been constructed. It has been shown that form III is the high-pressure, low-temperature form and the stable form at room temperature. Form II is stable under intermediary conditions and form I is the low pressure, high temperature form, which possesses a stable melting point. The present paper demonstrates the strength of the topological approach based on the Clapeyron equation and the alternation rule when combined with high-pressure measurements.


95. Tripathi R.K.P., Rai G.K., Ayyannan S.R. Exploration of a Library of 3,4-(Methylenedioxy)aniline-Derived Semicarbazones as Dual Inhibitors of Monoamine Oxidase and Acetylcholinesterase: Design, Synthesis, and Evaluation // ChemMedChem. 2016. Vol. 11, № 11. P. 1145–1160.

A library of 3,4-(methylenedioxy)aniline-derived semicarbazones was designed, synthesized, and evaluated as monoamine oxidase (MAO) and acetylcholinesterase (AChE) inhibitors for the treatment of neurodegenerative diseases. Most of the new compounds selectively inhibited MAO-B and AChE, with IC50 values in the micro-or nanomolar ranges. Compound 16, 1-(2,6-dichlorobenzylidene)-4-(benzo[1,3]dioxol-5-yl) semicarbazide presented a balanced multifunctional profile of MAO-A (IC50 = 4.52 +/- 0.032 mu m), MAO-B (IC50= 0.059 +/- 0.002 mu m), and AChE (IC50 = 0.0087 +/- 0.0002 mu m) inhibition without neurotoxicity. Kinetic studies revealed that compound 16 exhibits competitive and reversible inhibition against MAOA and MAO-B, and mixed-type inhibition against AChE. Molecular docking studies further revealed insight into the possible interactions within the enzyme-inhibitor complexes. The most active compounds were found to interact with the enzymes through hydrogen bonding and hydrophobic interactions. Additionally, in silico molecular properties and ADME properties of the synthesized compounds were calculated to explore their drug-like characteristics.


96. Tsypysheva I.P. et al. Synthesis and neuropharmacological activity of N-1-adamantylcytisine-12-carbamide and its 12-thiocarbonyl analog // Chem. Nat. Compd. 2013. Vol. 49, № 4. P. 707–711.

The neuropharmacological activity of two (-)-cytisine derivatives with adamantyl fragments was studied. It was shown that N-1-adamantylcytisine-12-thiocarbamide exhibited in tests in vivo a pronounced mnestic effect, increased the lifespan of laboratory animals under hypoxic conditions, and also enhanced in vitro binding of transcription factors NFAT and NF-kappa B to the DNA sequences corresponding to them.


97. Tsypysheva I.P. et al. Synthesis and Nootropic Activity of new 3-Amino-12-N-Methylcytisine Derivatives // Chem. Nat. Compd. 2015. Vol. 51, № 5. P. 910–915.

Reductive alkylation of 3-amino-12-N-methylcytisine by aromatic aldehydes synthesized a series of secondary amines. The nootropic activity of the synthesized compounds was studied in vivo (mnestic and antihypoxic properties) and in vitro (antiradical properties and ability to affect transcription factor HIF-1 DNA-binding activity). The cytotoxicity of the synthesized compounds was assessed. The lead compound was identified.


98. Tsypysheva I.P. et al. Synthesis and specific nootropic activity of (-)-cytisine derivatives with carbamide and thiocarbamide moieties in their structure // Chem. Nat. Compd. 2012. Vol. 48, № 4. P. 629–634.

N-(methylcytisinyl)-N'-substituted ureas, N-substituted cytisine-12-carbamides, and cytisine-12-thiocarbamide were prepared by reaction of (-)-cytisine with urea and thiourea and of (-)-cytisine and its 12-N-methyl-3-amino derivative with isocyanates. Their specific nootropic activity was studied in vivo. The therapeutic index was determined for the lead compound. Promising candidates for further pharmacological testing were found.


99. Tyurenkov I.N. et al. Comparison of Nootropic and Neuroprotective Features of Aryl-Substituted Analogs of Gamma-Aminobutyric Acid // Bull. Exp. Biol. Med. 2016. Vol. 160, № 4. P. 465–469.

GABA analogs containing phenyl (phenibut) or para-chlorophenyl (baclofen) substituents demonstrated nootropic activity in a dose of 20 mg/kg: they improved passive avoidance conditioning, decelerated its natural extinction, and exerted antiamnestic effect on the models of amnesia provoked by scopolamine or electroshock. Tolyl-containing GABA analog (tolibut, 20 mg/kg) exhibited antiamnestic activity only on the model of electroshock-induced amnesia. Baclofen and, to a lesser extent, tolibut alleviated seizures provoked by electroshock, i.e. both agents exerted anticonvulsant effect. All examined GABA aryl derivatives demonstrated neuroprotective properties on the maximum electroshock model: they shortened the duration of coma and shortened the period of spontaneous motor activity recovery. In addition, these agents decreased the severity of passive avoidance amnesia and behavioral deficit in the open field test in rats exposed to electroshock. The greatest neuroprotective properties were exhibited by phenyl-containing GABA analog phenibut.


