Neurons In Substantia Nigra Research Articles

Leaky Optoelectrical Fiber for Optogenetic Stimulation and Electrochemical Detection of Dopamine Exocytosis from Human Dopaminergic Neurons.

In Parkinson's disease, the degeneration of dopaminergic neurons in substantia nigra leads to a decrease in the physiological levels of dopamine in striatum. The existing dopaminergic therapies effectively alleviate the symptoms, albeit they do not revert the disease progression and result in significant adverse effects. Transplanting dopaminergic neurons derived from stem cells could restore dopamine levels without additional motor complications. However, the transplanted cells disperse in vivo and it is not possible to stimulate them on demand to modulate dopamine release to prevent dyskinesia. In order to address these issues, this paper presents a multifunctional leaky optoelectrical fiber for potential neuromodulation and as a cell substrate for application in combined optogenetic stem cell therapy. Pyrolytic carbon coated optical fibers are laser ablated to pattern micro‐optical windows to permit light leakage over a large area. The pyrolytic carbon acts as an excellent electrode for the electrochemical detection of dopamine. Human neural stem cells are genetically modified to express the light sensitive opsin channelrhodopsin‐2 and are differentiated into dopaminergic neurons on the leaky optoelectrical fiber. Finally, light leaking from the micro‐optical windows is used to stimulate the dopaminergic neurons resulting in the release of dopamine that is detected in real‐time using chronoamperometry.

Novel Target Sites for Drug Screening: A Special Reference to Cancer, Rheumatoid Arthritis and Parkinson’s Disease

Background:The humans can be affected by more than 100 types of cancers in which about 22 % cancer death are caused by tobacco, 10% due to alcohol and obesity, 5-10 % by genetic defects and 20 % by infections. Rheumatoid arthritis, an autoimmune disorder, occurs mostly in middle age, affects 2.5 times more to females than males and till 2015, more than 24.5 Million people get affected from this disorder. The deaths due to rheumatoid arthritis were 28000 in 1990 and increased to 38000 in 2013. Parkinson’s disease, a neurodegenerative disorder of central nervous system affects about 6.2 million people in 2015 and responsible for approximately 117400 deaths worldwide. Parkinson’s disease occurs mainly over the age of 60 and males get more affected than females.Methods:Bibliographic database has created by mendeley desktop software for available literature in peer reviewed research articles especially by titles and disease names as keywords with AND Boolean operator (title AND year or author AND year). The intervention and findings of quality papers were extracted by detailed study and a conceptual framework has developed.Results:Total 121 research and review articles are cited in this review to produce high impact in literature for pathophysiology and receptors involved in all three diseases. Changes in enzyme action, prohibition of angiogenesis and inhibition of microtubule are the main areas where anticancer molecules may perform significant effect. The immune system is not a good target for rheumatic treatment due to many complications that occur in body but fibroblast, like synoviocytes, proteases which are responsible for cartilage destruction and osteoclast differentiation may be the beneficial targets for pharmacoactive molecules in the treatment of rheumatoid arthritis. In Parkinson’s disease, supply of dopamine to brain from outside results in brain dopamine synthesis decrement which increase drug dependency. The compounds which stimulate secretion, reuptake inhibitor and increment in dopaminergic neurons may be good targets.Conclusion:Alteration of signal transduction by a drug is the goal of chemogenomics, a new branch formed by combination of chemistry and genomics. The proliferation, angiogenesis and apoptosis of cancer cells are regulated by cellular signaling of transcription factors, protein kinases, transmembrane receptors, extracellular ligands and some external factors like oncogenic mutations, ubiquitin-proteasome pathway with epigenetic changes. Traditional anticancer drugs either alter DNA synthesis or control cell division while new drugs retard tumor growth or induce apoptosis. The deterioration of dopaminergic neurons in substantia nigra results in Parkinson’s disease with mental confusion, cognitive dysfunction and sleep disorder. Rheumatoid arthritis is characterized by inflammation, autoimmunity, joint destruction, deformity and premature mortality and treated mainly by anti-inflammatory and antirheumatic drugs. This review provides a comprehensive summary of objects which may act as potential targets for many health disorders.

