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Последние достижения нейробиологии. Нервные и нейроэндокринные регуляции. Нейродегенеративные заболевания

Журнальные статьи

Arena J.E., Stoessl A.J. Optimizing diagnosis in Parkinson’s disease: Radionuclide imaging // Parkinsonism & Related Disorders. 2016. Vol. 22, Supplement 1. P. S47–S51.

Parkinson's disease (PD) and other disorders characterized by basal ganglia dysfunction are often associated with limited structural imaging changes that might assist in the clinical or research setting. Radionuclide imaging has been used to assess characteristic functional changes. Presynaptic dopaminergic dysfunction in PD can be revealed through the imaging of different steps in the process of dopamine synthesis and storage: L-aromatic amino acid decarboxylase (AADC) activity, Vesicular Monoamine Transporter type 2 (VMAT2) binding or its reuptake via the dopamine transporter (DAT). Postsynaptic dopamine dysfunction can also be studied with a variety of different tracers that primarily assess D2-like dopamine receptor availability. The function of other neurotransmitters such as norepinephrine, serotonin and acetylcholine can be imaged as well, giving important information about the underlying pathophysiologic process of PD and its complications. The imaging of metabolic activity and pathologic changes has also provided great advances in the field. Together, these techniques have allowed for a better understanding of PD, may be of aid for differentiating PD from other forms of parkinsonism and will undoubtedly be useful for the establishment of new therapeutic targets.

Bellucci A. et al. Review: Parkinson’s disease: from synaptic loss to connectome dysfunction // Neuropathology and Applied Neurobiology. 2016. Vol. 42, № 1. P. 77–94.

Parkinson's disease (PD) is a common neurodegenerative disorder with prominent loss of nigro-striatal dopaminergic neurons. The resultant dopamine (DA) deficiency underlies the onset of typical motor symptoms (MS). Nonetheless, individuals affected by PD usually show a plethora of nonmotor symptoms (NMS), part of which may precede the onset of motor signs. Besides DA neuron degeneration, a key neuropathological alteration in the PD brain is Lewy pathology. This is characterized by abnormal intraneuronal (Lewy bodies) and intraneuritic (Lewy neurites) deposits of fibrillary aggregates mainly composed of -synuclein. Lewy pathology has been hypothesized to progress in a stereotypical pattern over the course of PD and -synuclein mutations and multiplications have been found to cause monogenic forms of the disease, thus raising the question as to whether this protein is pathogenic in this disorder. Findings showing that the majority of -synuclein aggregates in PD are located at presynapses and this underlies the onset of synaptic and axonal degeneration, coupled to the fact that functional connectivity changes correlate with disease progression, strengthen this idea. Indeed, by altering the proper action of key molecules involved in the control of neurotransmitter release and re-cycling as well as synaptic and structural plasticity, -synuclein deposition may crucially impair axonal trafficking, resulting in a series of noxious events, whose pressure may inevitably degenerate into neuronal damage and death. Here, we provide a timely overview of the molecular features of synaptic loss in PD and disclose their possible translation into clinical symptoms through functional disconnection.

Benabid A.L., Torres N. New targets for DBS // Parkinsonism & Related Disorders. 2012. Vol. 18, Supplement 1. P. S21–S23.

The specific effect of DBS at high frequency, discovered during a VIM thalamotomy, was extended to the older targets of ablative neurosurgery such as the pallidum, for tremor in Parkinson's disease (PD), dyskinesias, essential tremor, as well as the internal capsule to treat psychiatric disorders (OCD). A second wave of targets came from basic research, enabled by the low morbidity, reversibility, and adaptability of DBS. This was the case for the subthalamic nucleus (STN) which improves the triad of dopaminergic symptoms, and the pedunculopontine nucleus (PPN) for gait disorders in PD. The new concepts of the role of basal ganglia in psychiatric disorders indicate the subgenual cortex CG 25 for severe resistant depression, the accumbens nucleus for depression, anorexia nervosa, and addiction, and the thalamus intralaminar nuclei for minimally conscious states. Serendipity and a scientific approach have provided several instances where targets have produced unexpected effects (such as STN in OCD), as well as limbic effects observed during attempts at VMH stimulation for obesity: this might offer a novel way to treat mild cognitive impairment, or memory deficits reported in Alzheimer's disease. While these might provide solutions for as yet unsolved problems, attention must be paid to ethical considerations.

Bukhatwa S. et al. A comparison of changes in proteasomal subunit expression in the substantia nigra in Parkinson’s disease, multiple system atrophy and progressive supranuclear palsy // Brain Res. 2010. Vol. 1326. P. 174–183.

Dysfunction of the ubiquitin-proteasome system (UPS) occurs in dopaminergic neurones in the SN in PD and it is associated with Lewy body formation. However, it remains unknown whether this is specific to PD or whether it also occurs in multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) where nigral dopaminergic neurones also degenerate. In the present study, we investigated changes in the expression of proteasomal subunits in the SN in PD, MSA and PSP. Immunohistochemistry double staining showed that proteasome 205-alpha 4 and -alpha 6, and 20S-beta 3 and -beta Si subunits are colocalized with tyrosine hydroxylase (TH)-positive cells in the SN of control, PD, MSA and PSP brain. Semi-quantitative analysis showed a significant loss of 20S-alpha 4 and -alpha 6 subunits TH-positive cells in PD, MSA and PSP compared to control tissue. There was no change in the expression of 20S-beta 3 and -beta Si subunits in any of the disease states. The expression of PA700-Rpt5 subunits was not changed in PSP or PD but was significantly increased in MSA compared to control SN. PA700-Rpn10 subunit was not colocalized with TH within dopamine cells but was co-expressed with glial fibrillary acid protein (GFAP) positive astrocytes in the SN of all groups. PA28-alpha immunoreactivity was low in TH positive neurones in control tissue and quantification was not possible. Qualitative analysis suggested a decrease in PD and no immunoreactivity was detected in MSA or PSP. The results show that changes in proteasomal structure occur in the SN in PD, MSA and PSP and that these are similar in nature suggesting that dysfunction of UPS is not specific to PD or to Lewy body formation. (C) 2010 Elsevier BM. All rights reserved.

Casteels C. et al. In vivo type 1 cannabinoid receptor mapping in the 6-hydroxydopamine lesion rat model of Parkinson’s disease // Brain Res. 2010. Vol. 1316. P. 153–162.

Type 1 cannabinoid (CB1) receptors are expressed in high concentrations in the central nervous system, including the basal ganglia, and could have direct or indirect effects on motor behavior through modulation of dopaminergic, glutamatergic and GABA-ergic neurotransmission. Using the CB1 receptor radioligand [(18)F]MK-9470 and small-animal PET, we investigated for the first time in vivo cerebral changes in [(18)F]MK-9470 binding in the 6-hydroxydopamine (6-OHDA) rat model of Parkinson's disease (PD), parallel to dopamine transporter (DAT) imaging, tyrosine hydroxylase (TH) staining, and behavioral measurements. In the 6-OHDA model, relative [(18)F]MK-9470 PET binding decreased in the contralateral cerebellum (-9%, p<0.0004) and caudate-putamen bilaterally (ipsilateral -8%, contralateral -7%; p=0.001 and p<0.0003, respectively). The number of TH(+) neurons in the substantia nigra was inversely correlated to CB1 receptor binding in the ipsilateral cerebellum (p=1.10(-6)). The behavioral outcome was positively related to regional CB1 receptor binding in the contralateral somatosensory cortex (p =4.10(-6)). in vivo [(18F)]MK-9470 PET imaging points to changes in endocannabinoid transmission, specifically for CB1 receptors in the 6-OHDA model of PD, with mainly involvement of the caudate-putamen, but also distant regions of the motor circuitry, including the cerebellum and somatosensory cortex. (C) 2009 Elsevier B.V. All rights reserved.

