Substantia Nigra Pars Compacta Region Research Articles

Microstructural abnormalities of substantia nigra in Parkinson's disease: A neuromelanin sensitive MRI atlas based study.

Microstructural changes associated with degeneration of dopaminergic neurons of the substantia nigra pars compacta (SNc) in Parkinson's disease (PD) have been studied using Diffusion Tensor Imaging (DTI). However, these studies show inconsistent results, mainly due to methodological variations in delineation of SNc. To mitigate this, our work aims to construct a probabilistic atlas of SNc based on a 3D Neuromelanin Sensitive MRI (NMS‐MRI) sequence and demonstrate its applicability to investigate microstructural changes on a large dataset of PD. Using manual segmentation and deformable registration we created a novel SNc atlas in the MNI space using NMS‐MRI sequences of 27 healthy controls (HC). We first quantitatively evaluated this atlas and then employed it to investigate the micro‐structural abnormalities in SNc using diffusion MRI from 133 patients with PD and 99 HCs. Our results demonstrated significant increase in diffusivity with no changes in anisotropy. In addition, we also observed an asymmetry of the diffusion metrics with a higher diffusivity and lower anisotropy in the left SNc than the right. Finally, a multivariate classifier based on SNc diffusion features could delineate patients with PD with an average accuracy of 71.7%. Overall, from this work we establish a normative baseline for the SNc region of interest using NMS‐MRI while the application on PD data emphasizes on the contribution of diffusivity measures rather than anisotropy of white matter in PD.

Iron Redox Chemistry and Implications in the Parkinson's Disease Brain.

The etiology of Parkinson's disease (PD) is linked with cellular inclusions in the substantia nigra pars compacta region of the brain that are enriched in the misfolded presynaptic protein α-synuclein (αS) and death of the dopaminergic neurons. Brain iron homeostasis governs both neurotransmission and neurodegeneration; hence, the role of iron in PD progression and neuronal health is apparent. Elevated iron deposits become prevalent in the cerebral region upon aging and even more so in the PD brain. Structural as well as oxidative modifications can result from coordination of αS with redox active iron, which could have functional and/or pathological implications. In this review, we will discuss iron-mediated αS aggregation, alterations in iron metabolism, and the role of the iron-dopamine couple. Moreover, iron interactions with N-terminally acetylated αS, the physiologically relevant form of the human protein, will be addressed to shed light on the current understanding of protein dynamics and the physiological environment in the disease state. Oxidative pathways and biochemical alterations resulting from aberrant iron-induced chemistry are the principal focus of this review in order to highlight the plethora of research that has uncovered this emerging dichotomy of iron playing both functional and disruptive roles in PD pathology.

Magnesium-Induced Cell Survival Is Dependent on TRPM7 Expression and Function

Mg2+ homeostasis is essential for cell survival and the loss of this regulation has been associated with many neurodegenerative diseases, including loss of dopaminergic neurons. Although the neurotoxin-mediated loss of dopaminergic neurons in Parkinson disease models is extensively studied, the ion channel(s) that regulate Mg2+ homeostasis and thus could prevent neuronal cell death is not yet identified. Here, we show that TRPM7 (transient receptor potential melastatin 7) is involved in regulating Mg2+ homeostasis in dopaminergic cells. Importantly, transient loss of TRPM7 decreased intracellular Mg2+ levels and decreased dopaminergic cells/neurons survival. We provide further evidence that both increases in extracellular Mg2+ or transiently increasing TRPM7 levels protected dopaminergic SH-SY5Y cells against neurotoxin-mediated cell death. Neurotoxin treatment significantly decreased TRPM7 levels in both SH-SY5Y cells and the substantia nigra pars compacta region of mice, along with a decrease in Mg2+ influx. Moreover, Mg2+ supplementation showed a concentration-dependent decrease in caspase-3 activity, an increase in cell survival, restored mitochondrial membrane potential, and increase TRPM7 levels in neurotoxin-treated cells. In contrast, transient silencing of TRPM7 inhibited the positive effect of Mg2+ supplementation in protecting against neurotoxins. Whereas, TRPM7 overexpression not only maintained Mg2+ homeostasis but also inhibited caspase 3 activity that induced cell survival. Overall, these results suggest a significant role of TRPM7 channels in Mg2+ homeostasis and the survival of neurotoxin-induced loss of dopaminergic cells.