100. Tyurenkov I.N. et al. Nootropic Activity of Some Quinazoline Amides // Pharm. Chem. J. 2015. Vol. 49, № 2. P. 88–90.

A series of quinazoline acetanilide derivatives were synthesized using direct alkylation of quinazoline-4(3H)-one by alpha-chlorocarboxylic acid anilides. The nootropic properties of 10 alpha-[4-oxoquinazolin-3(4H)-yl]carboxylic acid derivatives were studied. Pronounced nootropic activity was found for compounds III, IV, VI, and X, for which further detailed studies are planned.


101. Van Dam D., De Deyn P.P. Non human primate models for Alzheimer’s disease-related research and drug discovery // Expert. Opin. Drug Discov. 2017. Vol. 12, № 2. P. 187–200.

Introduction: Pathophysiological mechanisms underlying Alzheimer's disease (AD) remain insufficiently documented for the identification of accurate diagnostic markers and purposeful target discovery and development. Nonhuman primates (NHPs) have important translational value given their close phylogenetic relationship to humans and similar developmental paths in (neuro)anatomy, physiology, genetics, and neural functions, as well as cognition, emotion, and social behavior. Areas covered: This review deals with the past and future role of NHP-based research in AD pathophysiology, diagnosis and drug discovery, and touches upon ethical and legal aspects. Expert opinion: Aging NHPs are not complete phenocopies of human AD. Conceivably, no other species or experimental model will ever develop the full spectrum of AD-typical alterations. Nevertheless, partial - and even negative - models can increase knowledge of disease mechanisms. Modeling complex brain disorders should not be based on a single model or species. Understanding brain diseases relies on knowledge of healthy brain functioning, and given their close phylogenetic relationship to humans, NHPs serve excellent tools in this respect. NHP-based studies remain essential in the development and validation of radiopharmaceuticals for early diagnostic imaging biomarkers, as well as in the efficacy and safety evaluation of new therapeutic approaches, with active immunization or vaccination approaches as front runners.


102. Vanmierlo T. et al. The PDE4 inhibitor roflumilast improves memory in rodents at non-emetic doses // Behav. Brain Res. 2016. Vol. 303. P. 26–33.

Enhancement of central availability of the second messenger CAMP is a promising approach to improve cognitive function. Pharmacological inhibition of phosphodiesterase type 4 (PDE4), a group of cAMP hydrolyzing enzymes in the brain, has been shown to improve cognitive performances in rodents and monkeys. However, inhibition of PDE4 is generally associated with severe emetic side-effects. Roflumilast, an FDA-approved PDE4 inhibitor for treatment of chronic obstructive pulmonary disease (COPD), is yielding only mild emetic side effects. In the present study we investigate the potential of roflumilast as a cognition enhancer and to determine the potential coinciding emetic response in comparison to rolipram, a classic PDE4 inhibitor with pronounced emetic effects. Cognition enhancement was evaluated in mice and it was found that both roflumilast and rolipram enhanced memory in an object location task (0.03 mg/kg), whereas only roflumilast was effective in a spatial Y-maze (0.1 mg/kg). Emetic potential was measured using competition of PDE4 inhibition for alpha 2-adrenergic receptor antagonism in which recovery from xylazine/ketamine-mediated anesthesia is used as a surrogate marker. While rolipram displayed emetic properties at a dose 10 times the memory-enhancing dose, roflumilast only showed increased emetic-like properties at a dose 100 times the memory-enhancing dose. Moreover, combining sub-efficacious doses of the approved cognition enhancer donepezil and roflumilast, which did not improve memory when given alone, fully restored object recognition memory deficit in rats induced by the muscarinic receptor antagonist scopolamine. These findings suggest that roflumilast offers a more favorable window for treatment of cognitive deficits compared to rolipram.


103. Varvel S.A., Wise L.E., Lichtman A.H. Are CB1 Receptor Antagonists Nootropic or Cognitive Impairing Agents? // Drug Dev. Res. 2009. Vol. 70, № 8. P. 555–565.