Chang K.-H. et al. Impairment of proteasome and anti-oxidative pathways in the induced pluripotent stem cell model for sporadic Parkinson’s disease // Parkinsonism & Related Disorders. 2016. Vol. 24. P. 81–88.

Background Parkinson's disease (PD) is associated with the progressive degeneration of dopaminergic neurons with abnormal accumulation of ?-synuclein mainly in the ventral midbrain. However, the lack of live human neurons from PD patients and their heterogeneous pathogenic nature limit mechanistic studies and therefore the development of drugs to modify the disease progression of PD. The evolution of induced pluripotent stem cell (iPSC) technology makes it possible to generate patient-specific neurons to explore the pathogenesis in individual PD patients. Methods We generated PD-iPSCs from a sporadic early onset PD patient carrying a heterozygous deletion of exon 5 (Ex5del) in PARK2. The expression of ?-synuclein and proteasome and anti-oxidative functions were examined in differentiated iPSC-derived neurons. Results The neurons derived from our PD-iPSCs demonstrated abnormal ?-synuclein accumulation and down-regulation of the proteasome and anti-oxidative pathways. Environmental triggers such as proteasome inhibitor MG132 and H2O2 markedly induced cell death, while the proteasome enhancer benzamil and anti-oxidative compound genipin significantly rescued these increased susceptibilities. Conclusions These results demonstrate that unique genetic–environmental interactions are involved in neuronal death in PD patients. Our findings also provide a new model to identify potential disease-modifying strategies and an insight into personalized medicine for patients with PD.

Choi H. Soon et al. Phosphorylation of ?-synuclein is crucial in compensating for proteasomal dysfunction // Biochemical and Biophysical Research Communications. 2012. Vol. 424, № 3. P. 597–603.

?-Synuclein can be degraded by both the ubiquitin–proteasomal system and the chaperone–lysosomal system. However, the switching mechanism between the two pathways is not clearly understood. In our study, we investigated the mutual association between the binding of ?-synuclein to heat shock cognate 70 and the lysosomal translocation of ?-synuclein. Tyrosine phosphorylation of Y136 on ?-synuclein increased when it bound to heat shock protein 70. We also found that tyrosine phosphorylation of ?-synuclein can be regulated by focal adhesion kinase pp125 and protein tyrosine phosphatase 1B. Furthermore, protein tyrosine phosphatase 1B inhibitor protected dopaminergic neurons against cell death and rescued rotarod performance in a Parkinson’s disease animal model. This study provides evidence that the regulation of Y136 phosphorylation of ?-synuclein can improve behavioral performance and protect against neuronal death by promoting the turnover of lysosomal degradation of ?-synuclein. As a result, protein tyrosine phosphatase 1B inhibitor may be used as a potential therapeutic agent against Parkinson’s disease.

Chou K.L., Kotagal V., Bohnen N.I. Neuroimaging and clinical predictors of fatigue in Parkinson disease // Parkinsonism & Related Disorders. 2016. Vol. 23. P. 45–49.

Background Fatigue is disabling in Parkinson disease. It is often associated with other non-motor symptoms, but little is known about its underlying pathophysiology. Objective To investigate neuroimaging (using dopaminergic and cholinergic PET) and clinical factors associated with fatigue severity in PD. Methods 133 PD subjects (96M/37F) completed the Fatigue Severity Scale, Movement Disorders Society-Sponsored Revision of the Unified PD Rating Scale (MDS-UPDRS), Hoehn-Yahr staging, validated scales for depression, anxiety, apathy, sleep, and cognition, and underwent [11C]methyl-4-piperidinyl propionate (PMP) acetylcholinesterase (AChE) and [11C]dihydrotetrabenazine (DTBZ) monoaminergic PET imaging. We explored contributions to PD fatigue using separate regression models based either on neuroimaging parameters or clinicometric scales. Results In a neuroimaging regression model, neither striatal DTBZ uptake nor AChE PMP uptake were predictors of fatigue in PD. In a post-hoc neuroimaging regression model, stratifying the total cohort into mild vs. moderate-to-severe PD, striatal DTBZ uptake was a significant predictor of fatigue in mild but not moderate-to-severe PD. In a clinicometric regression model, higher Beck Depression Inventory-somatic subscore, higher levodopa dose equivalents and younger age were all significant predictors of fatigue in PD, but the MDS-UPDRS non-motor experiences of daily living score was the best predictor overall. Conclusions Cholinergic uptake was not a predictor of fatigue in PD, but nigrostriatal dopaminergic denervation predicted fatigue in mild disease. Total non-motor symptom burden, somatic affective symptoms, levodopa dose equivalents, and younger age were independent clinical predictors of fatigue.

Cobb C.A., Cole M.P. Oxidative and nitrative stress in neurodegeneration // Neurobiology of Disease. 2015. Vol. 84. P. 4–21.

Aerobes require oxygen for metabolism and normal free radical formation. As a result, maintaining the redox homeostasis is essential for brain cell survival due to their high metabolic energy requirement to sustain electrochemical gradients, neurotransmitter release, and membrane lipid stability. Further, brain antioxidant levels are limited compared to other organs and less able to compensate for reactive oxygen and nitrogen species (ROS/RNS) generation which contribute oxidative/nitrative stress (OS/NS). Antioxidant treatments such as vitamin E, minocycline, and resveratrol mediate neuroprotection by prolonging the incidence of or reversing OS and NS conditions. Redox imbalance occurs when the antioxidant capacity is overwhelmed, consequently leading to activation of alternate pathways that remain quiescent under normal conditions. If OS/NS fails to lead to adaptation, tissue damage and injury ensue, resulting in cell death and/or disease. The progression of OS/NS-mediated neurodegeneration along with contributions from microglial activation, dopamine metabolism, and diabetes comprise a detailed interconnected pathway. This review proposes a significant role for OS/NS and more specifically, lipid peroxidation (LPO) and other lipid modifications, by triggering microglial activation to elicit a neuroinflammatory state potentiated by diabetes or abnormal dopamine metabolism. Subsequently, sustained stress in the neuroinflammatory state overwhelms cellular defenses and prompts neurotoxicity resulting in the onset or amplification of brain damage.

Colabufo N.A. et al. Perspectives of P-Glycoprotein Modulating Agents in Oncology and Neurodegenerative Diseases: Pharmaceutical, Biological, and Diagnostic Potentials // J. Med. Chem. 2010. Vol. 53, № 5. P. 1883–1897.

Cossu G., Melis M. The peripheral nerve involvement in Parkinson Disease: A multifaceted phenomenon // Parkinsonism & Related Disorders. 2016. Vol. 25. P. 17–20.

In the last decade the possible relationship between Parkinson's disease (PD) and peripheral neuropathy (PN) has received increasing attention. Given that PN is quite common in Parkinson's disease, much controversy has arisen on whether it is part of the neurogenerative process itself - actually one of the possible causes - or a complication of levodopa administration. In this article we will discuss the different hypotheses, as well as our perspective on these open issues.

de Munter J.P.J.M., Melamed E., Wolters E.C. Stem cell grafting in parkinsonism – Why, how and when // Parkinsonism & Related Disorders. 2014. Vol. 20, Supplement 1. P. S150–S153.