In vivo functional diversity of midbrain dopamine neurons within identified axonal projections.

Functional diversity of midbrain dopamine (DA) neurons ranges across multiple scales, from differences in intrinsic properties and connectivity to selective task engagement in behaving animals. Distinct in vitro biophysical features of DA neurons have been associated with different axonal projection targets. However, it is unknown how this translates to different firing patterns of projection-defined DA subpopulations in the intact brain. We combined retrograde tracing with single-unit recording and labelling in mouse brain to create an in vivo functional topography of the midbrain DA system. We identified differences in burst firing among DA neurons projecting to dorsolateral striatum. Bursting also differentiated DA neurons in the medial substantia nigra (SN) projecting either to dorsal or ventral striatum. We found differences in mean firing rates and pause durations among ventral tegmental area (VTA) DA neurons projecting to lateral or medial shell of nucleus accumbens. Our data establishes a high-resolution functional in vivo landscape of midbrain DA neurons.

Noradrenaline is crucial for the substantia nigra dopaminergic cell maintenance

In Parkinson's disease, degeneration of substantia nigra dopaminergic neurons is accompanied by damage on other neuronal systems. A severe denervation is for example seen in the locus coerulean noradrenergic system. Little is known about the relation between noradrenergic and dopaminergic degeneration, and the effects of noradrenergic denervation on the function of the dopaminergic neurons of substantia nigra are not fully understood. In this study, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) was injected in rats, whereafter behavior, striatal KCl-evoked dopamine and glutamate releases, and immunohistochemistry were monitored at 3 days, 3 months, and 6 months. Quantification of dopamine-beta-hydroxylase-immunoreactive nerve fiber density in the cortex revealed a tendency towards nerve fiber regeneration at 6 months. To sustain a stable noradrenergic denervation throughout the experimental timeline, the animals in the 6-month time point received an additional DSP4 injection (2 months after the first injection). Behavioral examinations utilizing rotarod revealed that DSP4 reduced the time spent on the rotarod at 3 but not at 6 months. KCl-evoked dopamine release was significantly increased at 3 days and 3 months, while the concentrations were normalized at 6 months. DSP4 treatment prolonged both time for onset and reuptake of dopamine release over time. The dopamine degeneration was confirmed by unbiased stereology, demonstrating significant loss of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra. Furthermore, striatal glutamate release was decreased after DSP4. In regards of neuroinflammation, reactive microglia were found over the substantia nigra after DSP4 treatment. In conclusion, long-term noradrenergic denervation reduces the number of dopaminergic neurons in the substantia nigra and affects the functionality of the nigrostriatal system. Thus, locus coeruleus is important for maintenance of nigral dopaminergic neurons.

Gene Co-expression Analysis Identifies Histone Deacetylase 5 and 9 Expression in Midbrain Dopamine Neurons and as Regulators of Neurite Growth via Bone Morphogenetic Protein Signaling.

Parkinson’s disease is characterized by the intracellular accumulation of α-synuclein which has been linked to early dopaminergic axonal degeneration. Identifying druggable targets that can promote axonal growth in cells overexpressing α-synuclein is important in order to develop strategies for early intervention. Class-IIa histone deacetylases (HDACs) have previously emerged as druggable targets, however, it is not known which specific class-IIa HDACs should be targeted to promote neurite growth in dopaminergic neurons. To provide insight into this, we used gene co-expression analysis to identify which, if any, of the class-IIa HDACs had a positive correlation with markers of dopaminergic neurons in the human substantia nigra. This revealed that two histone deacetylases, HDAC5 and HDAC9, are co-expressed with TH, GIRK2 and ALDH1A1 in the human SN. We further found that HDAC5 and HDAC9 are expressed in dopaminergic neurons in the adult mouse substantia nigra. We show that siRNAs targeting HDAC5 or HDAC9 can promote neurite growth in SH-SY5Y cells, and that their pharmacological inhibition, using the drug MC1568, promoted neurite growth in cultured rat dopaminergic neurons. Moreover, MC1568 treatment upregulated the expression of the neurotrophic factor, BMP2, and its downstream transcription factor, SMAD1. In addition, MC1568 or siRNAs targeting HDAC5 or HDAC9 led to an increase in Smad-dependent GFP expression in a reporter assay. Furthermore, MC1568 treatment of cultured rat dopaminergic neurons increased cellular levels of phosphorylated Smad1, which was prevented by the BMP receptor inhibitor, dorsomorphin. Dorsomorphin treatment prevented the neurite growth-promoting effects of siRNAs targeting HDAC5, as did overexpression of dominant-negative Smad4 or of the inhibitory Smad7, demonstrating a functional link to BMP signaling. Supplementation with BMP2 prevented the neurite growth-inhibitory effects of nuclear-restricted HDAC5. Finally, we report that siRNAs targeting HDAC5 or HDAC9 promoted neurite growth in cells overexpressing wild-type or A53T-α-synuclein and that MC1568 protected cultured rat dopaminergic neurons against the neurotoxin, MPP+. These findings establish HDAC5 and HDAC9 as novel regulators of BMP-Smad signaling, that additionally may be therapeutic targets worthy of further exploration in iPSC-derived human DA neurons and in vivo models of Parkinson’s disease.