For more than a decade, a considerable amount of research has examined the effects of rimonabant (SR 141716) and other CB1 receptor antagonists in both in vivo and in vitro models of learning and memory. In addition to its utility in determining whether the effects of drugs are mediated though 3 CB, receptor mechanism of action, these antagonists are useful in providing insight into the physiological function of the endogeneous cannabinoid system. Several groups have reported that CB1 receptor antagonists enhance memory duration in I variety of spatial and operant paradigms, but not in all paradigms. Conversely, disruption of CB1 receptor signaling also impairs extinction learning in which the animal actively suppresses a learned response when reinforcement has been withheld. These extinction deficits occur in aversively motivated tasks, such as in fear conditioning or escape behavior in the Morris water maze task, but not in appetitively motivated tasks. Similarly, in electrophysiological models, CB1 receptor antagonists elicit a variety of effects, including enhancement of long-term potentiation (LTP), while disrupting long-term depression (LTD) and interfering with transient forms of plasticity, including depolarization-induced suppression of inhibition (DSI) and depolarization-induced Suppression of excitation (DSE). The collective results of the in vivo and in vitro studies employing CB1 receptor antagonists, demonstrate that these receptors play integral roles in different components of cognitive processing. Functionally, pharmacological blockade of CB1 receptors may strengthen memory duration, hut interferes with extinction of learned behaviors that are associated with traumatic or aversive memories.


104. Veinberg G. et al. Stereochemistry of phenylpiracetam and its methyl derivative: improvement of the pharmacological profile // Chem. Heterocycl. Compds. 2015. Vol. 51, № 7. P. 601–606.

Since the discovery of piracetam its structural analogs based on the pyrrolidin-2-one pharmacophore have aroused great interest as a source of effective pharmacological central nervous system agents capable to facilitate memory processes and to attenuate the impairment of cognitive functions associated with head traumas, stroke, age, and age-related pathologies. The present review summarizes the data published during the last decade concerning the design, synthesis, and biological activity exploration of enantiomerically pure (4R)-2-oxo-4-phenylpyrrolidine-1-carboxamide ((R)-phenylpiracetam) and (4R, 5S)-5-methyl-2-oxo-4-phenylpyrrolidine-1-carboxamide (E1R) and providing evidence for the direct relationship between the configuration of the stereocenters and biological properties of the respective enantiomers. The methodological approaches leading to the preparation of the single stereoisomers of molecules with one or two chiral centers are reviewed. The results of comparative pharmacological testing of individual enantiomers provides the evidence of their pharmacological advantages, justifying the choice of the most effective stereoisomer and the necessity for drug substance purification from the less active one(s).


105. Wadhwa R., Konar A., Kaul S.C. Nootropic potential of Ashwagandha leaves: Beyond traditional root extracts // Neurochem. Int. 2016. Vol. 95. P. 109–118.

Rapidly increasing aging population and environmental stressors are the two main global concerns of the modern society. These have brought in light rapidly increasing incidence of a variety of pathological conditions including brain tumors, neurodegenerative & neuropsychiatric disorders, and new challenges for their treatment. The overlapping symptoms, complex etiology and lack of full understanding of the brain structure and function to-date further complicate these tasks. On the other hand, several herbal reagents with a long history of their use have been asserted to possess neurodifferentiation, neuroregenerative and neuroprotective potentials, and hence been recommended as supplement to enhance and maintain brain health and function. Although they have been claimed to function by holistic approach resulting in maintaining body homeostasis and brain health, there are not enough laboratory studies in support to these and mechanism(s) of such beneficial activities remain largely undefined. One such herb is Ashwagandha, also called "Queen of Ayurveda" for its popular use in Indian traditional home medicine because of its extensive benefits including anticancer, anti-stress and remedial potential for aging and neurodegenerative pathologies. However, active principles and underlying mechanism(s) of action remain largely unknown. Here we provide a review on the effects of Ashwagandha extracts and active principles, and underlying molecular mechanism(s) for brain pathologies. We highlight our findings on the nootropic potential of Ashwagandha leaves. The effects of Ashwagandha leaf extracts are multidimensional ranging from differentiation of neuroblastoma and glioma cells, reversal of Alzheimer and Parkinson's pathologies, protection against environmental neurotoxins and enhancement of memory.


106. Wang P.-P. et al. Racemic oleracein E increases the survival rate and attenuates memory impairment in D-galactose/NaNO2-induced senescent mice // Phytomedicine. 2016. Vol. 23, № 5. P. 460–467.