" Parkinson's disease is a devastating, progressive neurodegenerative disorder that affects the central and peripheral nervous systems. Although recent advancements have led to a better understanding of the disorder, there is currently no long-term disease-modifying strategy. Recently, preclinical data have identified the significant effects of pluripotent stem cell grafting in 6-OHDA and MPTP animal models of motor parkinsonism; there have also been some clinical data in patients with motor parkinsonism. Pluripotent stem cells can nestle in affected organs and can differentiate into a variety of cells, including neural (dopamine producing) cells. Depending on the environment into which they are grafted, these stem cells can also influence immune responses by regulating the activity of B-cells, T-cells, and NK-cells. Pluripotent stem cells can also produce chemotrophins, including BDNF (brain-derived neurotrophic factor), GDNF (glial-derived neurotrophic factor), NGF (nerve growth factor), TGF-? (transforming growth factor-?), IGF-1 (insulin-like growth factor 1), NT-3 (neurotrophin 3), and SCF-1 (stem cell factor 1). Influencing these trophic factors can influence plasticity. This article explores the potential of pluripotent stem cells in the treatment of PD. We will explore the utilization of pluripotent stem cells in the immunomodulation of B-cells, T-cells and NK-cells, the transdifferentiation of pluripotent stems cells into DA-cells, and the secretion of trophic factors and its relation to plasticity. We will also cover how best to conduct a clinical trial, which stem cells can be safely used in patients, what are the methods of induction before application, and how to re-apply stem cells in patients by intravasal, intrathecal or intracerebral methods. Finally, we will describe how to objectively record the clinical results."

Ding H. et al. Identification of a panel of five serum miRNAs as a biomarker for Parkinson’s disease // Parkinsonism & Related Disorders. 2016. Vol. 22. P. 68–73.

Background and objective Parkinson's disease (PD) is the second most common age-related neurodegenerative disorder after Alzheimer's disease. The aim of this work was to determine whether the differences of serum miRNAs profiling could distinguish PD patients from healthy individuals. Methods We collected serum samples from 106 sporadic PD patients and 91 age/gender-matched healthy controls. Serum miRNAs were analysed by Solexa sequencing followed by a qRT-PCR examination. The qRT-PCR assay, which was divided into two phases, was used to validate the expression of miRNAs screened by Solexa sequencing. Receiver operating characteristic (ROC) curve analysis and clustering analysis were performed to determine the diagnostic usefulness of the selected miRNAs for PD. Results In this study, we generated a profile of 5 serum miRNAs: miR-195 was up-regulated, and miR-185, miR-15b, miR-221 and miR-181a were down-regulated. Conclusion This group of five miRNAs can precisely distinguish PD patients from health individuals and may be used as a potential serum-based biomarker for the diagnosis of PD.

Ezzati A. et al. Higher-level motion detection deficit in Parkinson’s disease // Brain Res. 2010. Vol. 1320. P. 143–151.

Previous research has suggested that Parkinson's disease (PD) impairs motion perception. First-order motion consists of moving luminance-defined attributes. Second-order motion, on the other hand, consists of moving patterns whose motion attributes are not luminance-defined. The detection of first and second-order motion is thought to be mediated by different mechanisms. Here, we compare the ability of Parkinson's disease patients (PDPs) to detect first-order/second-order motion with normal subjects. Subjects had to discriminate the drift. direction of first-order motion (luminance-modulated noise) and a second-order motion pattern (named as noise base motion) over a range of stimulus speeds and strengths. Results show that the first-order motion detection deficits could only be seen with lower motion strengths suggesting a ceiling effect with higher motion strengths. However, second order motion detection deficits were seen across high and low motion strengths, suggesting that the second order motion detection may be more affected in PD than the first-order motion detection. Our results indicate that higher-level visual cortex plays an important role in PD patients' disabilities in motion perception. (C) 2010 Elsevier B.V. All rights reserved.

Franco-Iborra S., Vila M., Perier C. The Parkinson Disease Mitochondrial Hypothesis: Where Are We at? // Neuroscientist. 2016. Vol. 22, № 3. P. 266–277.

Parkinson's disease is a common, adult-onset neurodegenerative disorder whose pathogenesis is still under intense investigation. Substantial evidence from postmortem human brain tissue, genetic- and toxin-induced animal and cellular models indicates that mitochondrial dysfunction plays a central role in the pathophysiology of the disease. This review discusses our current understanding of Parkinson's disease-related mitochondrial dysfunction, including bioenergetic defects, mitochondrial DNA alterations, altered mitochondrial dynamics, activation of mitochondrial-dependent programmed cell death, and perturbations in mitochondrial tethering to the endoplasmic reticulum. Whether a primary or secondary event, mitochondrial dysfunction holds promise as a potential therapeutic target to halt the progression of neurodegeneration in Parkinson's disease.

Gagnon D., Di Paolo T., Parent M. Increased serotonin innervation of the sensorimotor striatum in a primate model of Parkinson’s disease // Parkinsonism & Related Disorders. 2016. Vol. 22, Supplement 2. P. e181–e182.

Our findings demonstrate the highly plastic nature of 5-HT striatal afferent projections, a feature that becomes obvious in the absence of dopamine. Although the number of dorsal raphe neurons remains constant in parkinsonian monkeys, their ascending axonal projections undergo marked proliferative and synaptic adaptive changes that might play a significant role in the expression of L-Dopa-induced dyskinesia.

Gahete M.D. et al. Role of ghrelin system in neuroprotection and cognitive functions: Implications in Alzheimer’s disease // Peptides. 2011. Vol. 32, № 11. P. 2225–2228.

Alzheimer's disease (AD) is a multifactorial progressive neurodegenerative disorder characterized by loss of memory and cognitive deficits, strongly influenced by the metabolic status, in which the impairment of neuropeptides/neurotransmitters systems has been previously observed. Ghrelin is a multifunctional hormone produced in a wide variety of tissues, which has been associated with the progression of obesity and metabolic syndrome, but has been also linked to neuromodulation, neuroprotection and memory and learning processes. In addition, ghrelin system also acts in an autocrine/paracrine fashion where the majority of its components [ghrelin variants (native ghrelin, In1-ghrelin), acylation enzyme (GOAT) and receptors (GHS-Rs)] are expressed in the different regions of central nervous system. In spite of all these pieces of information strongly suggesting a close association between ghrelin system and AD, which could be of pathophysiological relevance, few studies have been addressed to clarify this relationship. In this work, the role of ghrelin system in neuroprotection, memory consolidation and learning is reviewed, and its influence in AD, as well as the regulation of its expression in the brain of AD patients, is discussed. (C) 2011 Elsevier Inc. All rights reserved.

Ghosh B. et al. Development of (S)-N-6-(2-(4-(Isoquinolin-1-yl)piperazin-1-yl)ethyl)-N-6-propyl-4,5,6, 7-tetrahydrobenzo[d]-thiazole-2,6-diamine and Its Analogue as a D3 Receptor Preferring Agonist: Potent in Vivo Activity in Parkinson’s Disease Animal Models // J. Med. Chem. 2010. Vol. 53, № 3. P. 1023–1037.