HDAC Inhibition by Valproic Acid Induces Neuroprotection and Improvement of PD-like Behaviors in LRRK2 R1441G Transgenic Mice.

Parkinson’s disease (PD) is one of the late-onset neurodegenerative movement disorder. Major pathological markers of PD include progressive loss of dopaminergic neurons, Lewy body formation, genetic mutations, and environmental factors. Epigenetic regulation of specific gene expression via impaired histone acetylation is associated with neuronal dysfunction in various neurodegenerative diseases. In this study, we hypothesized that histone deacetylase (HDAC) inhibitor, valproic acid (VPA), can improve motor function by enhancing cell survival in PD genetic model mice with LRRK2 R1441G mutation. To address this question, we administered VPA in LRRK2 R1441G transgenic mice to determine whether VPA affects 1) histone acetylation and HDAC expression, 2) dopaminergic neuron survival, 3) inflammatory responses, 4) motor or non-motor symptoms. As results, VPA administration increased histone acetylation level and the number of tyrosine hydroxylase (TH) positive neurons in substantia nigra of LRRK2 R1441G mice. VPA reduced iba-1 positive activated microglia and the mRNA levels of pro-inflammatory marker genes in LRRK2 R1441G mice. In addition, VPA induced the improvement of PD-like motor and non-motor behavior in LRRK2 R1441G mice. These data suggest that the inhibition of HDAC can be further studied as potential future therapeutics for PD.

Deep Brain Stimulation in Sub-Thalamic Nucleus in idiopathic Parkinson’s disease – our initial experience in four cases

Parkinson’s Disease ( PD ) is a chronic neurodegenerative disease . It’s cardinal features are resting tremor, Rigidity, Akinesia and postural instability. Idiopathic Parkinson’s disease develops mainly due to degeneration of Dopaminergic neurons of Substantia Nigra. The role of Subthalamic Nucleus ( STN ) in the development of Parkinsonian Tremmor and other cardinal features is not completely understood yet. However previous studies in monkeys , administration of MPTP ( 1-methyl-4-phenyl- 1.2.3.6.-tetrahydropyridine ) proved that sub thalamic nucleus has a direct role in the development of Parkinsonian tremor and other features. We used no Micro Electrode Recording (MER) system,only studied clinically that Parkinsonian tremor stopped immediately after placement of electrode and same thing happened after micro stimulation of the sensorymotor region of the sub thalamic nucleus .Then high frequency deep brain stimulation ( DBS ) of these same four patients were assessed six months after surgery which led to a significant reduction of Parkinsonian tremor as well as other cardinal features of PD ( p< 0.001 ) . Both postural and resting tremor disappeared completely in three cases and significantly reduced in one case
 Bang. J Neurosurgery 2019; 9(1): 78-83

Interplay of dopamine and GABA in substantia nigra for the regulation of rapid eye movement sleep in rats