An injectable conductive Gelatin-PANI hydrogel system serves as a promising carrier to deliver BMSCs for Parkinson's disease treatment

Parkinson's disease (PD) is a long-term neurodegenerative disorders that characterized by a progressive loss of dopaminergic neurons in substantia nigra pars compacta (SNc). Bone marrow stromal cells (BMSCs) are promising therapeutic agents for neurodegenerative disease due to their multipotent capacity. To promote the potential therapeutic effect of BMSCs on PD, we developed an injectable Gelatin-PANI hydrogels as a novel carrier for delivering BMSCs to the SNc region in mice with PD by stereotactic injection. Histology results showed that the BMSCs-loaded hydrogels lead to increased numbers of tyrosine hydroxylase positive (TH+) dopaminergic neurons and fibers in the SNc and striatum, and increased expression of brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF) in the SNc. Meanwhile, rotarod and open field evaluation demonstrated BMSCs-loaded hydrogels significantly improved the behavioral performance of PD mice. Importantly, BMSCs-loaded hydrogels imparted more sustained protective effects than BMSCs alone in PD mice. Overall, the current data indicate that the hydrogel serves as a promising carrier to deliver BMSCs to the SNc for the treatment of PD.

(-)-Epigallocatechin-3-gallate modulates peripheral immunity in the MPTP-induced mouse model of Parkinson's disease.

(−)-Epigallocatechin-3-gallate (EGCG) is the most widely studied catechin in green tea and has been identified to regulate immune function. The objective of the present study was to explore the possible application of EGCG in the treatment of Parkinson's disease (PD) by examining its effects on the peripheral immune system in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model. The results demonstrated that EGCG treatment restored the movement behavior of the mice impaired by MPTP, and protected tyrosine hydroxylase-positive cells in the substantia nigra pars compacta region from MPTP toxicity. Flow cytometric analysis indicated that the ratio of CD3+CD4+ to CD3+CD8+ T lymphocytes in the peripheral blood increased in MPTP-treated mice following treatment with EGCG, and EGCG reduced expression of inflammatory factors tumor necrosis factor-α and interleukin-6 in serum. The present findings indicated that EGCG serves neuroprotective effects in an MPTP-induced PD mice model and may exert this through modulating peripheral immune response.

Medicinal Plants as Protective Strategies Against Parkinson's Disease.

Parkinson's disease is a neurodegenerative disease caused by the loss of dopaminergic neurons in the substantia nigra pars compacta region. An important mechanism contributing to its development is oxidative stress, induced by the imbalance between the endogenous antioxidant defenses and free radicals production. Naturally occurring bioactive compounds exhibit high antioxidant capacity that may help reducing oxidative stress and even reverse the damage induced by ROS. Fruits are particularly rich in phytochemicals with antioxidant effect, and their properties against the development of neurodegenerative diseases are of great interest. This review discusses how the fruits bioactive compounds and synthetic analogs have been assessed for their ability to regulate molecular pathways involved in neuronal survival such as MAPK, Nrf2, and NF-κB, thus elucidating the possible therapeutic and neuroprotective actions of these compounds.

Gender and age-related differences in morphometric characteristics of neurons in human brain substantia nigra

Introduction. Age-related morphological changes in the brain and those taking place in Parkinson disease (PD) are similar in their nature but differ in intensity. Quantitative evaluation of the neurons’ characteristics in substantia nigra pars compacta (SNc) in men and women during aging will allow to use obtained values as a reference while studying PD. Objective: to study gender- and age-related morphometric characteristics of neurons in SNc of the human brain. Materials and methods. Morphometric evaluation of SNc neurons in autopsy human brain specimens (n=12) of normal aging men and women (aged 52–87 years) was performed. The sections were stained with cresyl violet and for thyrosine hydroxylase (dopamine marker). A total number of neurons and number of dopaminergic neurons in particular in ventral and dorsal regions of SNc were counted; cellular and nuclear size was also estimated. Results. In the aging brain, the most pronounced morphological changes occur in the medial, lateral, and intermediate segments of the ventral region of SNc. In the medial segment, the overall neuronal density was decreased by 33%, while in the lateral and intermediate segments of the ventral region of SNc it was decreased by 23%. In the medial and in the lateral and intermediate segments, density of the dopaminergic neurons was decreased by 28% and 24% respectively. Survived neurons showed increased cellular size and reduced nuclear size. In women, basic morphometric characteristics of neurons in the lateral and intermediate segments of the ventral region of SNc were higher than in men. Conclusions. In normal aging, involution of the brain structures in SNc is more pronounced in its ventral region. Interestingly, involution occurs more slowly in a female brain than in a male brain.

