Midbrain Substantia Nigra Research Articles

Parkin mutation decreases neurite complexity and maturation in neurons derived from human fibroblasts

BackgroundParkinson’s disease (PD) is one of the most common neurodegenerative disorders, and mainly characterized by the progressive degeneration of dopaminergic (DA) neurons in the midbrain substantia nigra and non-DA neurons in many other parts of the brain. Previous studies have shown that several genes associated with the causes of PD can influence neurite outgrowth. Mutations of PRKN (encoding parkin, an E3 ubiquitin ligase) are the most frequent cause of recessively inherited PD. The lack of a PD phenotype in Prkn-knockout mice may imply a unique vulnerability of neurons to parkin mutations. MethodsCRISPR/Cas9 technology was used to target random mutations into exon3 of PRKN in human fibroblasts cell line MRC-5. The induced DA neurons were achieved from direct conversion of fibroblasts (with or without PRKN mutations) via a cocktail of transcriptional factors (Ascl1, Nurr1, Lmx1a, miRNA124, p53 shRNA) and chemicals (CHIR99021, Purmorphamine, TGFβ3, BDNF, GDNF, NGF and Y27632). ResultsHerein, we successfully established human neuronal cell models with parkin mutations from fibroblast-reprogrammed neurons. In these neurons, not only were the induced ratio and number of mature neurons markedly decreased, but also the complexity of the neuronal processes, measured by total neurite length and number of terminals, was greatly reduced, in TH+ and TH−neurons with PRKN mutations. ConclusionsThe results suggest that parkin not only maintains the morphological complexity of human neurons, but also influences maturation and differentiation in the fibroblast reprogramming process.

Brain and Neuronal Aging: Aged Brain Controls via Gene Expression Fidelity and Master Regulatory Factors

Providing plausible strategies for brain aging protection should be a critical concern for countries with large elderly populations including Japan. Age-related cognitive impairments and movement disorders, such as Alzheimer's and Parkinson's diseases, are caused by neurodegeneration that primarily initiates in the hippocampus and the midbrain substantia nigra, respectively. Neurons are postmitotic, and therefore, the accuracy of cellular metabolism should be crucial for maintaining neural functions throughout their life. Thus accuracy of protein synthesis is a critical concern in discussing mechanisms of aging. The essence of the so-called "error catastrophe theory" of aging was on the fidelity of ribosomal translation and/or aminoacylation of tRNA. There is evidence that reduced protein synthesis accuracy results in neurodegeneration. Similarly, reduced proteostasis via autophagy and proteasomes in aging is crucial for protein quality control and well documented as a risk for aging. In both neurodegeneration and protein quality controls, various proteins are involved in their regulation, but recent evidence suggests that repressor element-1 silencing transcription factor (REST) could be a master regulatory protein that is crucial for orchestrating the neural protecting events in human brain aging. REST is induced in the aged brain, and protects neurons against oxidative stress and protein toxicity. Interestingly, REST is identical with neuron-restrictive silencer factor (NRSF), the master regulator of neural development. Thus NRSF/REST play important roles in both neurogenesis and neurodegeneration. In this review, I summarize the interesting scientific crossover, and discuss the potential use of NRSF/REST as a pharmaceutical target for controlling aging, particularly in relation to brain aging.

Curcumin prevents the midbrain dopaminergic innervations and locomotor performance deficiencies resulting from chronic aluminum exposure in rat

Aluminum (Al) among the abundant metals on the earth crust, is able to cross the biological barriers via the gastrointestinal and lung tissues. Once in the body, this heavy metal accumulates in different organs, especially the central nervous system. Though its influence is evidently shown in the substantia nigra of Parkinson’s disease patients and other brain areas in other neurodegenerative diseases, few studies have demonstrated that Al could trigger profound changes in neurotransmission systems including the dopaminergic (DAergic) system. A variety of medicinal plants may be prescribed in such contamination, including some culinary spices such as Curcumin (Cur). Several studies have proven Cur to exhibit a wide variety of biological and pharmacological activities, especially its antioxidant potential. Using the immunohistochemistry, of tyrosine hydroxylase (TH), in the midbrain substantia nigra pars compact (SNc) and the ventral tegmental area (VTA) and the open field test, we examined the DAergic system together with the locomotor behavior respectively in rats exposed chronically to Al (0,3%) in drinking water during 4 months since the intra-uterine age, as well as the neuroprotective effect of the concomitant administration of Cur I (30 mg/kg B.W) of chronic Al exposed rats. Our results have shown a significant decrease of TH immureactivity in both SNc and VTA associated to a loss of the number of crossed boxes, leading to a difficient locomotor performance in the Al group while Cur I prevents such TH immunoreactivity impairment and maintains a higher locomotor activity in the Al-CurI group. Our findings lead to suppose a powerful and obvious neuroprotective potential of CurI against Al-induced neurotoxicity of the DAergic system involved in the control of the locomotor behavior.