Substantia nigra (SN) is rich in dopamine (DA)-ergic and GABA-ergic neurons, which project to and receive inputs from locus coeruleus (LC) and pedunculo-pontine tegmentum (PPT) possessing REM-OFF and REM-ON neurons, respectively. Loss of DA-ergic neurons and disturbed REM sleep (REMS) are associated with Parkinson’s disease, depression and REMS behavior disorder. GABA-ergic projections from SN act pre-synaptically on the noradrenaline (NA)-ergic terminals coming from the LC-REM-OFF neurons onto the REM-ON neurons in PPT and play a critical role in initiating REMS. However, it was unknown how SN neurons get activated and whether the SN-DA-ergic neurons interact with the SN-GABA-ergic neurons for REMS regulation. In freely moving chronically prepared rats, neurons in SN (bilateral) were stimulated by local microinjection of Glutamate (Glut), sparing the fibers of passage, in the presence and absence of i.p. Haloperidol (Hal, DA-antagonist). In other sets, either Hal or Bicuculine (Bic, GABA-antagonist) alone or simultaneously was microinjected bilaterally into the SN and the effects on sleep-wakefulness were recorded. We observed that Glut in SN significantly increased REMS, which was prevented by Hal. REMS was decreased and increased by Hal and Bic, respectively; while their co-injection neutralized (ineffective) the individual effects. Combining these findings with previous reports suggest that the SN-DA-ergic neurons act on the SN-GABA-ergic to regulate REMS. The results advance our understanding of the neuro-anatomo-chemical connections and pharmaco-physiological regulation of REMS in health and diseases.

Neuroprotective and Neurotherapeutic Effects of Tetrahedral Framework Nucleic Acids on Parkinson's Disease in Vitro.

Parkinson's disease (PD) is a neurodegenerative disease characterized by a series of progressive motor disorders. PD is caused by dysfunction of basal ganglia, decrease of dopaminergic neurons in substantia nigra, and abnormal accumulation of Lewy bodies and Lewy neurites. Antiparkinsonian agents, which are currently used for treatment of PD, exhibit unsatisfactory effects on disease control. In recent years, tetrahedral framework nucleic acids (TFNAs) have been considered as multifunctional nanomaterials, and their scope of application has been extended to a wide range of areas. In previous studies, TFNAs were shown to exert positive effects on various cell types in processes such as cell proliferation, cell differentiation, and apoptosis. In the present study, we explored the role of TFNAs in the treatment and prevention of PD in vitro and elucidated its underlying mechanisms of action. On the basis of the experiments conducted, we demonstrated that TFNAs could inhibit and repair the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced apoptosis of PC12 cells through decreasing the accumulation of α-synuclein, one of the characteristic biomarkers of PD. Genes and proteins related to the AKT/PI3K signaling and mitochondrial apoptotic pathways were examined to further support this finding. Most importantly, TFNAs exhibited unexpected neuroprotective and neurorestorative effects on PC12 cells, providing a novel approach for reducing the neuropathological changes caused by PD.

α-Arbutin Protects Against Parkinson's Disease-Associated Mitochondrial Dysfunction In Vitro and In Vivo.

Parkinson's disease (PD), the most common neurodegenerative movement disorder, is characterized by the progressive loss of dopaminergic neurons in substantia nigra. The underlying mechanisms of PD pathogenesis have not been fully illustrated and currently PD remains incurable. Accumulating evidences suggest that mitochondrial dysfunction plays pivotal role in the dopaminergic neuronal death. Therefore, discovery of novel and safe agent for rescuing mitochondrial dysfunction would benefit PD treatment. Here we demonstrated for the first time that α-Arbutin (Arb), a natural polyphenol extracted from Ericaceae species, displayed significant protective effect on the rotenone (Rot)-induced mitochondrial dysfunction and apoptosis of human neuroblastoma cell (SH-SY5Y). We further found that the neuroprotective effect of Arb was associated with ameliorating oxidative stress, stabilizing of mitochondrial membrane potential, and enhancing adenosine triphosphate production. To investigate the underlying mechanism, we checked the AMP-activated protein kinase and autophagy pathway and we found that both were involved in the neuroprotection of Arb. Moreover, we explored the protective effect of Arb in drosophila PD model and found that Arb rescued parkin deficiency-induced motor function disability and mitochondrial abnormality of drosophila. Taken together, our study demonstrated that Arb got excellent neuroprotective effect on PD models both in vitro and in vivo and Arb might serve as a potent therapeutic agent for the treatment of PD.