Here we report structure-activity relationship study of a novel hybrid series of compounds where structural alteration of aromatic hydrophobic moieties connected to the piperazine ring and bioisosteric replacement of the aromatic tetralin moieties were carried out, Binding assays were carried out with HEK-293 cells expressing either D2 or D3 receptors with tritiated spiperone to evaluate inhibition constants (K-i). Functional activity of selected compounds in stimulating GTP gamma S binding was assessed with CHO cells expressing human D2 receptors and AtT-20 cells expressing human D3 receptors. SAR results identified compound (-)-24c (D301) as one of the lead molecules with preferential agonist activity for D3 receptor (EC50 (GTP gamma S); D3 = 0.52 nM; D2/D3 (EC50): 223). Compounds (-)-24b and (-)-24c exhibited potent radical scavenging activity. The two lead compounds, (-)-24b and (-)-24c, exhibited high in vivo activity in two Parkinson's disease (PD) animal models, reserpinized rat model and 6-OHDA induced unilaterally lesioned rat model. Future studies will explore potential use of these compounds in the neuroprotective therapy for PD.

Ghosh B. et al. Discovery of 4-(4-(2-((5-Hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethy l)piperazin-1-yl)quinolin-8-ol and Its Analogues as Highly Potent Dopamine D2/D3 Agonists and as Iron Chelator: In Vivo Activity Indicates Potential Application in Symptomatic and Neuroprotective Therapy for Parkinson’s Disease // J. Med. Chem. 2010. Vol. 53, № 5. P. 2114–2125.

The role of iron in the pathogenesis of Parkinson's disease (PD) has been implicated strongly because of generation of oxidative stress leading to dopamine cell death. In our overall goal to develop bifunctional/multifunctional drugs, we designed dopamine D2/D3 agonist molecules with a capacity to bind to iron. Binding assays were carried out with HEK-293 cells expressing either D2 or D3 receptor with tritiated spiperone to evaluate inhibition constants (K(i)). Functional activity of selected compounds was carried out with GTP gamma S binding assay. SAR results identified compounds (+)-19a and (-)-19b as two Potent agonists for both D2 and D3 receptors (EC(50) (GTP gamma S); D2 = 4.51 and 1.69 nM and D3 = 1.58 and 0.74 nM for (-)-19b and (+)-19a, respectively). In vitro complexation Studies with 19b demonstrated efficient chelation with iron. Furthermore, the deoxyribose assay with 19b demonstrated potent antioxidant activity. In PD animal model study, (-)-19b exhibited potent in vivo activity in reversing locomotor activity in reserpinized rats and also in producing potent rotational activity in 6-OHDA lesioned rats. This reports initial development of unique lead molecules that might find potential use in Symptomatic and neuroprotective treatment of PD.

Gregoire L. et al. Safinamide reduces dyskinesias and prolongs l-DOPA antiparkinsonian effect in parkinsonian monkeys // Parkinsonism & Related Disorders. 2013. Vol. 19, № 5. P. 508–514.

"Introduction Safinamide is a compound under investigation for use in the treatment of Parkinson's disease for combination with pharmacological therapy currently available. The objective of this study was to test the effects of safinamide in an animal model of l-DOPA-induced dyskinesias (LID), the MPTP lesioned dyskinetic macaque monkey, in comparison to and in combination with amantadine. Methods LID and parkinsonian symptoms were measured in dyskinetic monkeys treated with l-DOPA with and without several dose levels of safinamide, amantadine, and the two in combination. Safinamide plasma levels were monitored during the experiments. Results Safinamide pre-treatment (3, 10, 20 and 30 mg/kg) dose-dependently reduced LID scores, in two acute and one semi-chronic experiment. Intensity and duration of LID were reduced and inversely correlated with safinamide blood levels. All doses of safinamide tested prolonged the duration of the beneficial antiparkinsonian effect of l-DOPA. Amantadine (5 and 20 mg/kg) reduced LID, but reduced duration of antiparkinsonian response to l-DOPA. When added to amantadine (5 mg/kg), safinamide showed no (3 mg/kg) or modest (20 mg/kg) additional beneficial effects on LID while the combined treatment prevented the reduction of the duration of the l-DOPA antiparkinsonian effect observed with amantadine only. Conclusions Safinamide and amantadine reduced LID in this primate model while only safinamide increased the duration of the antiparkinsonian response of l-DOPA, suggesting that safinamide may have effects on LID that are pharmacologically distinct from amantadine, which is in current clinical use for control of LID."

Haddad D., Nakamura K. Understanding the susceptibility of dopamine neurons to mitochondrial stressors in Parkinson’s disease // Febs Letters. 2015. Vol. 589, № 24. P. 3702–3713.

Mitochondria are undoubtedly changed in Parkinson's disease (PD), and mitochondrial functions are disrupted in genetic and pharmacologic models of PD. However, many of these changes might not truly drive neurodegeneration. PD is defined by the particular susceptibility of nigrostriatal dopamine (DA) neurons, but little is understood about the mitochondria in these cells. Here, we critically review the evidence that mitochondrial stressors cause PD. We then consider how changes in the intrinsic function of mitochondria and in their mass, distribution, and dynamics might synergize with an increased need for mitochondria and produce PD, and the importance of understanding how mitochondria contribute to its pathogenesis.

Hegarty S.V., Sullivan A.M., O’Keeffe G.W.Midbrain dopaminergic neurons: A review of the molecular circuitry that regulates their development // Developmental Biology. 2013. Vol. 379, № 2. P. 123–138.

Dopaminergic (DA) neurons of the ventral midbrain (VM) play vital roles in the regulation of voluntary movement, emotion and reward. They are divided into the A8, A9 and A10 subgroups. The development of the A9 group of DA neurons is an area of intense investigation to aid the generation of these neurons from stem cell sources for cell transplantation approaches to Parkinson's disease (PD). This review discusses the molecular processes that are involved in the identity, specification, maturation, target innervation and survival of VM DA neurons during development. The complex molecular interactions of a number of genetic pathways are outlined, as well as recent advances in the mechanisms that regulate subset identity within the VM DA neuronal pool. A thorough understanding of the cellular and molecular mechanisms involved in the development of VM DA neurons will greatly facilitate the use of cell replacement therapy for the treatment of PD.

Jackson-Lewis V., Blesa J., Przedborski S. Animal models of Parkinson’s disease // Parkinsonism & Related Disorders. 2012. Vol. 18, Supplement 1. P. S183–S185.

Parkinson's disease (PD) is a disease of an aging population and its etiology is still unknown. In vivo models are attempts to capture as many of the hallmarks of PD as possible. To this end, a number of animal models are in use. These models parallel our thinking about the etiology of PD. Thus, herein, we discuss the most popular neurotoxin animal models, 6-hydroxydopamine and MPTP as one school of thought believes that PD is the result of a toxic insult. Since several researchers think that pesticide and herbicide use can increase the risk of developing PD, we review some of the aspects of rotenone and paraquat in rodents. Furthermore, now that we know that 10% of all PD cases are genetic in nature, we discuss some of the more common genetic rodent models of PD. None of the above models captures all of the hallmarks of PD. Thus, a given model should never be used indiscriminately to investigate every question, but should instead be carefully selected on the basis of being the most suitable model for the question being asked.