Naringenin Produces Neuroprotection Against LPS-Induced Dopamine Neurotoxicity via the Inhibition of Microglial NLRP3 Inflammasome Activation.

Background: Parkinson's disease (PD) is the second most prevalent central nervous system (CNS) degenerative disease and characterized by slow and progressive loss of dopamine (DA) neurons in the midbrain substantia nigra. Microglia-mediated neuroinflammation has been considered as the major central event in the process of DA neuronal loss. Thus, inhibition of neuroinflammation could possess a more viable strategy for PD treatment. Naringenin (NAR), a natural flavanoid contained in citrus fruit and grapefruits, possesses amounts of pharmacological activities. Recent studies indicated that NAR produced neuroprotection against several neurological disorders. However, the mechanisms underlying NAR-generated neuroprotection are not fully illuminated.Methods: In the present study, rat nigral stereotaxic injection of lipopolysaccharide (LPS)-induced DA neuronal loss was performed to investigate NAR-mediated neuroprotection. In addition, BV-2 and MN9D cell lines were applied to explore the underlying mechanisms.Results: NAR protected DA neurons against LPS-induced neurotoxicity. Also, NAR suppressed microglial nod-like receptor protein 3 (NLRP3) inflammasome signaling activation and the subsequent pro-inflammatory factors release. In addition, NAR-mediated DA neuroprotection was dependent on the inhibition of microglial NLRP3 inflammasome activation, as evidenced by the observations that NAR-reduced pro-inflammatory factors production and further NAR-exerted DA neuroprotection against LPS-induced neuronal damage was not discerned after microglial NLRP3 siRNA treatment.Conclusions: This study demonstrated that NAR targeted microglial NLRP3 inflammasome to protect DA neurons against LPS-induced neurotoxicity. These findings suggest NAR might hold a promising therapeutic potential for PD.

ERK/MAP Kinase Activation is Evident in Activated Microglia of the Striatum and Substantia Nigra in an Acute and Chronically-Induced Mouse Model of Parkinson's Disease.

Parkinson's Disease (PD) is a debilitating, age-related disorder characterized by selective degeneration of dopaminergic neurons in the midbrain substantia nigra (SNc). Dopaminergic neurons originating in the midbrain project to the striatum (Caudate-putamen-CPU). Although studies have suggested that the extracellular signal-regulated kinase ½ (ERK ½) in the brain is activated after 1-Methyl-4-phenyl-1, 2,3,6-tetrahydropyridine (MPTP) exposure, to our knowledge no study has yet been done to demonstrate whether such activation occurs in neurons or in glia. In the current study, we utilized both an acute and a repeat dose mouse model of PD using the neurotoxicant MPTP as the causative agent. Immunohistochemical studies using phospho ERK ½ antibody suggested that ERK ½ activation takes place in the striatum (CPU) and SNc of both animal models. Moreover, double immunolabeling studies using phospho ERK ½ and the microglial marker, CD11b or the astrocyte marker, Glial Fibrillary Acidic Protein (GFAP) suggested that the phospho ERK ½ was present exclusively in the microglia and not in the astrocytes. Western Blot results suggested that there were no alterations in ERK in either MPTPtreated animals or in control animals; however, phospho ERK ½ was found to be significantly increased in the striatum and SNc in both acute chronic mouse PD models. Tyrosine Hydroxylase (TH) immunolabeling revealed significant decreases in dopaminergic neurons in the SNc in both animal models' concomitant with activation of microglia and ERK activation. These observations suggest that ERK activation takes place following MPTP treatment and that activation of ERK occurs primarily in the microglia. The data provided also suggest that ERK activation may be involved in transcriptional activation of microglia following neurotoxicant insults.