Oxidative stress and α-synuclein conspire in vulnerable neurons to promote Parkinson's disease progression.

Patients with Parkinson's disease (PD) show selective degeneration of dopaminergic neurons in the substantia nigra and cholinergic neurons in the dorsal motor nucleus (DMnX), but the drivers of this specific susceptibility are unknown. In this issue of the JCI, Musgrove et al. report on their use of an impressive array of in vivo and ex vivo tools for interrogating DMnX neurons and demonstrate that this population exhibits enhanced sensitivity to oxidative stress. Remarkably, this sensitivity was amplified by the overexpression of α-Synuclein (α-Syn), a pathological protein in PD. They further show that oxidative stress augments cell-cell transfer of α-Syn, which may be an important mechanism underlying the development and progression of PD.

Luteolin-7-O-glucoside protects dopaminergic neurons by activating estrogen-receptor-mediated signaling pathway in MPTP-induced mice

BackgroundParkinson's disease (PD) is a neurodegenerative disorder that is characterized by the degeneration of dopaminergic neurons in substantia nigra (SN). Accumulating evidences implicate the beneficial role of estrogen in the therapy of PD. MethodsIn the present study, the protective function of luteolin-7-O-glucoside (LUT-7G), a natural flavonoid, was investigated in 1-methyl-4-phenylpyridinium (MPP+) treated SH-SY5Y cells and 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) induced mice. ResultsPre-treatment of LUT-7G increased the viability and reduced the apoptosis of SH-SY5Y cells treated by MPP+. At molecular level, the Bcl-2/Bax ratio was increased, while the expression of cleaved caspase 3 was markedly lessened. Moreover, LUT-7G increased the expression of estrogen receptor (ER), ERα and ERβ, and enhanced the activation of ERK1/2/STAT3/c-Fos that could be abolished by ER antagonists. Furthermore, in vivo experiment indicated that pre-treatment of LUT-7G improved the bradykinesia, and enhanced the muscle strength as well as the balancing capacity of mice treated with MPTP. And LUT-7G prevented the injury of TH positive cells in substantia nigra and increased TH positive nerve fibers in striatum. In addition, pre-treatment of LUT-7G also significantly diminished the MPTP-induced gliosis in substantia nigra. ConclusionsLUT-7G effectively protected dopaminergic neurons against MPP+ or MPTP-induced toxicity, probably by activating the ER-mediated signaling pathway. Our findings explore the therapeutic potential of LUT-7G for PD therapy.

FGF-2 isoforms influence the development of dopaminergic neurons in the murine substantia nigra, but not anxiety-like behavior, stress susceptibility, or locomotor behavior

BackgroundLoss of fibroblast growth factor 2 (FGF-2) is responsible for the development of an increased number of dopaminergic (DA) neurons in the murine substantia nigra pars compacta (SNpc). Furthermore, dysregulation of its expression patterns within the central nervous system (CNS) is associated with behavioral abnormalities in mice. Until now, the contributions of the individual FGF-2 isoforms (one low (LMW) and two high molecular weight (HMW) isoforms) in the CNS are elusive. MethodsTo unravel the specific effects of FGF-2 isoforms, we compared three knockout mouse lines, one only deficient for LMW, one deficient for HMW and another lacking both isoforms, regarding DA neuronal development. With this regard, three time points of ontogenic development of the SNpc were stereologically investigated. Furthermore, behavioral aspects were analyzed in young adult mice, supplemented by corticosterone measurements. ResultsJuvenile mice lacking either LMW or HMW develop equal supernumerary DA neuron numbers in the SNpc. Compensatory increased LMW expression is observed in animals lacking HMW. Meanwhile, no knockout mouse line demonstrated changes in anxiety-like behavior, stress susceptibility, or locomotor behavior. ConclusionsBoth FGF-2 isoforms crucially influence DA neuronal development in the murine SNpc. However, absence of LMW or HMW alone alters neither anxiety-like nor locomotor behavior, or stress susceptibility. Therefore, FGF-2 is not a determinant and causative factor for behavioral alterations alone, but probably in combination with appropriate conditions, like environmental or genetic factors.