Background: Compounds that possess a pyrrolidone skeleton are a rich resource for the discovery of nootropic drugs. Oleracein E (OE), which possesses both tetrahydroisoquinoline and pyrrolidone skeletons, was first isolated from the medicinal plant Portulaca oleracea L. and was thought to be an active component in the cognition-improvement effect induced by this herb. The aim of this study was to investigate the effect of OE on cognitive impairment in senescent mice and its underlying mechanism of action. Method: Senescent Kunming mice were established by the intraperitoneal injection of D-galactose (D-gal, 1250 mg/kg/d) and NaNO2 (90 mg/kg/d) for 8 weeks. OE (3 mg/kg/d, 15 mg/kg/d) was orally administered for 8 weeks, and the nootropic drug piracetam (PA, 400 mg/kg/d) was used as a positive control. A Morris water maze was used to assess cognitive ability. GSH and MDA levels and T-AOC, SOD, and CAT activities in the brain or plasma were determined. Hippocampal morphology was observed by HE staining, and expression of the anti-apoptotic protein Bcl-2 and the pro-apoptotic proteins Bax and Caspase-3 was observed by immunohistochemical staining. Results: Large-dosage treatments with D-gal/NaNO2 for 8 weeks significantly reduced survival, impaired spatial memory capacity, compensatorily up-regulated GSH level and T-AOC and SOD activities, decreased CAT activity, and induced hippocampal neuronal damage and apoptosis as reflected by the apparent low expression of Bcl-2 and high expression of Bax and Caspase-3. OE significantly prolonged lifespan and was more potent than PA. Similar to PA, OE at 15 mg/kg/d improved memory capacity. The underlying mechanism of action was related to the reversal of abnormal brain antioxidant biomarkers (GSH, T-AOC, and SOD) to normal levels and the inhibition of hippocampal neuronal apoptosis. Conclusion: OE from P. oleracea is an active compound for improving cognitive function and is also a candidate nootropic drug for the treatment of age-related dementia.


107. Wei P.-J. et al. Tenuigenin enhances hippocampal Schaffer collateral-CA1 synaptic transmission through modulating intracellular calcium // Phytomedicine. 2015. Vol. 22, № 9. P. 807–812.

Background: Tenuigenin (TEN), a natural product from the Chinese herb Polygala tenuifolia root, has been reported to improve cognitive function and exhibits neuroprotective effects in pharmacological studies of the central nervous system. Synaptic transmission is the essential process of brain physiological functions such as learning and memory formation, and TEN has been shown to facilitate the basic synaptic transmission. Hypothesis/Purpose: Although our previous work has demonstrated that TEN is able to potentiate the basic synaptic transmission, the potential mechanism remains unclear. Here we investigated the effect of TEN on the synaptic transmission and analysed the potential mechanism. We hope that these findings will contribute to explain the role of TEN as a nootropic product or neuroprotective drug in the future. Methods: Field excitatory postsynaptic potentials (fEPSPs), spontaneous excitatory postsynaptic currents (sEPSCs) and miniature spontaneous excitatory postsynaptic currents (mEPSCs) were recorded, by using in vitro field potential electrophysiology and whole cell patch clamp techniques in acute hippocampal slices from rats. Results: TEN perfusion significantly enhanced the slope of fEPSPs and reduced the ratio of paired pulse facilitation. Moreover, TEN increased the frequency and amplitude of sEPSCs but only improved the frequency of mEPSCs rather than amplitude in hippocampal CA1 pyramidal neurons. With removal of extracellular calcium, TEN treatment also enhanced the mEPSCs frequency without affecting amplitude. Interestingly, the increase of mEPSCs frequency caused by TEN was blocked by chelation of intracellular calcium with BAPTA-AM. Conclusion: These results indicate that TEN enhances the basic synaptic transmission via stimulating presynaptic intracellular calcium.


108. Woolley M.L. et al. Evaluation of the pro-cognitive effects of the AMPA receptor positive modulator, 5-(1-piperidinylcarbonyl)-2,1,3-benzoxadiazole (CX691), in the rat // Psychopharmacology. 2009. Vol. 202, № 1–3. P. 343–354.

Positive allosteric modulators of the glutamatergic alpha-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid (AMPA) receptor do not stimulate AMPA receptors directly but delay deactivation of the receptor and/or slow its desensitisation. This results in increased synaptic responses and enhanced long-term potentiation. Thus, it has been suggested that such compounds may have utility for the treatment of cognitive impairment. The objective of the study was to investigate the effect of an AMPA positive modulator, CX691, (1) in three rodent models of learning and memory, (2) on neurochemistry in the dorsal hippocampus and medial prefrontal cortex following acute administration, and (3) on brain-derived neurotrophic factor (BDNF) messenger RNA (mRNA) expression in the rat hippocampus following acute and sub-chronic administration. CX691 attenuated a scopolamine-induced impairment of cued fear conditioning following acute administration (0.1 mg/kg p.o.) and a temporally induced deficit in novel object recognition following both acute (0.1 and 1.0 mg/kg p.o.) and sub-chronic (bi-daily for 7 days) administration (0.01, 0.03, 0.1 mg/kg p.o.). It also improved attentional set-shifting following sub-chronic administration (0.3 mg/kg p.o.). Acute CX691 (0.1, 0.3 and 1.0 mg/kg, p.o.) increased extracellular levels of acetylcholine in the dorsal hippocampus and medial prefrontal cortex and dopamine in the medial prefrontal cortex. Sub-chronic administration of CX691 (0.1 mg/kg, p.o.) elevated BDNF mRNA expression in both the whole and CA(1) sub-region of the hippocampus (P < 0.05). Collectively, these data support the pro-cognitive activity reported for AMPA receptor positive modulators and suggest that these compounds may be of benefit in treating disorders characterised by cognitive deficits such as Alzheimer's disease and schizophrenia.