Hinokitiol Offers Neuroprotection Against 6-OHDA-Induced Toxicity in SH-SY5Y Neuroblastoma Cells by Downregulating mRNA Expression of MAO/α-Synuclein/LRRK2/PARK7/PINK1/PTEN Genes.

Parkinson's disease (PD) remarks its pathology by affecting the patient's movements and postural instability by dopaminergic loss in the substantia nigra of midbrain. The disease is characterized by the accumulation of alpha-synuclein protein followed by dementia symptoms. Moreover, the pathology enhances the production of monoamine oxidases A and B (MAO A and B), leucine-rich repeat kinase 2 (LRRK2), phosphate and tensin homolog (PTEN), PTEN-induced putative kinase 1 (PINK1), and PARK7 (deglycase 1 (DJ-1)). Hinokitiol (HIN), a tropolone-related compound, has widely been reported as an antioxidant, antineuralgic as well as a neuroprotective agent. Hence, in this study, we have examined the effect of hinokitol to act as a neuroprotective agent against 6-OHDA-induced toxicity in SH-SY5Y neuroblastoma cells through downregulation of the mRNA expression of PD pathological proteins like alpha-synuclein, MAO A and B, LRRK2, PTEN, PINK1, and PARK7 (deglycase 1 (DJ-1)). The study revealed that the 6-OHDA-induced elevation in the mRNA expression of the pathology marker proteins was subsequently downregulated by the treatment with HIN and was referenced with the positive control, amantadine (AMA), widely used nowadays as a treatment drug for PD symptoms. Thus, the study suggests that hinokitiol could be a drug of choice against 6-OHDA-induced neurotoxicity in SH-SY5Y neuroblastoma cells.

Association of Serum Ceruloplasmin Level with Parkinson’s’s Disease

Background: Parkinson’s disease, though a common neurodegenerative disease, is still elusive regarding its pathobiology. Neuronal degeneration in the midbrain substantia nigra by excess oxidative stress may play a role. As ceruloplasmin (Cp), a plasma protein is important to maintain intracellular iron homeostasis and reduce cellular oxidative stress, decreased serum Cp level may be an important factor in the pathogenesis of Parkinson’s disease. Methods: This case-control study was conducted in the department of Neurology, BSMMU. Forty-five Parkinson’s disease patients and equal number of controls were selected. Serum ceruloplasmin level was measured in the department of Biochemistry and Molecular Biology, BSMMU. Results: Mean serum Cp level was significantly lower (p-value <0.001) in case (27.64 mg/dl) than in control group (33.10 mg/dl). Conclusion: The association of low serum Cp level with Parkinson’s disease may indicate a possible iron homeostasis abnormality as a pathogenic factor in Parkinson’s disease. Bangladesh Journal of Neuroscience 2018; Vol. 34 (2): 63-65

Long Noncoding RNA SNHG1 Promotes Neuroinflammation in Parkinson’s Disease via Regulating miR-7/NLRP3 Pathway

Parkinson’s disease (PD) is the second most common neurodegenerative disorders. Neuroinflammation plays an important role in the pathogenesis of PD. Long noncoding RNA small nucleolar RNA host gene 1 (SNHG1) was elevated in the brain specimens of PD patients and MPP+-treated SH-SY5Y cells. The expression of mouse Snhg1 and miR-7 was firstly determined in lipopolysaccharide (LPS)-induced BV2 cells. The role and mechanism of SNHG1 in the neuroinflammation of PD were investigated using gain- and loss-of function approaches both in vitro and in vivo. Snhg1 expression was elevated, whereas miR-7 reduced in LPS-induced BV2 cells. Upregulation of Snhg1 elevated, and Snhg1 knockdown suppressed LPS-induced BV2 microglial activation and inflammation. miR-7 reversed, while anti-miR-7 further enhanced the effects of Snhg1 on BV2 cells. Furthermore, we found that Snhg1 functioned as a competing endogenous RNA for miR-7 to regulate nod-like receptor protein 3 (NLRP3) expression, leading to the activation of NLRP3 inflammasome. In the microglial culture supernatant transfer model, knockdown of Snhg1 or NLRP3 in LPS-stimulated BV2 cells inhibited primary neurons from apoptosis and elevated caspase-3 activity. Additionally, Snhg1 was increased in MPTP-induced PD mouse models. Downregulation of Snhg1 elevated miR-7 expression, suppressed the activation of microglia and NLRP3 inflammasome as well as dopaminergic neuron loss in the midbrain substantia nigra pars compacta in MPTP-treated mice. In conclusion, our study suggests that SNHG1 promotes neuroinflammation in the pathogenesis of PD via modulating miR-7/NLRP3 pathway.