Enhanced ATP release and CD73-mediated adenosine formation sustain adenosine A2A receptor over-activation in a rat model of Parkinson's disease.

Parkinson's disease (PD) involves an initial loss of striatal dopamine terminals evolving into degeneration of dopamine neurons in substantia nigra (SN), which can be modelled by 6-hydroxydopamine (6-OHDA) administration. Adenosine A2A receptor blockade attenuates PD features in animal models, but the source of the adenosine causing A2A receptor over-activation is unknown. As ATP is a stress signal, we have tested if extracellular catabolism of adenine nucleotides into adenosine (through ecto-5'-nucleotidase or CD73) leads to A2A receptor over-activation in PD. Effects of blocking CD73 with α,β-methylene ADP (AOPCP) were assayed in 6-OHDA-treated rats and dopamine-differentiated neuroblastoma SH-SY5Y cells. 6-OHDA increased ATP release and extracellular conversion into adenosine through CD73 up-regulation in SH-SY5Y cells. Removing extracellular adenosine with adenosine deaminase, blocking CD73 with AOPCP, or blocking A2A receptors with SCH58261 were equi-effective in preventing 6-OHDA-induced damage in SH-SY5Y cells. In vivo striatal exposure to 6-OHDA increased ATP release and extracellular formation of adenosine from adenosine nucleotides and up-regulated CD73 and A2A receptors in striatal synaptosomes. Intracerebroventricular administration of AOPCP phenocopied effects of SCH58261, attenuating 6-OHDA-induced (a) increase of contralateral rotations after apomorphine, (b) reduction of dopamine content in striatum and SN, (c) loss of TH staining in striatum and SN, (d) motor dysfunction in the cylinder test, and (e) short-term memory impairment in the object recognition test. Our data indicate that increased ATP-derived adenosine formation is responsible for A2A receptor over-activation in PD, suggesting CD73 as a new target to manage PD.

Sex-specific neuroprotection by inhibition of the Y-chromosome gene, SRY, in experimental Parkinson’s disease

Parkinson's disease (PD) is a debilitating neurodegenerative disorder caused by the loss of midbrain dopamine (DA) neurons. While the cause of DA cell loss in PD is unknown, male sex is a strong risk factor. Aside from the protective actions of sex hormones in females, emerging evidence suggests that sex-chromosome genes contribute to the male bias in PD. We previously showed that the Y-chromosome gene, SRY, directly regulates adult brain function in males independent of gonadal hormone influence. SRY protein colocalizes with DA neurons in the male substantia nigra, where it regulates DA biosynthesis and voluntary movement. Here we demonstrate that nigral SRY expression is highly and persistently up-regulated in animal and human cell culture models of PD. Remarkably, lowering nigral SRY expression with antisense oligonucleotides in male rats diminished motor deficits and nigral DA cell loss in 6-hydroxydopamine (6-OHDA)-induced and rotenone-induced rat models of PD. The protective effect of the SRY antisense oligonucleotides was associated with male-specific attenuation of DNA damage, mitochondrial degradation, and neuroinflammation in the toxin-induced rat models of PD. Moreover, reducing nigral SRY expression diminished or removed the male bias in nigrostriatal degeneration, mitochondrial degradation, DNA damage, and neuroinflammation in the 6-OHDA rat model of PD, suggesting that SRY directly contributes to the sex differences in PD. These findings demonstrate that SRY directs a previously unrecognized male-specific mechanism of DA cell death and suggests that suppressing nigral Sry synthesis represents a sex-specific strategy to slow or prevent DA cell loss in PD.

Moxibustion Exerts a Neuroprotective Effect through Antiferroptosis in Parkinson's Disease.