Association of freezing of gait with nigral iron accumulation in patients with Parkinson's disease

Background and purposeThe objective of this work was to investigate whether patients with and without freezing of gait (FOG) in Parkinson's disease (PD) have differences in iron accumulation in substantia nigra using R2* relaxometry. Materials and methodsThis study included seventeen PD patients with FOG [FOG (+)], equal number of age and gender matched patients without FOG [FOG (−)] and 34 healthy controls (HC). T2* images were obtained from a 3-Tesla MRI system using multi-echo sequence. R2* values were extracted from Substantia Nigra (SN) and red nucleus and were compared among the three groups and correlated with clinical findings. ResultsR2* values were increased in PD group as a whole compared to HC in rostral and caudal segments of Substantia Nigra pars compacta (SNc) and in Substantia Nigra pars reticulata (SNr) but not in red nucleus. Within PD subgroups, FOG (+) group had increased iron accumulation in SNc compared to FOG (−) and HC. FOG score positively correlated with R2* values in the caudal region of SNc in FOG (+) group. ConclusionsOur study reveals higher nigral iron content in FOG (+) compared to FOG (−) and HCs. In addition, we observed positive correlation of FOG score with iron accumulation in SNc. Results of this study emphasize possible role of higher nigral iron content in the pathogenesis of FOG in PD.

Molecular mechanism of JNK attenuation by parkin

Parkinson's disease (PD) is characterized by the disappearing pigmentation, accumulation of lewy bodies, and the ultimate degeneration of neurons in the substantia nigra pars compacta region of the brain. The most prevalent indication of hereditary PD is a mutation in the PARKIN gene. Parkin facilitates the proteasomal degradation of target proteins through its ubiquitination‐catalyzing activity. The E3 ubiquitin ligase has been further implicated in attenuating the activation of the c‐jun N‐terminal kinase (JNK) pathway, a pro‐apoptotic mitogen‐activated protein kinase (MAPK) signaling cascade, implying neuroprotective characteristics. However, the mechanism whereby parkin regulates the JNK pathway remains obscure. Utilizing in vitro pull‐down assays in tandem with co‐immunoprecipitation methods, we have identified a novel interaction between parkin and apoptosis signal‐regulating kinase (ASK‐1), an upstream kinase in the JNK pathway. This interaction was characterized through co‐overexpression in HEK293T cells, which indicated the parkin‐induced degradation of ASK1. In vitro ubiquitination assays showed an enhanced activation of parkin in the presence of ASK1. Our results suggest the interaction with ASK1 is able to disrupt the intrinsic auto‐inhibition of parkin, enhancing its activation to carry out the ubiquitin‐signaled degradation of ASK1.Support or Funding InformationTennessee Technological University Chemistry Department Student Research Grant

Activin A Inhibits MPTP and LPS-Induced Increases in Inflammatory Cell Populations and Loss of Dopamine Neurons in the Mouse Midbrain In Vivo.

Parkinson’s disease is a chronic neurodegenerative disease characterized by a significant loss of dopaminergic neurons within the substantia nigra pars compacta region and a subsequent loss of dopamine within the striatum. A promising avenue of research has been the administration of growth factors to promote the survival of remaining midbrain neurons, although the mechanism by which they provide neuroprotection is not understood. Activin A, a member of the transforming growth factor β superfamily, has been shown to be a potent anti-inflammatory following acute brain injury and has been demonstrated to play a role in the neuroprotection of midbrain neurons against MPP+-induced degeneration in vitro. We hypothesized that activin A may offer similar anti-inflammatory and neuroprotective effects in in vivo mouse models of Parkinson’s disease. We found that activin A significantly attenuated the inflammatory response induced by both MPTP and intranigral administration of lipopolysaccharide in C57BL/6 mice. We found that administration of activin A promoted survival of dopaminergic and total neuron populations in the pars compacta region both 8 days and 8 weeks after MPTP-induced degeneration. Surprisingly, no corresponding protection of striatal dopamine levels was found. Furthermore, activin A failed to protect against loss of striatal dopamine transporter expression in the striatum, suggesting the neuroprotective action of activin A may be localized to the substantia nigra. Together, these results provide the first evidence that activin A exerts potent neuroprotection and anti-inflammatory effects in the MPTP and lipopolysaccharide mouse models of Parkinson’s disease.