Icariin Reduces Dopaminergic Neuronal Loss and Microglia-Mediated Inflammation in Vivo and in Vitro.

Parkinson’s disease (PD) is one of the most common neurodegenerative diseases characterized with a gradual loss of midbrain substantia nigra (SN) dopamine (DA) neurons. An excessive evidence demonstrated that microglia-mediated inflammation might be involved in the pathogenesis of PD. Thus, inhibition of neuroinflammation might possess a promising potential for PD treatment. Icariin (ICA), a single active component extracted from the Herba Epimedii, presents amounts of pharmacological properties, such as anti-inflammation, anti-oxidant, and anti-aging. Recent studies show ICA produced neuroprotection against brain dysfunction. However, the mechanisms underlying ICA-exerted neuroprotection are fully illuminated. In the present study, two different neurotoxins of 6-hydroxydopamine (6-OHDA) and lipopolysaccharide (LPS)-induced rat midbrain DA neuronal damage were applied to investigate the neuroprotective effects of ICA. In addition, primary rat midbrain neuron-glia co-cultures were performed to explore the mechanisms underlying ICA-mediated DA neuroprotection. In vitro data showed that ICA protected DA neurons from LPS/6-OHDA-induced DA neuronal damage and inhibited microglia activation and pro-inflammatory factors production via the suppression of nuclear factor-κB (NF-κB) pathway activation. In animal results, ICA significantly reduced microglia activation and significantly attenuated LPS/6-OHDA-induced DA neuronal loss and subsequent animal behavior changes. Together, ICA could protect DA neurons against LPS- and 6-OHDA-induced neurotoxicity both in vivo and in vitro. These actions might be closely associated with the inhibition of microglia-mediated neuroinflammation.

Tetrahydroxystilbene Glucoside Produces Neuroprotection against 6-OHDA-Induced Dopamine Neurotoxicity.

Parkinson's disease (PD) was one of the most common neurodegenerative diseases with a slow and progressive loss of dopamine (DA) neurons in the midbrain substantia nigra (SN). Neuroinflammation was identified to be an important contributor to PD pathogenesis with the hallmark of microglia activation. Tetrahydroxystilbene glucoside (TSG) was the main active component extracted from Polygonum multiflorum and held amounts of pharmacological activities including antioxidant, free radical-scavenging, anti-inflammation, and cardioprotective properties. Recent studies demonstrated that TSG exerted neuroprotection from several neurodegenerative disease models. However, the underlying mechanisms were not completely elucidated. In the present study, rat nigral stereotaxic injection of 6-hydroxydopamine- (6-OHDA-) elicited DA neuronal injury was performed to investigate TSG-mediated neuroprotection on DA neurons. In addition, primary rat midbrain neuron-glia cocultures were applied to explore the mechanisms underlying TSG-exerted neuroprotection. Results showed that daily intraperitoneal injection of TSG for 14 consecutive days significantly protected DA neurons from 6-OHDA-induced neurotoxicity and suppressed microglia activation. Similar neuroprotection was shown in primary neuron-glia cocultures. In vitro studies further demonstrated that TSG inhibited microglia activation and subsequent release of proinflammatory factors. Moreover, TSG-mediated neuroprotection was closely related with the inactivation of mitogen-activated protein kinase (MAPK) signaling pathway. Together, TSG protects DA neurons from 6-OHDA-induced neurotoxicity via the inhibition of microglia-elicited neuroinflammation. These findings suggest that TSG might hold potential therapeutic effects on PD.

Galangin Reduces the Loss of Dopaminergic Neurons in an LPS-Evoked Model of Parkinson's Disease in Rats.