Jadiya P. et al. Anti-Parkinsonian effects of Bacopa monnieri: Insights from transgenic and pharmacological Caenorhabditis elegans models of Parkinson’s disease // Biochem. Biophys. Res. Commun. 2011. Vol. 413, № 4. P. 605–610.

Neurodegenerative Parkinson's disease (PD) is associated with aggregation of protein alpha synuclein and selective death of dopaminergic neurons, thereby leading to cognitive and motor impairment in patients. The disease has no complete cure yet: the current therapeutic strategies involve prescription of dopamine agonist drugs which turn ineffective after prolonged use. The present study utilized the powerful genetics of model system Caenorhabditis elegans towards exploring the anti-Parkinsonian effects of a neuroprotective botanical Bacopa monnieri. Two different strains of C elegans; a transgenic model expressing "human" alpha synuclein [NL5901 (P(unc)-54::alphasynuclein::YFP+unc-119)], and a pharmacological model expressing green fluorescent protein (GFP) specifically in the dopaminergic neurons [BZ555 (P(dat-1)::GFP)] treated with selective catecholaminergic neurotoxin 6-hydroxy dopamine (6-OHDA), were employed for the study. B. monnieri was chosen for its known neuroprotective and cognition enhancing effects. The study examined the effect of the botanical, on aggregation of alpha synuclein, degeneration of dopaminergic neurons, content of lipids and longevity of the nematodes. Our studies show that B. monnieri reduces alpha synuclein aggregation, prevents dopaminergic neurodegeneration and restores the lipid content in nematodes, thereby proving its potential as a possible anti-Parkinsonian agent. These findings encourage further investigations on the botanical, and its active constituent compounds, as possible therapeutic intervention against Parkinson's disease. (C) 2011 Elsevier Inc. All rights reserved.

Kiferle L. et al. Nigral involvement and nigrostriatal dysfunction in Huntington’s disease: Evidences from an MRI and SPECT study // Parkinsonism & Related Disorders. 2013. Vol. 19, № 9. P. 800–805.

" Huntington disease (HD) is pathologically characterized by a selective neurodegeneration of vulnerable populations of neurons, with an early marked neuronal loss and atrophy in the neostriatum. Dopaminergic innervations of neostriatal neurons originate in the substantia nigra pars compacta. Few studies investigated the neuronal loss and the functional role of the substantia nigra in modulating clinical features in HD. Our results confirm that the degeneration of nigrostriatal pathway may occur in symptomatic HD patients. If confirmed by larger studies, the lack of any kind of correlation between clinical and neuropsychological features with striatal uptake and volume of substantia nigra suggests that motor and cognitive aspects in HD are not directly related to nigrostriatal degeneration."

Kim J.-M. et al. Loss of substantia nigra hyperintensity on 7 Tesla MRI of Parkinson’s disease, multiple system atrophy, and progressive supranuclear palsy // Parkinsonism & Related Disorders. 2016. Vol. 26. P. 47–54.

Background Seven Tesla (7T) MRI can visualize anatomical alterations occurring in a hyperintense structure of the substantia nigra in Parkinson's disease (PD). Objective We investigated whether 7T MRI can detect the loss of substantia nigra hyperintensity in patients with PD, multiple system atrophy (MSA), and progressive supranuclear palsy (PSP). Methods Using 7T MRI, we evaluated 26 healthy subjects, 30 patients with PD, 7 patients with MSA, and 3 patients with PSP. Two blinded readers independently assessed the images. We carried out a comparative analysis of five patients with hemiparkinsonism via 123I-2?-carbomethoxy-3?-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane (123I-FP-CIT) SPECT. Results 7T MRI revealed a definitive shape of nigral hyperintensity in healthy subjects, nearly identical to neuropathological characterization of nigrosome 1, and enabled instantaneous determination of its presence or absence in all subjects. Nigral hyperintensity was lost in all patients with PD, MSA with predominant parkinsonism, and PSP. One of five patients with MSA with predominant cerebellar ataxia showed an intact nigral hyperintensity. The side effects were mild and tolerable, and imaging was successful in patients with dyskinesia. Motion artifact incidence was higher in elderly subjects. In hemiparkinsonism cases, we observed partial loss of nigral hyperintensity on the side of less reduced 123I-FP-CIT binding, suggesting an ongoing iron deposition on the unaffected side in hemiparkinsonism. Conclusions The present findings suggest that 7T MRI represents an excellent tool for evaluating nigral hyperintensity in PD, MSA, and PSP, with tolerable side effects and limited motion artifacts. Thus, imaging of parkinsonism may benefit from using 7T MRI.

Ko J.H., Strafella A.P. Dopaminergic Neurotransmission in the Human Brain: New Lessons from Perturbation and Imaging // Neuroscientist. 2012. Vol. 18, № 2. P. 149–168.

Dopamine plays an important role in several brain functions and is involved in the pathogenesis of several psychiatric and neurological disorders. Neuroimaging techniques such as positron emission tomography allow us to quantify dopaminergic activity in the living human brain. Combining these with brain stimulation techniques offers us the unique opportunity to tackle questions regarding region-specific neurochemical activity. Such studies may aid clinicians and scientists to disentangle neural circuitries within the human brain and thereby help them to understand the underlying mechanisms of a given function in relation to brain diseases. Furthermore, it may also aid the development of alternative treatment approaches for various neurological and psychiatric conditions.

Lee H.J., Lee K., Im H. ?-Synuclein modulates neurite outgrowth by interacting with SPTBN1 // Biochemical and Biophysical Research Communications. 2012. Vol. 424, № 3. P. 497–502.

?-Synuclein is the major component of Lewy bodies and Lewy neurites, the pathological hallmarks of surviving neuronal cells in Parkinson’s disease patients. However, the physiological role played by ?-synuclein remains unclear. In this study, spectrin beta non-erythrocyte 1 (SPTBN1) interacted with ?-synuclein in phage display assays using a normalized human brain cDNA library. A direct interaction between ?-synuclein and SPTBN1 was confirmed by GST pull-down and co-immunoprecipitation assays. SPTBN1 and ?-synuclein proteins colocalized in N2a neuronal cells. Transfection of SPTBN1 caused human SH-SY5Y dopaminergic neuron cells to inappropriately induce neurites, which extended from cell bodies. Cotransfection with ?-synuclein reversed SPTBN1-induced excessive neurite branching in SH-SY5Y cells, and only a single neurite extended from each neuron. These results suggest that ?-synuclein modulates neurite outgrowth by interacting with cytoskeletal proteins such as SPTBN1.

Louis E.D. Re-thinking the biology of essential tremor: From models to morphology // Parkinsonism & Related Disorders. 2014. Vol. 20, Supplement 1. P. S88–S93.

Remarkably little has been written on the biology of essential tremor (ET), despite its high prevalence. The traditional pathophysiological model for ET, the olivary model, states that ET is a primary electrical//electrophysiological entity, the result of pacemaking neurons in the inferior olivary nucleus that begin firing in a coupled and rhythmic manner, and thus, through an abnormal olivo-cerebellar output, produce tremor. Though this model is based on several sound neurophysiological observations, there are major problems as well. Despite its shortcomings, however, the model persists. With the traditional focus in ET on clinical neurophysiology, there has been little research on pathological anatomy, cell biology, and molecular mechanisms, and over the years, there have been few alternatives to the olivary model. However, rigorous tissue-based studies have recently identified a series of structural changes in the ET brain, most of which are centered on the Purkinje cell and connected neuronal populations, and which may involve a partial loss of Purkinje cells. An implication of these newer studies is that ET could be degenerative. This shift in paradigm opens the door for research that aims to identify the primary set of molecular triggers and the cascade of molecular/cellular events that accompany this disease.