Differential spread of anoxic depolarization contributes to the pattern of neuronal injury after oxygen and glucose deprivation (OGD) in the Substantia Nigra in rat brain slices

Anoxic depolarization (AD) is an acute event evoked by brain ischemia, involving a profound loss of cell membrane potential and swelling that spreads over susceptible parts of the gray matter. Its occurrence is a strong predictor of the severity of neuronal injury. Little is known about this event in the Substantia Nigra, a midbrain nucleus critical for motor control. We tested the effects of oxygen and glucose deprivation (OGD), an in vitro model of brain ischemia, in rat midbrain slices. AD developed within 4min from OGD onset and spread in the Substantia Nigra pars reticulata (SNr), but not through the Substantia Nigra pars compacta (SNc). This differential effect involved a contrasting pattern of changes in membrane potential between dopamine-producing SNc and non-dopaminergic SNr neurons. A fast depolarization in SNr neurons was not followed by repolarization after the end of OGD, and was associated with swollen somata and beaded dendrites. In contrast, slowly developing depolarization of SNc neurons led to repolarization after OGD ended, and no changes in neuronal morphology were observed. The AD-resistance of the SNc involved smaller dysregulations of K+ and Ca2+ ions, and a slower loss of energy metabolites. Our results show that acute ischemia profoundly impairs the function and morphology of SNr neurons but not adjacent SNc neurons, and that the surprising higher tolerance of SNc neurons correlates with the resistance of the SNc region to AD. This differential response may affect the pattern of early neuronal injury that develops in the brainstem after acute ischemic insults.

Correlation between neuromelanin-sensitive MR imaging and (123)I-FP-CIT SPECT in patients with parkinsonism.

Neuromelanin-sensitive MR imaging (MRI) can visualize neuromelanin-containing neurons in the substantia nigra pars compacta (SNc), and its utility has been reported in the evaluation of parkinsonism. Conversely, dopamine transporter imaging by (123)I-N-v-fluoropropyl-2b-carbomethoxy-3b-(4-iodophenyl)nortropane (FP-CIT) SPECT (DaTSCAN) is now an established method for evaluating parkinsonism, detecting presynaptic dopamine neuronal dysfunction. Both methods can assist differentiating neurodegenerative and other forms of parkinsonism. However, to our knowledge, there have been no studies concerning a correlation between the two methods. The aim of this study was to assess the utility of neuromelanin-sensitive MRI for diagnosing parkinsonism by examining a correlation with DaTSCAN. Twenty-three patients with parkinsonism who underwent both neuromelanin-sensitive MRI and DaTSCAN were included. We measured the neuromelanin-positive SNc region volume by manually contouring the high signal intensity region of the SNc on neuromelanin-sensitive MRI and measured the specific binding ratio (SBR) on DaTSCAN. The asymmetry index of neuromelanin-positive SNc volume and the asymmetry index of SBR were also calculated. The volume of the neuromelanin-positive SNc region showed significant correlation with specific binding ratio (SBR) (right P < .001, ρ = 0.78, left P < .001, ρ = 0.86). The asymmetry index of neuromelanin-positive SNc volume also showed significant correlations with the asymmetry index of SBR (P < .001, ρ = 0.73). Decrease of the high signal intensity region of the SNc on neuromelanin-sensitive MRI would indicate damage to the nigrostriatal dopaminergic function as well as loss of dopaminergic neurons. We conclude that neuromelanin-sensitive MRI is a useful diagnostic biomarker for parkinsonism.

MiRNA-331-5p expression level is altered in neuronal cell under elevated oxidative stress