109. Yazlovitskii A.V., Garazd M.M., Kartsev V.G. Synthesis of N-Acylamino-Acid Derivatives of Cytisine // Chem. Nat. Compd. 2016. Vol. 52, № 2. P. 272–275.

N-acylamino-acid derivatives of cytisine were prepared by reacting cytisine with methyl esters of aminoacid isocyanates.


110. Zarezadeh M. et al. Garlic active constituent s-allyl cysteine protects against lipopolysaccharide-induced cognitive deficits in the rat: Possible involved mechanisms // Eur. J. Pharmacol. 2017. Vol. 795. P. 13–21.

Neuroinflammation is known as a risk factor for cognitive deficit and dementia and its incidence increases with aging. S-allyl cysteine (SAC) is the active and main component of aged garlic extract with anti-inflammatory, neuroprotective, and nootropic potential. In this study, the protective effect of SAC against lipopolysaccharide (LPS)-induced cognitive deficit in the rat was investigated. For induction of learning and memory impairment and neuroinflammation, LPS was intraperitoneally injected at a dose of 167 mu g/kg for 7 days and SAC was administered p.o. at doses of 25, 50, or 100 mg/kg/day, 30 min after LPS, for seven days. Treatment of LPS-injected rats with SAC at a dose of 100 mg/kg improved spatial recognition memory in Y maze, discrimination ratio in novel object discrimination task, and retention and recall in passive avoidance test. In addition, SAC at the latter dose mitigated lipid peroxidation marker malondialdehyde (MDA) and augmented key antioxidant defensive elements including superoxide dismutase (SOD), catalase and glutathione (GSH) in hippocampal homogenate and lowered acetylcholinesterase activity. Meanwhile, SAC down-regulated hippocampal nuclear factor=- kappa B, toll-like receptor 4 (TLR4), glial fibrillary acidic protein (GFAP), and interleukin 1 beta (IL-beta) and up-regulated nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in addition to lowering ibal-immunoreactive intensity in the hippocampus of LPS-injected group. Taken together, SAC administration could mitigate LPSinduced cognitive deficits via attenuation of oxidative stress, neuroinflammation, astrogliosis, and acetylcholinesterase activity.


111. Zhang Q. et al. Comparative pharmacokinetic studies of racemic oxiracetam and its pure enantiomers after oral administration in rats by a stereoselective HPLC method // J. Pharm. Biomed. Anal. 2015. Vol. 111. P. 153–158.

Oxiracetam (ORC), a nootropic drug used for improving the cognition and memory, has an asymmetric carbon in its structure and exists as (S)- and (R)-ORC. The pharmacokinetic profiles of racemic oxiracetam and its pure enantiomers in rats were evaluated and compared by enantioselective high-performance liquid chromatography, which was performed on a Chiralpak ID column with a mobile phase of hexane-ethanol-trifluoroacetic acid (78:22:0.1, v/v/v). The method was validated with respect to selectivity, linearity, accuracy and precision, stability and the limit of quantification. The validation acceptance criteria were met in all cases. A saturating phenomenon of (S)-ORC was observed when the dosage ranged from 200 mg/kg to 800 mg/kg. The two enantiomers showed similar profiles in the absorb phase, and reached the maximum concentration at 2 h after oral administration. However, compared with the racemate group, the AUC/dose and C-max/dose ratios of (S)-ORC were higher and Cl/f was lower in enanpure (S)-ORC group. The C-max of (S)-ORC decreased from 21.3 +/- 1 5.0 mu g/ml to 13.2 +/- 1 4.2 when (R)-ORC was co-administrated at the dose of 200 mg/kg. AUC(0-t) values of (S)-ORC were different after oral administration of 200 mg/kg (S)-ORC and 400 mg/kg racemic ORC (96.7 +/- 15.5 and 50.1 +/- 16.3 mu gh/ml). The higher absorption and slower elimination suggest that enantiopure (S)-ORC could be a promising drug that efficiently reduces clinical dosage, improves therapeutic indices, decreases toxicology risks, and results in increased therapeutic ration.


112. Zvejniece L. et al. Investigation into Stereoselective Pharmacological Activity of Phenotropil // Basic Clin. Pharmacol. Toxicol. 2011. Vol. 109, № 5. P. 407–412.