Luchetti S., Huitinga I., Swaab D.F. Neurosteroid and Gaba-a Receptor Alterations in Alzheimer’s Disease, Parkinson’s Disease and Multiple Sclerosis // Neuroscience. 2011. Vol. 191. P. 6–21.

Steroid hormones (e.g. estrogens, androgens, progestagens) which are synthesized de novo or metabolized within the CNS are called neurosteroids. There is substantial evidence from animal studies suggesting that these steroids can affect brain function by modulating neurotransmission, and influence neuronal survival, neuronal and glial differentiation and myelination in the CNS by regulating gene expression of neurotrophic factors and anti-inflammatory molecules. Indeed, evidence is emerging that expression of the enzymes responsible for the synthesis of neurosteroids changes in neurodegenerative diseases. Some of these changes may contribute to the pathology, while others, conversely, may represent an attempted rescue program in the diseased brain. Here we review the data on changes in neurosteroid levels and neurosteroid synthesis pathways in the human brain in three neurodegenerative conditions, Alzheimers's (AD) and Parkinson's (PD) diseases and Multiple Sclerosis (MS) and the extent to which these findings may implicate protective or pathological roles for neurosteroids in the course of these diseases. Some neurosteroids can modulate neurotransmitter activity, for example, the pregnane steroids allopregnanolone and 3 alpha 5 alpha-tetrahydro-deoxycorticosterone which are potent positive allosteric modulators of ionotropic GABA-A receptors. Therefore, neurosteroid-modulated GABA-A receptor subunit alterations found in AD and PD will also be discussed. These data imply an involvement of neurosteroid changes in the neurodegenerative and neuroinflammatory processes and suggest that they may deserve further investigation as potential therapeutic agents in AD, PD and MS. Finally, suggestions for therapeutic strategies will be included. This article is part of a Special Issue entitled: Neuroactive Steroids: Focus on Human Brain. (C) 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

Luna E., Luk K.C. Bent out of shape: alpha-Synuclein misfolding and the convergence of pathogenic pathways in Parkinson’s disease // Febs Letters. 2015. Vol. 589, № 24. P. 3749–3759.

Protein inclusions made up primarily of misfolded alpha-synuclein (alpha-Syn) are the hallmark of a set of disorders known as synucleinopathies, most notably Parkinson's disease (PD). It is becoming increasingly appreciated that alpha-Syn misfolding can spread to anatomically connected regions in a prion-like manner. The protein aggregates that ensue are correlated with neurodegeneration in the various yet select neuronal populations that are affected. Recent advances have begun to shed light on the spreading and toxicity mechanisms that may be occurring in PD. Several key emerging themes are arising from this work suggesting that alpha-Syn mediated neurodegeneration is due to a combination of relative alpha-Syn expression level, connectivity to affected brain regions, and intrinsic vulnerability to pathology.

Marchetti B. et al. Nigrostriatal degeneration dictates a top-down genetic program for neuroplasticity and neurorepair: Focus on the hippocampus and Wnt/GSK-3?/?-catenin signaling cascade // Parkinsonism & Related Disorders. 2016. Vol. 22, Supplement 2. P. e183–e184.

These results highlight the key role of Wnt/?-catenin signaling in DG adaptive response to nigrostriatal DA degeneration.

Mehta S.H., Adler C.H. Advances in Biomarker Research in Parkinson’s Disease // Current Neurology and Neuroscience Reports. 2016. Vol. 16, № 1. P. 7.

Parkinson's disease (PD) is the second most common neurodegenerative disease, and the numbers are projected to double in the next two decades with the increase in the aging population. An important focus of current research is to develop interventions to slow the progression of the disease. However, prerequisites to it include the development of reliable biomarkers for early diagnosis which would identify at-risk groups and disease progression. In this review, we present updated evidence of already known clinical biomarkers (such as hyposmia and rapid eye movement (REM) sleep behavior disorder (RBD)) and neuroimaging biomarkers, as well as newer possible markers in the blood, CSF, and other tissues. While several promising candidates and methods to assess these biomarkers are on the horizon, it is becoming increasingly clear that no one candidate will clearly fulfill all the roles as a single biomarker. A multimodal and combinatorial approach to develop a battery of biomarkers will likely be necessary in the future.

Odagiri S. et al. Brain expression level and activity of HDAC6 protein in neurodegenerative dementia // Biochem. Biophys. Res. Commun. 2013. Vol. 430, № 1. P. 394–399.

Histone deacetylase 6 (HDAC6) is a multifunctional cytoplasmic protein that plays an especially critical role in the formation of aggresomes, where aggregates of excess protein are deposited. Previous immunohistochemical studies have shown that HDAC6 accumulates in Lewy bodies in Parkinson's disease and dementia with Lewy bodies (DLB) as well as in glial cytoplasmic inclusions in multiple system atrophy (MSA). However, it is uncertain whether the level and activity of HDAC6 are altered in the brains of patients with neurodegenerative dementia. In the present study, we demonstrated that the level of HDAC6 was not altered in the temporal cortex of patients with Alzheimer's disease and DLB in comparison with controls. In contrast, the level of HDAC6 was significantly increased in the temporal cortex of patients with frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) and in the cerebellar white matter of patients with MSA. However, the level of acetylated alpha-tubulin, one of the substrates of HDAC6, was not altered in FTLD-TDP and MSA relative to controls. These findings suggest that the induced level of HDAC6 in the brain is insufficient for manifestation of its activity in FTLD-TDP and MSA. (C) 2012 Elsevier Inc. All rights reserved.

Ohta E. et al. Dominant-negative effects of LRRK2 heterodimers: A possible mechanism of neurodegeneration in Parkinson’s disease caused by LRRK2 I2020T mutation // Biochemical and Biophysical Research Communications. 2013. Vol. 430, № 2. P. 560–566.

Leucine-rich repeat kinase 2 (LRRK2) is the molecule responsible for autosomal-dominant Parkinson’s disease (PD), PARK8, but the etiologic effects of its mutation remain unknown. In the present study, we investigated a novel mechanism for the neurodegeneration induced by I2020T mutant LRRK2. Using native gel electrophoresis and immunoprecipitation, we found that wild-type (WT) LRRK2 formed a heterodimer with I2020T LRRK2 in transfected cells, and that the heterodimer exhibited a markedly lower intracellular protein level than the WT/WT-homodimer. An increased amount of I2020T LRRK2 decreased the protein level of co-transfected WT LRRK2. A pulse-chase experiment revealed that the intracellular protein lifetime of WT LRRK2 was shortened by co-transfection with I2020T LRRK2. These results suggest that I2020T LRRK2 enhances the intracellular degradation of WT LRRK2 through WT/I2020T-heterodimer formation. Overexpression of WT LRRK2 in HEK293 cells increased the phosphorylation level of Akt1 (S473), a possible physiological substrate of LRRK2, and made cells resistant to hydrogen peroxide-induced apoptosis. However, both Akt1 phosphorylation and apoptosis resistance were reduced in WT/I2020T-expressing cells in comparison with WT/WT-expressing cells. Reduction of Akt1 phosphorylation and apoptosis resistance were also evident when a neuroblastoma SH-SY5Y clone overexpressing WT LRRK2 was transfected with the I2020T LRRK2. Altogether, these results suggest that the I2020T mutation enhances the intracellular degradation of LRRK2 through WT/I2020T-heterodimer formation, leading to reduced Akt1 phosphorylation and diminished protectivity against apoptosis. Our findings suggest the possibility of a dominant-negative mechanism of neurodegeneration in PD caused by I2020T LRRK2 mutation.