Event Abstract Back to Event MiRNA-331-5p expression level is altered in neuronal cell under elevated oxidative stress Pei Ling Yeo1, Soi Moi Chye2, Rhun Yian Koh2, Kenny G. Voon3 and Khuen Yen Ng4, 5* 1 International Medical University, Postgraduate Studies and Research, Malaysia 2 International Medical University, Department of Human Biology, Malaysia 3 International Medical University, Department of Pathology, Malaysia 4 Monash University Malaysia, Jeffrey Cheah School of Medicine and Health Sciences, Malaysia 5 Monash University Malaysia, School of Pharmacy, Malaysia Parkinson’s Diseases (PD) is a debilitating neurodegenerative disorder causing movement and neurological disabilities. Apoptotic death of the dopaminergic neurons in the substantia nigra pars compacta region of midbrain of PD patients are known to be the devastating events following the buildup of oxidative stress. MicroRNA (miRNA) is a class of small, non-coding RNA which plays important roles in regulating gene expression post-transcriptionally. Increasing evidence suggested that miRNA profile might be altered in PD. A recent investigation reported that miRNA-331-5p was significantly elevated (~ 22 folds of that in controls) in the blood plasma of PD patients. However, no study has been conducted to understand the pathological involvement of this miRNA in PD. Thus, this study aims to investigate whether levels of miRNA-331-5p in neuronal cells are affected under high oxidative stress. In this study, neurotoxin, 6-hydroxydopamine (6-OHDA) was added to SH-SY5Y cells for 6, 12, and 24 hours to induce oxidative stress. Cell viability was assessed with MTT assay whereas levels of reactive oxygen species (ROS) was quantified with DCFH-DA fluorescent probe staining. Expression of miRNA-331-5p in the cells was quantified using quantitative Real-time PCR. Result shows that 6-OHDA treatment caused a time-dependent increased in ROS generation most pronounced in 100 and 200 µM (up to 6 folds) treatment groups. 6-OHDA treatment also resulted in a time-dependent decreased of cell viability to 7% across all concentration tested. Subsequently, miRNA expression level showed significant up-regulation with 12 and 24 hours treatment groups. This increase in miRNA-331-5p level is correlated to the increase in ROS level and neuronal cell death. In conclusion, these findings suggest that miRNA-331-5p might be involved in the pathogenesis of PD as its expression is altered under elevated oxidative stress. Keywords: Oxidative Stress, miRNA, Pathogenesis, Parkinson’s disease, neurodegeneration Conference: 14th Meeting of the Asian-Pacific Society for Neurochemistry, Kuala Lumpur, Malaysia, 27 Aug - 30 Aug, 2016. Presentation Type: Poster Presentation Session Topic: 14th Meeting of the Asian-Pacific Society for Neurochemistry Citation: Yeo P, Chye S, Koh R, Voon KG and Ng K (2016). MiRNA-331-5p expression level is altered in neuronal cell under elevated oxidative stress. Conference Abstract: 14th Meeting of the Asian-Pacific Society for Neurochemistry. doi: 10.3389/conf.fncel.2016.36.00119 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 04 Aug 2016; Published Online: 11 Aug 2016. * Correspondence: Dr. Khuen Yen Ng, Monash University Malaysia, Jeffrey Cheah School of Medicine and Health Sciences, Bandar Sunway, Selangor, Malaysia, ng.khuen.yen@monash.edu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Pei Ling Yeo Soi Moi Chye Rhun Yian Koh Kenny G Voon Khuen Yen Ng Google Pei Ling Yeo Soi Moi Chye Rhun Yian Koh Kenny G Voon Khuen Yen Ng Google Scholar Pei Ling Yeo Soi Moi Chye Rhun Yian Koh Kenny G Voon Khuen Yen Ng PubMed Pei Ling Yeo Soi Moi Chye Rhun Yian Koh Kenny G Voon Khuen Yen Ng Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Withania somnifera shows ability to counter Parkinson's Disease: An Update

Withania somnifera (Ashwagandha) is a very revered herb of the Indian Ayurvedic system of medicine. It is useful for treating various kinds of disease processes and especially used as a nervine tonic. Withania somnifera (Ws) contain a wide array of active components including withaferin A, withanone and other flavonoids exhibiting strong anti-oxidant properties. Many scientific studies on Ws were carried out previously that showed its anti-oxidative effect, synergistic effect with other medicinal herbs and its efficiency to increase catecholamines level and regulation of apoptotic processes. Furthermore, treatment of Parkinsonian mice models with Ws has shown neuroprotection of dopaminergic neurons in substantia nigra pars compacta region of mid-brain. The present review enlightens the crucial role of Indian Ginseng to curb neurodegenerative disorder such as Parkinson’s disease. Extensive studies are needed to prove its therapeutic efficacy in neuronal disorders.

Protective Mechanisms of Flavonoids in Parkinson's Disease.