Phenotropil [N-carbamoylmethyl-4-aryl-2-pyrrolidone (2-(2-oxo-4-phenyl-pyrrolidin-1-yl) acetamide; carphedon)] is clinically used in its racemic form as a nootropic drug that improves physical condition and cognition. The aim of this study was to compare the stereoselective pharmacological activity of R-and S-enantiomers of phenotropil in different behavioural tests. Racemic phenotropil and its enantiomers were tested for locomotor, antidepressant and memory-improving activity and influence on the central nervous system (CNS) using general pharmacological tests in mice. After a single administration, the amount of compound in brain tissue extracts was determined using an ultra performance liquid chromatography-tandem mass spectrometry (UPLC/MS/MS) method in a positive ion electrospray mode. In the open-field test, a significant increase in locomotor activity was observed after a single administration of R-phenotropil at doses of 10 and 50 mg/kg and S-phenotropil at a dose of 50 mg/kg. In the forced swim test, R-phenotropil induced an antidepressant effect at doses of 100 and 50 mg/kg, and S-phenotropil was active at a dose of 100 mg/kg. R-phenotropil significantly enhanced memory function in a passive avoidance response test at a dose of 1 mg/kg; the S-enantiomer did not show any activity in this test. However, the concentrations of R-and S-phenotropils in brain tissue were similar. In conclusion, the antidepressant and increased locomotor activity relies on both R-and S-phenotropils, but the memory-improving activity is only characteristic of R-phenotropil. These results may be important for the clinical use of optically pure isomers of phenotropil.


113. Zvejniece L. et al. R-phenibut binds to the alpha(2)-delta subunit of voltage-dependent calcium channels and exerts gabapentin-like anti-nociceptive effects // Pharmacol. Biochem. Behav. 2015. Vol. 137. P. 23–29.

Phenibut is clinically used anxiolytic, mood elevator and nootropic drug. R-phenibut is responsible for the pharmacological activity of racemic phenibut, and this activity correlates with its binding affinity for GABA(B) receptors. In contrast, S-phenibut does not bind to GABAB receptors. In this study, we assessed the binding affinities of R-phenibut, S-phenibut, baclofen and gabapentin (GBP) for the alpha(2)-delta subunit of the voltage-dependent calcium channel (VDCC) using a subunit-selective ligand, radiolabelled GBP. Binding experiments using rat brain membrane preparations revealed that the equilibrium dissociation constants (K(i)s) for R-phenibut, S-phenibut, baclofen and GBP were 23, 39, 156 and 0.05 mu M, respectively. In the pentylenetetrazole (PTZ)-induced seizure test, we found that at doses up to 100 mg/kg, R-phenibut did not affect PTZ-induced seizures. The anti-nociceptive effects of R-phenibut were assessed using the formalin-induced paw-licking test and the chronic constriction injury (CCI) of the sciatic nerve model. Pre-treatment with R-phenibut dose-dependently decreased the nociceptive response during both phases of the test. The anti-nociceptive effects of R-phenibut in the formalin-induced paw-licking test were not blocked by the GABAB receptor-selective antagonist CGP35348. In addition, treatment with R- and S-phenibut alleviated the mechanical and thermal allodynia induced by CCI of the sciatic nerve. Our data suggest that the binding affinity of R-phenibut for the alpha(2)-delta subunit of the VDCC is 4 times higher than its affinity for the GABAB receptor. The anti-nociceptive effects of R-phenibut observed in the tests of formalin-induced paw licking and CCI of the sciatic nerve were associated with its effect on the alpha(2)-delta subunit of the VDCC rather than with its effects on GABAB receptors. In conclusion, our results provide experimental evidence for GBP-like, anti-nociceptive properties of R-phenibut, which might be used clinically to treat neuropathic pain disorders.


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На моделях "поведенческого отчаяния" по Порсолту, условного рефлекса пассивного избегания исследована антидепрессивная, психостимулирующая и ноотропная активность средства из макро- и микроэлементов, содержащего KCl, RbNO3, магния сульфат и цинка сульфат. Установлено, что данное средство сокращает время иммобилизации в тесте Порсолта, способствует сохранности условного рефлнеса пассивного избегания. Наиболее выраженный психостимулирующий эффект средство проявляет в дозе 4.68 мг/кг, антидепрессивный — в дозе 18.72 мг/кг. Наибольшую ноотропную активность средство оказывает в дозе 93.6 мг/кг.


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Методом докирования ряда производных метанпиридо[1,2- a][1,5]диазоцина[(-)-цитизина] в активный центр никотинового ацетилхолинового рецептора осуществлен отбор перспективных веществ для лечения когнитивной дисфункции. На основе полученных данных можно заключить, что 6 структур из 21 могут являться потенциальными ингибиторами никотинового ацетилхолинового рецептора. Экспериментальное тестирование подтвердило наличие ноотропного действия у изученных соединений и позволило отобрать наиболее активные из них для дальнейших исследований.