The objective of this study was to explore the neuroprotective effect of moxibustion on rats with Parkinson's disease (PD) and its mechanism. A Parkinson's disease model was established in rats using a two-point stereotactic 6-hydroxydopamine injection in the right substantia nigra (SN) and ventral tegmental area. The rats received moxibustion at the Baihui (GV20) and Sishencong (EX-HN1) acupoints for 20 minutes, six times a week, for 6 weeks. The right SN tissue was histologically and immunohistochemically examined. Differentially expressed genes (DEGs) were identified through RNA sequencing. In addition, the levels of tyrosine hydroxylase (TH), glutathione peroxidase 4 (GPX4), and ferritin heavy chain 1 (FTH1) in SN were measured. In comparison to the model group, the moxibustion group showed a significantly greater TH immunoreactivity and a higher behavioural score. In particular, moxibustion led to an increase in the number and morphological stability of SN neural cells. The functional pathway analysis showed that DEGs are closely related to the ferroptosis pathway. GPX4 and FTH1 in the SN were significantly overexpressed in the moxibustion-treated rats with PD. Moxibustion can effectively reduce the death of SN neurons, decrease the occurrence of ferroptosis, and increase the TH activity to protect the neurons in rats with PD. The protective mechanism may be associated with suppression of the ferroptosis.

Electrophysiological Characterization of Nicotine-Induced Excitation of Dopaminergic Neurons in the Rat Substantia Nigra

Electrophysiological Characterization of Nicotine-Induced Excitation of Dopaminergic Neurons in the Rat Substantia Nigra

Downregulation of lncRNA UCA1 ameliorates the damage of dopaminergic neurons, reduces oxidative stress and inflammation in Parkinson's disease through the inhibition of the PI3K/Akt signaling pathway

This study is conducted to investigate the role of lncRNA urothelial carcinoma-associated 1 (UCA1) in the protection of dopaminergic neurons in Parkinson's disease (PD) through regulating the PI3K/Akt signaling pathway. PD rat model was induced by injection of 6-hydroxydopamine (6-OHDA) to damage the substantia nigra striatum. The successfully modeled PD rats were introduced with siRNA-negative control (NC) or UCA1-siRNA. The expression of UCA1 in neurobehavioral change, neuroinflammatory response and oxidative stress of PD rats were explored. The effect of UCA1 on the PI3K/Akt signaling pathway and downstream proteins IκBα and ERK was also investigated. The rats with PD exhibited aggregated neurobehavioral change, increased neuroinflammatory response and oxidative stress. Down-regulation of UCA1 up-regulated the expression of TH positive cells and DA content, reduced the apoptosis of substantia nigra neurons, the apoptosis of substantia nigra neurons and oxidative stress and improved the neuroinflammatory response in PD rats. Down-regulation of UCA1 inhibited the activation of the PI3K/AKT signaling pathway in substantia nigra of PD rats. Our study suggests that the downregulated lncRNA UCA1 ameliorates the damage of dopaminergic neurons, reduces oxidative stress and inflammation in PD rats through the inhibition of the PI3K/Akt signaling pathway.

α-synuclein−lipoprotein interactions and elevated ApoE level in cerebrospinal fluid from Parkinson's disease patients

The progressive accumulation, aggregation, and spread of α-synuclein (αSN) are common hallmarks of Parkinson's disease (PD) pathology. Moreover, numerous proteins interact with αSN species, influencing its toxicity in the brain. In the present study, we extended analyses of αSN-interacting proteins to cerebrospinal fluid (CSF). Using coimmunoprecipitation, followed by mass spectrometry, we found that αSN colocalize with apolipoproteins on lipoprotein vesicles. We confirmed these interactions using several methods, including the enrichment of lipoproteins with a recombinant αSN, and the subsequent uptake of prepared vesicles by human dopaminergic neuronal-like cells. Further, we report an increased level of ApoE in CSF from early PD patients compared with matched controls in 3 independent cohorts. Moreover, in contrast to controls, we observed the presence of ApoE-positive neuromelanin-containing dopaminergic neurons in substantia nigra of PD patients. In conclusion, the cooccurrence of αSN on lipoprotein vesicles, and their uptake by dopaminergic neurons along with an increase of ApoE in early PD, proposes a mechanism(s) for αSN spreading in the extracellular milieu of PD.

Type 2 diabetes and Parkinson's disease

Type 2 diabetes and Parkinson's disease