Parkinson's disease is a chronic, debilitating neurodegenerative movement disorder characterized by progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta region in human midbrain. To date, oxidative stress is the well accepted concept in the etiology and progression of Parkinson's disease. Hence, the therapeutic agent is targeted against suppressing and alleviating the oxidative stress-induced cellular damage. Within the past decades, an explosion of research discoveries has reported on the protective mechanisms of flavonoids, which are plant-based polyphenols, in the treatment of neurodegenerative disease using both in vitro and in vivo models. In this paper, we have reviewed the literature on the neuroprotective mechanisms of flavonoids in protecting the dopaminergic neurons hence reducing the symptoms of this movement disorder. The mechanism reviewed includes effect of flavonoids in activation of endogenous antioxidant enzymes, suppressing the lipid peroxidation, inhibition of inflammatory mediators, flavonoids as a mitochondrial target therapy, and modulation of gene expression in neuronal cells.

Oxidation of Survival Factor MEF2D in Neuronal Death and Parkinson's Disease

Dysfunction of myocyte enhancer factor 2D (MEF2D), a key survival protein and transcription factor, underlies the pathogenic loss of dopaminergic (DA) neurons in Parkinson's disease (PD). Both genetic factors and neurotoxins associated with PD impair MEF2D function in vitro and in animal models of PD. We investigated whether distinct stress conditions target MEF2D via converging mechanisms. We showed that exposure of a DA neuronal cell line to 6-hyroxydopamine (6-OHDA), which causes PD in animals models, led to direct oxidative modifications of MEF2D. Oxidized MEF2D bound to heat-shock cognate protein 70 kDa, the key regulator for chaperone-mediated autophagy (CMA), at a higher affinity. Oxidative stress also increased the level of lysosomal-associated membrane protein 2A (LAMP2A), the rate-limiting receptor for CMA substrate flux, and stimulated CMA activity. These changes resulted in accelerated degradation of MEF2D. Importantly, 6-OHDA induced MEF2D oxidation and increased LAMP2A in the substantia nigra pars compacta region of the mouse brain. Consistently, the levels of oxidized MEF2D were much higher in postmortem PD brains compared with the controls. Functionally, reducing the levels of either MEF2D or LAMP2A exacerbated 6-OHDA-induced death of the DA neuronal cell line. Expression of an MEF2D mutant that is resistant to oxidative modification protected cells from 6-OHDA-induced death. This study showed that oxidization of survival protein MEF2D is one of the pathogenic mechanisms involved in oxidative stress-induced DA neuronal death. Oxidation of survival factor MEF2D inhibits its function, underlies oxidative stress-induced neurotoxicity, and may be a part of the PD pathogenic process.

Dose-Dependent Effect of Flouxetine on 6-OHDA-Induced Catalepsy in Male Rats: A Possible Involvement of 5-HT1A Receptors.

Progressive loss of dopaminergic neurons of the substantia nigra pars compacta (SNc) in Parkinson's disease (PD) leads to impairment of motor skills. Several evidences show that the role of serotonergic system in regulation of normal movement is pivotal and mediates via 5-HT1A receptors. Our previous study has shown that fluoxetine in acute injections able to attenuate catalepsy in 6-hydroxydopamine (6-OHDA)-lesioned rats. Since drugs are used chronically in clinic, in this study we attempted to evaluate effect of chronic administration of fluoxetine on 6-OHDA-induced catalepsy. Catalepsy was induced by unilateral infusion of 6-OHDA (8 µg/2 µl/rat) into the central region of SNc and assayed by using bar-test. Fluoxetine (1, 2.5, 5 and 10 mg/kg) was injected intraperitonealy (ip) for 10 days and its anti-cataleptic effect was assessed at the 10th day. Fluoxetine in high doses (5 and 10 mg/kg) worsened 6-OHDA-induced catalepsy while it had anti-cataleptic effect at the dose of 1mg/kg. The anti-cataleptic effect of fluoxetine (1mg/kg) was reversed by co-administration with NAN-190 (0.5 mg/kg, ip), as a5-HT1Areceptor antagonist. According to the results it can be concluded that fluoxetine has anti-cataleptic effect in parkinsonian rats only at low doses, whereas at higher doses it worsens catalepsy. It's anti-cataleptic effect is exerted through affecting on 5-HT1Areceptors. However, at high doses other mechanisms may be involved. Further clinical studies are needed to prove it's possible clinical application as an adjuvant therapy in reducing catalepsy of PD.