Parkinson’s disease (PD) is caused by the loss of dopaminergic (DA) neurons in the midbrain substantia nigra (SN). Neuroinflammation, which is marked by microglial activation, plays a very important role in the pathogenesis of PD. Pro-inflammatory mediators produced by activated microglia could damage DA neurons. Hence, the inhibition of microglial activation may provide a new approach for treating PD. Galangin has been shown to inhibit inflammation in a variety of diseases, but not PD. In this study, we aimed to investigate the anti-inflammatory effect of galangin and the underlying mechanisms in Lipopolysaccharide (LPS) induced PD models. We first examined the protective effect of galangin in the LPS-induced PD rat model. Specifically, we investigated the effects on motor dysfunction, microglial activation, and the loss of DA neurons. Then, galangin was used to detect the impact on the inflammatory responses and inflammatory signaling pathways in LPS-induced BV-2 cells. The in vivo results showed that galangin dose-dependently attenuates the activation of microglia, the loss of DA neurons, and motor dysfunction. In vitro, galangin markedly inhibited LPS-induced expression of tumor necrosis factor α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β), cyclooxygenase 2 (COX-2), and induced nitric oxide synthase (iNOS) via associating with the phosphorylation of c-JUN N-terminal Kinase (JNK), p38, protein kinase B (AKT), and nuclear factor κB (NF-κB) p65. Collectively, the results indicated that galangin has a role in protecting DA neurons by inhibiting microglial activation.

The swallow tail appearance on 3T susceptibility weighted imaging to assist diagnosis of Parkinson's disease and related diseases

Background: Brain magnetic resonance imaging (MRI) of Parkinson's disease (PD) is performed to exclude the diagnosis of other parkinsonism diseases. In recent years, using the 3T-susceptibility weighted imaging (SWI), nigrosome-1 of the midbrain substantia nigra can be visualized and reported as useful for PD diagnosis. Nigrosome-1 can be visualized as a wedge high signal area using 3T-SWI, which is surrounded by substantia nigra and medial leminiscus, and it looks like a swallow tail appearance. In PD, the high signal of nigrosome-1 is obscured because it is presumed increase of the iron concentrations of the nigrosome-1.

N-Propargyl Caffeamide (PACA) Ameliorates Dopaminergic Neuronal Loss and Motor Dysfunctions in MPTP Mouse Model of Parkinson's Disease and in MPP+-Induced Neurons via Promoting the Conversion of proNGF to NGF.

Insufficient production of nerve growth factor (NGF) is implicated in Parkinson's disease (PD). We recently discovered that caffeic acid derivative N-propargyl caffeamide (PACA) not only potentiated NGF-induced neurite outgrowth but also attenuated 6-hydroxydopamine neurotoxicity in neuronal culture. The aim of the present study was to investigate whether PACA could increase NGF levels against 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) neurotoxicity in a mouse PD model. We induced parkinsonism in mice by intraperitoneal injection of MPTP for seven consecutive days. Animal motor functions were assessed by rotarod test and pole test. Our results showed that PACA ameliorated motor impairments in MPTP-challenged mice. Based on Western blot analysis and/or immunofluorescence staining of NGF and tyrosine hydroxylase (TH), PACA preserved TH levels in the midbrain substantia nigra pars compacta. PACA also increased NGF expression while it decreased proNGF accumulation. Interestingly, NGF was widely induced in the midbrains including astrocytes. To elucidate the mechanisms by which PACA induces NGF, we focused on the effects of PACA on two neurotrophic signaling pathways, the PI3K and MEK pathways. We found that PACA induced the phosphorylation of Akt, ERK, and CREB against MPTP-mediated alterations. Importantly, PACA increased NGF levels and subsequently induced TrkA activation in MPTP-treated mice. Consistently, PACA also increased NGF levels in dopaminergic PC12 cells and primary rat midbrain neurons against N-methyl-4-phenylpyridinium iodide (MPP+) toxicity. ERK and PI3K inhibitors attenuated the effects of PACA on NGF levels. Collectively, our results suggest that PACA may rescue NGF insufficiency via sequential activation of PI3K/Akt, ERK1/2, and CREB signaling pathways. Graphical Abstract ᅟ.