Okatsu K. et al. Mitochondrial hexokinase HKI is a novel substrate of the Parkin ubiquitin ligase // Biochemical and Biophysical Research Communications. 2012. Vol. 428, № 1. P. 197–202.

Dysfunction of Parkin, a RING-IBR-RING motif containing protein, causes autosomal recessive familial Parkinsonism. Biochemically, Parkin is a ubiquitin-ligating enzyme (E3) that catalyzes ubiquitin transfer from ubiquitin-activating and -conjugating enzymes (E1/E2) to a substrate. Recent studies have revealed that Parkin localizes in the cytoplasm and its E3 activity is repressed under steady-state conditions. In contrast, Parkin moves to mitochondria with low membrane potential, thereby activating the latent enzymatic activity of the protein, which in turn triggers Parkin-mediated ubiquitylation of numerous mitochondrial substrates. However, the mechanism of how Parkin-catalyzed ubiquitylation maintains mitochondrial integrity has yet to be determined. To begin to address this, we screened for novel Parkin substrate(s) and identified mitochondrial hexokinase I (HKI) as a candidate. Following a decrease in membrane potential, Parkin ubiquitylation of HKI leads to its proteasomal degradation. Moreover, most disease-relevant mutations of Parkin hinder this event and endogenous HKI is ubiquitylated upon dissipation of mitochondrial membrane potential in genuine-Parkin expressing cells, suggesting its physiological importance.

Rangel-Barajas C., Coronel I., Floran B. Dopamine Receptors and Neurodegeneration // Aging Dis. 2015. Vol. 6, № 5. P. 349–368.

Dopamine (DA) is one of the major neurotransmitters and participates in a number of functions such as motor coordination, emotions, memory, reward mechanism, neuroendocrine regulation etc. DA exerts its effects through five DA receptors that are subdivided in 2 families: D1-like DA receptors (D-1 and D-5) and the D-2-like (D-2, D-3 and D-4). All DA receptors are widely expressed in the central nervous system (CNS) and play an important role in not only in physiological conditions but also pathological scenarios. Abnormalities in the DAergic system and its receptors in the basal ganglia structures are the basis Parkinson's disease (PD), however DA also participates in other neurodegenerative disorders such as Huntington disease (HD) and multiple sclerosis (MS). Under pathological conditions reorganization of DAergic system has been observed and most of the times, those changes occur as a mechanism of compensation, but in some cases contributes to worsening the alterations. Here we review the changes that occur on DA transmission and DA receptors (DARs) at both levels expression and signals transduction pathways as a result of neurotoxicity, inflammation and in neurodegenerative processes. The better understanding of the role of DA receptors in neuropathological conditions is crucial for development of novel therapeutic approaches to treat alterations related to neurodegenerative diseases.

Shook B.C. et al. In Vivo Characterization of a Dual Adenosine A(2A)/A(1) Receptor Antagonist in Animal Models of Parkinson’s Disease // J. Med. Chem. 2010. Vol. 53, № 22. P. 8104–8115.

The in vivo characterization of a dual adenosine A(2A)/A(1) I receptor antagonist in several animal models of Parkinson's disease is described. Discovery and scale-up syntheses of compound 1 are described in detail, highlighting optimization steps that increased the overall yield of I from 10.0% to 30.5%. Compound 1 is a potent A(2A)/A(1) receptor antagonist in vitro (A(2A) K-i = 4.1 nM A(1) K-i = 17.0 nM) that has excellent activity, after oral administration, across a number of animal models of Parkinson's disease including mouse and rat models of haloperidol-induced catalepsy, mouse model of reserpine-induced akinesia, rat 6-hydroxydopamine (6-OHDA) lesion model of drug-induced rotation, and MPTP-treated non-human primate model.

Soto-Ortolaza A.I., Ross O.A. Genetic susceptibility variants in parkinsonism // Parkinsonism & Related Disorders. 2016. Vol. 22, Supplement 1. P. S7–S11.

Parkinsonism is an umbrella term for a group of disorders characterized by the clinical signs of tremor, bradykinesia, rigidity, and postural instability. On neuropathologic examination parkinsonism can display alternate protein pathologies (e.g. ?-synucleinopathy or tauopathy) but the degeneration of nigral neurons is consistent. The main forms of parkinsonism are, Parkinson's disease (PD), Dementia with Lewy Bodies (DLB), Multiple System Atrophy (MSA), Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD). Genetic studies from candidate gene, to unbiased genome-wide approaches including association and next-generation sequencing have nominated a number of disease determinants. Within this review we will highlight the genetic loci that are associated with disease and discuss the implications and importance for a better understanding of the genes involved and thus the underlying pathophysiology of these disorders.

Surendranathan A., Rowe J.B., O’Brien J.T. Neuroinflammation in Lewy body dementia // Parkinsonism & Related Disorders. 2015. Vol. 21, № 12. P. 1398–1406.

Neuroinflammation is increasingly recognized as a key factor in the pathogenesis of neurodegenerative conditions. However, it remains unclear whether it has a protective or damaging role. Studies of Alzheimer's disease and Parkinson's disease have provided much of the evidence for inflammatory pathology in neurodegeneration. Here we review the evidence for inflammation in dementia with Lewy bodies and Parkinson's disease dementia. Neuroinflammation has been confirmed in vivo using PET imaging, with microglial activation seen in Parkinson's disease dementia and recently in dementia with Lewy bodies. In Parkinson's disease and Parkinson's disease dementia, microglial activation suggests a chronic inflammatory process, although there is also evidence of its association with cognitive ability and neuronal function. Alpha-synuclein in various conformations has also been linked to activation of microglia, with a broad range of components of the innate and adaptive immune systems associated with this interaction. Evidence of neuroinflammation in Lewy body dementia is further supported by pathological and biomarker studies. Genetic and epidemiological studies support a role for inflammation in Parkinson's disease, but have yet to provide the same for Lewy body dementia. This review highlights the need to identify whether the nature and extent of microglial activation in Lewy body dementia can be linked to structural change, progression of domain specific cognitive symptoms and peripheral inflammation as a marker of central microglial pathology. Answers to these questions will enable the evaluation of immunotherapies as potential therapeutic options for prevention or treatment of dementia with Lewy bodies and Parkinson's disease dementia.

Ueda Y. et al. Effect of zonisamide co-administration with levodopa on global gene expression in the striata of rats with Parkinson’s disease // Biochemical and Biophysical Research Communications. 2012. Vol. 428, № 3. P. 401–404.

The anti-epileptic drug zonisamide is reported to exert beneficial effects in patients with Parkinson’s disease. To elucidate the pathophysiological mechanisms underlying the anti-parkinsonism effects of zonisamide, we examined the effect of zonisamide co-administered with levodopa in the striata of rats with 6-hydoroxydopamine hemiparkinsonism by using a DNA microarray for genome-wide gene expression profiling. We found that the expression of some genes related to metabolism and nervous system development and function were upregulated by zonisamide; expression of these genes was downregulated by levodopa. Furthermore, many genes related to the immune system and inflammation were downregulated by zonisamide, and their expression was upregulated by levodopa. These results indicate that zonisamide has a protective effect when co-administered with levodopa.