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Ранее сконструированный в качестве пептидного прообраза пирацетама цикло-L-пролилглицин (ЦПГ) обнаружен нами в мозге крыс в качестве эндогенного соединения, обладающего свойствами ноотропа и анксиолитика. В настоящей работе синтезирован этиловый эфир N-фенилацетилглицил-L-пролина (ГЗК-111). Показано, что ГЗК-111 метаболизируется до ЦПГ и проявляет ноотропную, анксиолитическую и антигипоксическую виды активности, характерные для ЦПГ, в дозах 0,1 - 1,5 мг/кг внутрибрюшинно. Эффекты ГЗК-111, как и ЦПГ, стереоселективны. Активны только L-энантиомеры. ГЗК-111 рассматривается как пролекарство, стимулирующее когнитивные функции, с анксиолитическим компонентом действия.


117. 006952

На основе прогнозируемых с помощью компьютерной программы PASS спектров биологической активности было отобрано несколько антигипертензивных препаратов из группы ингибиторов АПФ для экспериментальной оценки ноотропной активности. Эксперименты проведены на мышах по тесту спонтанной ориентации (поведения патрулирования) в крестообразном лабиринте. В результате проведенных экспериментов обнаружено, что периндоприл в дозе 1 мг/кг, а квинаприл и моноприл в дозе 10 мг/кг вызывают улучшение показателей поведения патрулирования лабиринта. Данный эффект имеет сходство с эффектами эталонных ноотропных препаратов пирацетама и меклофеноксата (в дозах 300 и 120 мг/кг соответственно). Обнаруженное нами ноотропное действие некоторых ингибиторов АПФ, скорее всего не связано с их антигипертензивным эффектом, поскольку ноотропное действие имело место лишь при относительно малых дозах периндоприла, квинаприла и моноприла и исчезало при дальнейшем увеличении дозы. Выявление ноотропных свойств у широко применяемых в медицинской практике антигипертензивных препаратов открывает возможности для их новых клинических применений с учетом соответствующих индивидуальных особенностей пациентов.


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Изучена мнестическая и противогипоксическая активность новых производных хинолизидинового алкалоида (-)-цитизина при выработке условного рефлекса пассивного избегания (УРПИ) у крыс и нормобарической (баночной) гипоксии у мышей. В результате скрининга установлено, что бензамид и N-(12-метилцитизин-3-ил)- N'-фенилмочевина не только улучшают обучение и память, но и повышают устойчивость мозга к гипоксии.


119. 000617

Аппликация ноотропного препарата "Ноопепт" на срезы гиппокампа крыс Вистар приводит к увеличению тормозной составляющей вызванного стимуляцией коллатералей Шаффера суммарного тока в пирамидных нейронах поля СА1, при этом на возбуждающий компонент препарат влияния не оказывает. Выявлена прямая зависимость величины приращения тормозного тока от концентрации вещества. Препарат не влияет на выделение тормозного медиатора из терминалей, оканчивающихся на пирамидных нейронах, что указывает на изменение свойств ГАМКергических интернейронов.


120. 006952

Синтезировано соединение N-ацетилгидразид (2-хлорэтокси-4'-диметиламинофенил)фосфорилуксусной кислоты (II), являющееся предполагаемым метаболитом КАПАХ (I) — препарата с ноотропной активностью. Изучены психотропное и антиаритмическое действие, проведен сравнительный анализ фармакологической активности I и II. Показано, что в отличие от I, II не проявил ноотропной и антидепрессивной активности, но обладает более выраженными антиаритмическими свойствами. Предполагается, что, являясь заместителем гидразидной группы, фрагмент C(O)CH 3 может затруднять проникновение соединения II через гематоэнцефалический барьер в мозг, что объясняет отсутствие у него психотропной активности.


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Тюренков И.Н. и др. НООТРОПНАЯ АКТИВНОСТЬ АМИДОВ ХИНАЗОЛИНОВОГО РЯДА // Хим.-фарм. Журн. 2015. Т. 49, № 2. P. 18–20.

Ацетанилидные производные хиназолина синтезированы прямым алкилированием хиназолин-4(3 H)-она анилидами ?-хлоркарбоновых кислот. Изучены ноотропные свойства 10 производных ?-[4-оксохиназолин-3(4 H)-ил]карбоновых кислот. Установлено выраженное ноотропное действие у веществ III, IV, VI и X, далее планируется их углубленное изучение.