Effect of <i>Pedalium murex</i> against lipopolysaccharide-induced neurotoxicity in substantia nigra of rat midbrain

Effect of <i>Pedalium murex</i> against lipopolysaccharide-induced neurotoxicity in substantia nigra of rat midbrain

Consolidation of altered associability information by amygdala central nucleus

The surprising omission of a reinforcer can enhance the associability of the stimuli that were present when the reward prediction error was induced, so that they more readily enter into new associations in the future. Previous research from this laboratory identified brain circuit elements critical to the enhancement of stimulus associability by the omission of an expected event and to the subsequent expression of that altered associability in more rapid learning. These elements include the amygdala, the midbrain substantia nigra, the basal forebrain substantia innominata, the dorsolateral striatum, the secondary visual cortex, and the posterior parietal cortex. Here, we found that consolidation of a surprise-enhanced associability memory in a serial prediction task depends on processing in the amygdala central nucleus (CeA) after completion of sessions that included the surprising omission of an expected event. Post-surprise infusions of anisomycin, lidocaine, or muscimol prevented subsequent display of surprise-enhanced associability. Because previous studies indicated that CeA function is unnecessary for the expression of associability enhancements that were induced previously when CeA function was intact (Holland & Gallagher, 2006), we interpreted these results as indicating that post-surprise activity of CeA (“surprise replay”) is necessary for the consolidation of altered associability memories elsewhere in the brain, such as the posterior parietal cortex (Schiffino et al., 2014a).

Neuroprotective and Therapeutic Strategies against Parkinson's Disease: Recent Perspectives.

Parkinsonism is a progressive motor disease that affects 1.5 million Americans and is the second most common neurodegenerative disease after Alzheimer’s. Typical neuropathological features of Parkinson’s disease (PD) include degeneration of dopaminergic neurons located in the pars compacta of the substantia nigra that project to the striatum (nigro-striatal pathway) and depositions of cytoplasmic fibrillary inclusions (Lewy bodies) which contain ubiquitin and α-synuclein. The cardinal motor signs of PD are tremors, rigidity, slow movement (bradykinesia), poor balance, and difficulty in walking (Parkinsonian gait). In addition to motor symptoms, non-motor symptoms that include autonomic and psychiatric as well as cognitive impairments are pressing issues that need to be addressed. Several different mechanisms play an important role in generation of Lewy bodies; endoplasmic reticulum (ER) stress induced unfolded proteins, neuroinflammation and eventual loss of dopaminergic neurons in the substantia nigra of mid brain in PD. Moreover, these diverse processes that result in PD make modeling of the disease and evaluation of therapeutics against this devastating disease difficult. Here, we will discuss diverse mechanisms that are involved in PD, neuroprotective and therapeutic strategies currently in clinical trial or in preclinical stages, and impart views about strategies that are promising to mitigate PD pathology.

Cytoskeletal Pathologies of Age-Related Diseases between Elderly Sri Lankan (Colombo) and Indian (Bangalore) Brain Samples.

Within South Asia, Sri Lanka represents fastest aging with 13% of the population was aged over 60's in 2011, whereas in India it was 8%. Majority of the Sri Lankan population based genetic studies have confirmed their origin on Indian mainland. As there were inadequate data on aging cytoskeletal pathologies of these two nations with their close genetic affiliations, we performed a comparison on their elderly. Autopsy brain samples of 50 individuals from Colombo, Sri Lanka (mean age 72.1 yrs ± 7.8, mean ± S.D.) and 42 individuals from Bangalore, India (mean age 65.9 yrs ± 9.3) were screened for neurodegenerative pathologies using immunohistochemical techniques. A total of 79 cases with incomplete clinical history (Colombo- 47 and Bangalore- 32) were subjected to statistical analysis and 13 cases, clinically diagnosed with dementia and/or Parkinsonism disorders were excluded. As per National Institute on Aging- Alzheimer's Association guidelines, between Colombo and Bangalore samples, Alzheimer's disease neuropathologic change for intermediate/ high level was 4.25% vs. 3.12% and low level was 19.15% vs. 15.62% respectively. Pathologies associated with Parkinsonism including brainstem predominant Lewy bodies- 6.4% and probable progressive supra nuclear palsy- 2.13% were found solely in Colombo samples. Alzheimer related pathologies were not different among elders, however, in Colombo males, neurofibrillary tangle grade was significantly higher in the region of hippocampus (odds ratio = 1.46, 95% confidence interval = 0.07-0.7) and at risk in midbrain substantia nigra (p = 0.075). Other age-related pathologies including spongiform changes (p < 0.05) and hippocampus cell loss in dentate gyrus region (p < 0.05) were also identified prominently in Colombo samples. Taken together, aging cytoskeletal pathologies are comparatively higher in elderly Sri Lankans and this might be due to their genetic, dietary and/ or environmental variations.