Recent Advances on the Neuroprotective Potential of Antioxidants in Experimental Models of Parkinson’s Disease

Parkinson’s disease (PD), a neurodegenerative movement disorder of the central nervous system (CNS) is characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta region of the midbrain. Although the etiology of PD is not completely understood and is believed to be multifactorial, oxidative stress and mitochondrial dysfunction are widely considered major consequences, which provide important clues to the disease mechanisms. Studies have explored the role of free radicals and oxidative stress that contributes to the cascade of events leading to dopamine cell degeneration in PD. In general, in-built protective mechanisms consisting of enzymatic and non-enzymatic antioxidants in the CNS play decisive roles in preventing neuronal cell loss due to free radicals. But the ability to produce these antioxidants decreases with aging. Therefore, antioxidant therapy alone or in combination with current treatment methods may represent an attractive strategy for treating or preventing the neurodegeneration seen in PD. Here we summarize the recent discoveries of potential antioxidant compounds for modulating free radical mediated oxidative stress leading to neurotoxicity in PD.

Expression and functional properties of TRPM2 channels in dopaminergic neurons of the substantia nigra of the rat

Transient receptor potential melastatin 2 (TRPM2) channels are sensitive to oxidative stress, and their activation can lead to cell death. Although these channels have been extensively studied in expression systems, their role in the brain, particularly in the substantia nigra pars compacta (SNc), remains unknown. In this study, we assessed the expression and functional properties of TRPM2 channels in rat dopaminergic SNc neurons, using acute brain slices. RT-PCR analysis revealed TRPM2 mRNA expression in the SNc region. Immunohistochemistry demonstrated expression of TRPM2 protein in tyrosine hydroxylase-positive neurons. Channel function was tested with whole cell patch-clamp recordings and calcium (fura-2) imaging. Intracellular application of ADP-ribose (50-400 μM) evoked a dose-dependent, desensitizing inward current and intracellular free calcium concentration ([Ca(2+)](i)) rise. These responses were strongly inhibited by the nonselective TRPM2 channel blockers clotrimazole and flufenamic acid. Exogenous application of H(2)O(2) (1-5 mM) evoked a rise in [Ca(2+)](i) and an outward current mainly due to activation of ATP-sensitive potassium (K(ATP)) channels. Inhibition of K(+) conductance with Cs(+) and tetraethylammonium unmasked an inward current. The inward current and/or [Ca(2+)](i) rise were partially blocked by clotrimazole and N-(p-amylcinnamoyl)anthranilic acid (ACA). The H(2)O(2)-induced [Ca(2+)](i) rise was abolished in "zero" extracellular Ca(2+) concentration and was enhanced at higher baseline [Ca(2+)](i), consistent with activation of TRPM2 channels in the cell membrane. These results provide evidence for the functional expression of TRPM2 channels in dopaminergic SNc neurons. Given the involvement of oxidative stress in degeneration of SNc neurons in Parkinson's disease, further studies are needed to determine the pathophysiological role of these channels in the disease process.

Reduction of Neuromelanin-Positive Nigral Volume in Patients with MSA, PSP and CBD

Diseases presenting extrapyramidal symptoms are accompanied by nigral cell loss. In the previous study, we demonstrated the reduction of the neuromelanin-positive volume of substantia nigra (SN) pars compacta (SNc) in patients with Parkinson's disease (PD) using 3-Tesla MRI. In the present study we investigated the neuromelanin-positive SNc volume in patients with the other parkinsonian disorders including multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) and compared the results with those with PD, spinocerebellar ataxia (SCA) and controls. Axial T1-weighted (T1W) images were obtained with a 3-Tesla MRI scanner. The border of the neuromelanin-positive region of the SNc was traced manually on these images with a pentablet pointing device and the SNc volume was calculated. The SNc volumes of 28 patients with MSA, 11 patients with PSP and 10 patients with CBD were compared with those of 80 patients with PD, 9 patients with SCA and 54 patients who had suffered mild acute ischemic stroke as controls. The mean volumes for the left and right SN were used for statistical analyses. The volumes of the neuromelanin-positive SNc region in patients with MSA, PSP and CBD, but not SCA were reduced to the same extent as PD patients compared with controls. Reduced volume of the neuromelanin-positive SNc region of patients with MSA, PSP and CBD was detected by neuromelanin MR imaging. Volumetric evaluation of neuromelanin MR imaging may provide a biomarker of nigral degeneration in patients with MSA, PSP and CBD as in patients with PD.