Vyas S. et al. Chronic Stress and Glucocorticoids: From Neuronal Plasticity to Neurodegeneration // Neural. Plast. 2016. P. 6391686.

Stress and stress hormones, glucocorticoids (GCs), exert widespread actions in central nervous system, ranging from the regulation of gene transcription, cellular signaling, modulation of synaptic structure, and transmission and glial function to behavior. Their actions are mediated by glucocorticoid and mineralocorticoid receptors which are nuclear receptors/transcription factors. While GCs primarily act to maintain homeostasis by inducing physiological and behavioral adaptation, prolonged exposure to stress and elevated GC levels may result in neuro- and psychopathology. There is now ample evidence for cause-effect relationships between prolonged stress, elevated GC levels, and cognitive and mood disorders while the evidence for a link between chronic stress/GC and neurodegenerative disorders such as Alzheimer's (AD) and Parkinson's (PD) diseases is growing. This brief review considers some of the cellular mechanisms through which stress and GC may contribute to the pathogenesis of AD and PD.

Wang Y. et al. Changes in firing rate and pattern of GABAergic neurons in subregions of the substantia nigra pars reticulata in rat models of Parkinson’s disease // Brain Res. 2010. Vol. 1324. P. 54–63.

The substantia nigra pars reticulata (SNr) plays a key role in the pathophysiology of Parkinson's disease (PD). It has been well documented that the SNr is not a homogeneous structure, and the lateral and medial subregions of the SNr receive different projections from the sensorimotor and limbic striatum, respectively. However, specific changes in firing activity of SNr subregions in PD remain unclear. In the present study, the spontaneous firing activity of GABAergic neurons in the lateral and medial SNr of rats with unilateral 6-hydroxydopamine lesions of the substantia nigra pars compacta (SNc) or medial forebrain bundle (MFB) has been examined. Extracellular recordings indicated that the firing rate of lateral SNr neurons increased significantly and firing pattern of these neurons changed towards more irregular and bursty after SNc or MFB lesions compared to normal rats. In contrast, the firing rate and pattern of medial SNr neurons in rats with SNc lesions were unaltered when compared with that of normal rats. However, MFB lesions in rats decreased the firing rate of medial SNr neurons and firing pattern of these neurons changed towards more bursty. In addition, SNc lesions in rats increased the firing rate of the neurons with regular and irregular firing patterns within lateral but not in medial SNr, while the firing rate of the neurons within lateral and medial SNr with each firing pattern was not altered after MFB lesions. These results suggest that GABAergic neurons of SNr subregions have differential change of firing activity in the pathophysiology of PD. (C) 2010 Elsevier B.V. All rights reserved.

Wight R.D. et al. Resveratrol effects on astrocyte function: Relevance to neurodegenerative diseases // Biochem. Biophys. Res. Commun. 2012. Vol. 426, № 1. P. 112–115.

Inflammatory molecules have been implicated in the pathogenesis of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and multiple sclerosis. Resveratrol is an anti-fungal compound found in the skins of red grapes and other fruits and nuts. We examined the ability of resveratrol to inhibit lipopolysaccharide (LPS)-induced production of inflammatory molecules from primary mouse astrocytes. Resveratrol inhibited LPS-induced production of nitric oxide (NO); the cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin 1-beta (IL-1 beta), and IL-6; and the chemokine monocyte chemotactic protein-1 (MCP-1), which play critical roles in innate immunity, by astrocytes. Resveratrol also suppressed astrocyte production of IL-12p40 and IL-23, which are known to alter the phenotype of T cells involved in adaptive immunity. Finally resveratrol inhibited astrocyte production of C-reactive protein (CRP), which plays a role in a variety of chronic inflammatory disorders. Collectively, these studies suggest that resveratrol may be an effective therapeutic agent in neurodegenerative diseases initiated or maintained by inflammatory processes. (C) 2012 Elsevier Inc. All rights reserved.

Zhang A. et al. Genetic analysis of SIRT1 gene promoter in sporadic Parkinson’s disease // Biochem. Biophys. Res. Commun. 2012. Vol. 422, № 4. P. 693–696.

Parkinson's disease (PD) is one of the most common neurodegenerative diseases. To date, genetic causes and underlying molecular mechanisms for sporadic PD remain largely unknown. Sirtuis are highly conserved NAD-dependent class III deacetylases. SIRT1, the closest to yeast Sir2, has deacetylase activity and ADP-ribosyltransferase activity. SIRT1 gene has been connected to many cellular processes and implicated in human diseases, such as obesity, type 2 diabetes, cancer and neurodegenerative diseases. Studies in animal model have also associated SIRT1 with aggregation of alpha-synuclein, a critical protein in the PD pathogenesis. We hypothesized that the genetic variants within the regulatory regions of SIRT1 gene that repress its gene expression, rather than mutations in its coding region that abolish SIRT1 function, may contribute to PD as a risk factor. In this study, we genetically analyzed the promoter region of SIRT1 gene in sporadic PD patients and ethic-matched healthy controls. Three novel heterozygous sequence variants, g.69644133C > G, g.69644213G > A and g.69644351G > A, were identified in PD patients, but in none of controls, which may alter the transcriptional activities of SIRT1 gene promoter, resulting in reduced SIRT1 levels. One novel heterozygous variant, g.69644219G > A, linked with single-nucleotide polymorphism - g.69644217A > C (rs932658), was only found in one control, which may have no functional activity. Therefore, our results suggested that genetic variants within the SIRT1 gene promoter may repress SIRT1 gene expression, contributing to PD as a risk factor. (C) 2012 Elsevier Inc. All rights reserved.

Zhang J. et al. Characterizing iron deposition in Parkinson’s disease using susceptibility-weighted imaging: An in vivo MR study // Brain Res. 2010. Vol. 1330. P. 124–130.

Brain-iron deposition has been proposed to play an important role in the pathophysiology of Parkinson's disease (PD). The aim of this study was to evaluate the feasibility of characterizing iron deposition in PD using susceptibility-weighted imaging (SWI), and to investigate the correlation of brain-iron accumulation with the clinical status in patients with PD. Forty patients with PD without dementia and 26 age- and sex-matched healthy controls underwent high-resolution susceptibility-weighted magnetic resonance (MR) imaging. The phase shift values of the bilateral red nucleus (RN), substantia nigra (SN), caudate nucleus (CA), globus pallidus (GP), putamen (PU), thalamus (TH) and frontal white matter (FWM) were examined for their relationship with the clinical status. The iron concentrations of the regions involved in PD, such as the SN, increased more significantly, while those in other regions of interest (ROI) did not elevate significantly. No correlation between the increase of the iron concentrations of the SN and duration of PD was observed. PD, however, was closely associated with the Unified Parkinson's Disease Rating Scale motor score (UPDRS-III). No significant differences were found between earlier-onset and later-onset PD patients in terms of the iron concentrations of the SN. Brain-iron concentration can be evaluated by SWI. Also, the brain-iron concentration in the SN correlated with UPDRS motor score, indicating that iron concentration can function as an in vivo biomarker to objectively evaluate the status of PD. (C) 2010 Elsevier B.V. All rights reserved.

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