Directed Differentiation of Dopamine-Secreting Cells from Nurr1/GPX1 Expressing Murine Embryonic Stem Cells Cultured on Matrigel-Coated PCL Scaffolds.

Parkinson's disease (PD) is a progressive neurological disorder characterized by a large number of motor and non-motor features and is known as the second most common neurodegenerative disorder after Alzheimer's disease. The hallmark pathology of PD is the damage and death of dopamine-producing neurons in the substantia-nigra of midbrain. Intrastriatal transplants of fetal mesencephalon derived DAergic neurons have provided proof-of-principle for the cell replacement strategy and have demonstrated reinnervation of the denervated striatum. However, ethical, technical, and practical limitations of deploying fetal DAergic neurons as the source for cell therapy in PD have ceased the spread of this procedure into clinical practice. Embryonic stem (ES) cells have emerged as a therapeutic alternative that can proliferate extensively and generate dopamine-producing neurons. To this extent and to surmount the obstacles related to embryonic neural cells, many investigations have focused on using pluripotent stem cells for the derivation of DAergic neurons. In the present study, a mouse embryonic stem (mES) R1 cell line was generated which could stably co-express Nurr1 (an essential transcription factor in DAergic neuron development) and GPX-1 (a neuroprotective enzyme against oxidative stress). The Nurr1/GPX-1-expressing ES cells (Nurr1/GPX-1-ES) were differentiated into DAergic-like cells via a three-dimensional culture environment consisting of Poly-ε-Caprolactone (PCL) nanofibrous scaffolds embedded by Matrigel (Mtg) in the presence of specific signaling molecules. DAergic neuron-specific genes were highly expressed in ES-derived DAergic neurons cultured and differentiated on PCL/Mtg scaffolds. Reverse-phase HPLC confirmed that the Nurr1/GPX-1-ES-cells differentiated on PCL/Mtg electrospun scaffolds could efficiently and exclusively secrete dopamine in response to stimulus. In conclusion, our results demonstrated that PCL/Matrigel nanofibrous scaffolds could efficiently support and promote the generation of functional DAergic-like cells from Nurr1/GPX-1-ES cells. The results of this study may have an impact on future tissue engineering for cell therapy of PD.

New Developments in the Treatment of Parkinson's Disease: Bridging the gap between Medical and Surgical Therapy for PD

Parkinson's Disease (PD) is a progressive neurologic disease caused by loss of dopaminergic neurons in the midbrain substantia nigra. Decreased activation of dopamine dependent motor pathways results in the classic features of PD including tremor, bradykinesia, rigidity, and gait impairment. The gold standard treatment of Parkinson's Disease (PD) is levodopa, which acts to replenish deficient endogenous dopamine production, combined with carbidopa, a decarboxylase inhibitor to decrease peripheral breakdown of levodopa.

Dopamine: Receptors, Functions, Synthesis, Pathways, Locations and Mental Disorders: Review of Literatures

Dopamine is monoamine neurotransmitter. Dopamine is produced in the dopaminergic neurons in the ventral tegmental area of the substantia nigra, midbrain and the arcuate nucleus of the hypothalamus. In the periphery, dopamine is found in the kidney where it functions to produce renal vasodilation, diuresis, and natriuresis. Dopamine neurons are more widely distributed than those of other monamines and it is found in hypothalamus, olfactory bulb, the midbrain substantia nigra and ventral tegmental area and in the periaqueductal gray and retina. There are five subtypes of dopamine receptors, D1, D2, D3, D4, and D5, which are members of the large G-protein coupled receptor super family. The dopamine receptor subtypes are divided into two major subclasses: types 1 and 5 are similar in structure and drug sensitivity, and these two receptors are referred to as the D1like group or class of receptors. Dopamine receptor types 2, 3, and 4 are called the D2like group. Dopamine plays central role in pleasurable reward behavior, inhibition of prolactin production (involved in lactation), sleep, mood, attention, learning, behavior, control of nausea and vomiting and pain processing. In addition it also involved in controlling movement, emotion and cognition. Due to extensive localization of dopamine receptor to brain areas and its role in wide range of functions, dopaminergic dysfunction has been implicated in the pathophysiology of schizophrenia, mood disorders, obsessive compulsive disorder (OCD), autism spectrum disorders, attention deficit–hyperactivity disorder (ADHD), tourette's syndrome, substance dependency, Parkinson's disease and other disorders.