122. 000617

Аналоги ГАМК, содержащие фенильный (фенибут) и пара -хлорфенильный (баклофен) заместители, в дозе 20 мг/кг проявляют ноотропную активность: улучшают выработку УРПИ и замедляют его естественное угашение с течением времени, оказывают антиамнестическое действие на моделях амнезии, вызванной скополамином и максимальным электрошоком. Толилсодержащий аналог ГАМК (толибут; 20 мг/кг) проявляет антиамнестические свойства только на модели электрошокиндуцированной амнезии. Баклофен и в меньшей степени толибут уменьшают выраженность судорог, вызванных электрошоком — оказывают противосудорожное действие. Все изученные арилпроизводные ГАМК проявляют нейропротективные свойства на модели максимального электрошока: сокращают длительность комы и время до восстановления спонтанной двигательной активности, а также уменьшают выраженность амнезии рефлекса пассивного избегания и поведенческого дефицита в тесте "открытое поле" у крыс, подвергшихся электрошоку. В наибольшей степени нейропротективные свойства выражены у фенилсодержащего аналога ГАМК фенибута.


123. 007832
Цыпышева И.П. и др. Синтез и нейрофармакологическая активность N-1-адамaнтилцитзин-12-карбамида и его 12-тиокарбаналога // Химия природ. соедин. 2013. № 4. с. 606–609.

124. 007832
Цыпышева И.П. и др. Синтез и ноотропная активность новых производных 3-амино-12-N-метилцитизина // Химия природ. соедин. 2015. № 5. С. 780–785.

125. 007832
Цыпышева И.П. и др. Синтез и специфическая ноотропная активность производных (-)-цитизина,имеющих в структуре фрагменты карбамидов и тио-карбамидов // Химия природ. соедин. 2012. № 4. P. 565–570.

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В результате исследования химического состава густого экстракта травы Alfredia cernua (L.) Cass., полученного обработкой сырья 95 % этанолом, с использованием метода хроматомасс-спектрометрии (ГХ/МС) идентифицировали 31 алифатическую, в том числе 2-гидрокси- и дикарбоновые, 3 фенолкарбоновых, 1 ди- и 2 тритерпеновых кислоты, 16 нейтральных липофильных компонента. 40 соединений обнаружены в альфредии поникшей впервые. В условиях модели «Т-образный лабиринт» установлено, что экстракт растения способствует изменениям в мотивационной сфере нормальных животных, активируя аппетитивное и консумматорное поведение за счет ноотропного и анксиолитического действия, превосходя эффективность пирацетама.


127. 000617
Шилова И.В., Суслов Н.И. НООТРОПНОЕ ДЕЙСТВИЕ ЭКСТРАКТОВ ЛАБАЗНИКА ОБЫКНОВЕННОГО // Бюлл. Эксп. Биол. Meд. 2014. Т. 158, № 11. С. 609–613.

В тесте "открытое поле", на моделях гипоксии гермообъема, УРПИ и принудительного плавания с утяжеляющим грузом изучали влияние экстрактов надземной части Filipendula vulgaris Moench на поведение и память после гипоксического воздействия, а также физическую работоспособность мышей. Экстракты увеличивали резистентность животных к гипоксическому воздействию, нормализовали ориентировочно-исследовательскую деятельность и улучшали сохранность УРПИ после гипоксической травмы, а также способствовали увеличению физической работоспособности. Водный экстракт лабазника обыкновенного оказывал наиболее выраженное действие, которое соответствовало эффекту препарата сравнения пирацетама. Обнаруженные эффекты, вероятно, обусловлены изменением деятельности гиппокампа.


128. 000617
Шилова И.В., Суслов Н.И., Амельченко В.П.НООТРОПНЫЕ СВОЙСТВА ФРАКЦИЙ ВОДНОГО ЭКСТРАКТА ЛАБАЗНИКА ОБЫКНОВЕННОГО // Бюлл. Эксп. Биол. Meд. 2015. Т. 159, № 3. С. 357–361.

На моделях гипоксии гермообъема, УРПИ, в тесте "открытое поле", а также в условиях принудительного плавания с утяжеляющим грузом показана ноотропная активность фракций водного экстракта надземной части лабазника обыкновенного ( Filipendulavulgaris Moench), их способность увеличивать резистентность к гипоксическому воздействию, нормализовать ориентировочно-исследовательское поведение и увеличивать сохранность рефлекса при проверках после гипоксической травмы, повышать физическую работоспособность. При разделении экстракта на фракции выявлена диссоциация составляющих эффекта, что указывает на наличие специфических свойств у отдельных составляющих суммы биологически активных веществ. В наибольшей степени ноотропная активность характерна для этилацетатной фракции, которая превышает по ряду показателей эффективность экстракта растения. Выявленные эффекты, вероятно, обусловлены изменением деятельности гиппокампа под действием фенольных и тритерпеновых соединений.


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Язловицкий A.В., Гаразд M.M., Карцев В.Г. Синтез N-ациламинокислотных производных цитизина // Химия природ. соедин. 2016. № 2. P. 239–242.

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