Neurons In Substantia Nigra Research Articles

Neuronal Presentation of Antigen and Its Possible Role in Parkinson's Disease.

Patients with Parkinson’s disease (PD) and other synucleinopathies often exhibit autoimmune features, including CD4+ and some CD8+ T lymphocytes that recognize epitopes derived from alpha-synuclein. While neurons have long been considered to not present antigens, recent data indicate that they can be induced to do so, particularly in response to interferons and other forms of stress. Here, we review literature on neuronal antigen presentation and its potential role in PD. Although direct evidence for CD8+ T cell-mediated neuronal death is lacking in PD, neuronal antigen presentation appears central to the pathology of Rasmussen’s encephalitis, a pediatric neurological disorder driven by cytotoxic T cell infiltration and neuroinflammation. Emerging data suggest that T cells enter the brain in PD and other synucleinopathies, where the majority of neuromelanin-containing substantia nigra and locus coeruleus neurons express MHC Class I molecules. In cell culture, CD8+ T cell recognition of antigen:MHC Class I complexes on neuronal membranes leads to cytotoxic responses and neuronal cell death. Recent animal models suggest the possibility of T cell autoreactivity to mitochondrial antigens in PD. It remains unclear if neuronal antigen presentation plays a role in PD or other neurodegenerative disorders, and efforts are underway to better elucidate the potential impact of autoimmune responses on neurodegeneration.

The effect of dopaminergic neuron transplantation and melatonin co-administration on oxidative stress-induced cell death in Parkinson’s disease

A gradual degeneration of the striatum and loss of nigral dopamine cells are characteristic of Parkinson's disease. Nowadays, combination therapy for neurodegenerative disease is considered. This study aimed to investigate the effects of melatonin and dopaminergic neurons derived from adipose tissue stem cells (ADSCs) in a rat model of Parkinson’s disease. Parkinson’s disease was induced in rats using neurotoxin 6-Hydroxydopamine. The treatment was performed using melatonin and dopaminergic neurons transplantation. Subsequently, behavioral tests, western blot analysis for Caspase-3 expression, GSH (Glutathione) content and stereology analysis for the volume and cell number of substantia nigra and striatum were performed. Treatment with melatonin and dopaminergic neuron transplantation increased the number of neurons in substantia nigra and striatum while the number of glial cell and the volume of substantia nigra and striatum did not show significant change between groups. Western blot analysis for caspase 3 indicated the significant differences between groups. The results also indicated the increased level of glutathione (GSH) content in treatment groups. this study showed that combination therapy with melatonin and dopaminergic neurons could greatly protect the neurons, reduce oxidative stress and improve the symptoms of PD.

6-Hydroxydopamine-Induced Neurotoxicity in Rat Model of Parkinson’s Disease: Is Reversed via Anti-Oxidative Activities of Curcumin and Aerobic Exercise Therapy

In the rat model, 6-hydroxydopamine (6-OHDA) known as a selective catecholaminergic neurotoxin used chiefly in modeling Parkinson's disease (PD). Continuous aerobic exercise and curcumin supplementations could play a vital role in neuroprotection. This study aimed to explore the neuroprotective roles of regular aerobic exercise and curcumin during PD. For this, rats were treated as follows for 8 consecutive weeks (5 d in a week): For this, animals were orally treated with curcumin (50 ml/kg) alone or in combination with aerobic exercise. Compared with a control group, induction of PD by 6-OHDA increased the amount of alpha-synuclein protein and malondialdehyde levels and decreased the number of substantia nigra neurons, total antioxidant capacity, and glutathione peroxidase activity in brain tissue. All these changes were abolished by the administration of curcumin with aerobic exercise treatments. Activity behavioral tests also confirmed the above-mentioned results by increasing the rod test time and the number of rotations due to apomorphine injection. Histopathology assays mimic the antioxidant activity and behavioral observations. Combined curcumin with aerobic exercise treatments is potentially an effective strategy for modifying the dopaminergic neuron dysfunction in 6-OHDA-induced rats modeling PD via dual inhibiting oxidative stress indices and regulating behavioral tasks.

Evaluation of iron overload in nigrosome 1 via quantitative susceptibility mapping as a progression biomarker in prodromal stages of synucleinopathies

Idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) is a prodromal stage of α-synucleinopathies, such as Parkinson's disease (PD), which are characterized by the loss of dopaminergic neurons in substantia nigra, associated with abnormal iron load. The assessment of presymptomatic biomarkers predicting the onset of neurodegenerative disorders is critical for monitoring early signs, screening patients for neuroprotective clinical trials and understanding the causal relationship between iron accumulation processes and disease development. Here, we used Quantitative Susceptibility Mapping (QSM) and 7T MRI to quantify iron deposition in Nigrosome 1 (N1) in early PD (ePD) patients, iRBD patients and healthy controls and investigated group differences and correlation with disease progression. We evaluated the radiological appearance of N1 and analyzed its iron content in 35 ePD, 30 iRBD patients and 14 healthy controls via T2*-weighted sequences and susceptibility (χ) maps. N1 regions of interest (ROIs) were manually drawn on control subjects and warped onto a study-specific template to obtain probabilistic N1 ROIs. For each subject the N1 with the highest mean χ was considered for statistical analysis. The appearance of N1 was rated pathological in 45% of iRBD patients. ePD patients showed increased N1 χ compared to iRBD patients and HC but no correlation with disease duration, indicating that iron load remains stable during the early stages of disease progression. Although no difference was reported in iron content between iRBD and HC, N1 χ in the iRBD group increases as the disease evolves. QSM can reveal temporal changes in N1 iron content and its quantification may represent a valuable presymptomatic biomarker to assess neurodegeneration in the prodromal stages of PD.

β2-subunit alternative splicing stabilizes Cav2.3 Ca2+ channel activity during continuous midbrain dopamine neuron-like activity.

In dopaminergic (DA) Substantia nigra (SN) neurons Cav2.3 R-type Ca2+-currents contribute to somatodendritic Ca2+-oscillations. This activity may contribute to the selective degeneration of these neurons in Parkinson's disease (PD) since Cav2.3-knockout is neuroprotective in a PD mouse model. Here, we show that in tsA-201-cells the membrane-anchored β2-splice variants β2a and β2e are required to stabilize Cav2.3 gating properties allowing sustained Cav2.3 availability during simulated pacemaking and enhanced Ca2+-currents during bursts. We confirmed the expression of β2a- and β2e-subunit transcripts in the mouse SN and in identified SN DA neurons. Patch-clamp recordings of mouse DA midbrain neurons in culture and SN DA neurons in brain slices revealed SNX-482-sensitive R-type Ca2+-currents with voltage-dependent gating properties that suggest modulation by β2a- and/or β2e-subunits. Thus, β-subunit alternative splicing may prevent a fraction of Cav2.3 channels from inactivation in continuously active, highly vulnerable SN DA neurons, thereby also supporting Ca2+ signals contributing to the (patho)physiological role of Cav2.3 channels in PD.

Role of Nrf2 in Parkinson's Disease: Toward New Perspectives.

Parkinson’s disease (PD) is one of the most common and chronic degenerative diseases in the central nervous system. The main pathology of PD formation is the progressive loss of dopaminergic neurons in substantia nigra and the formation of α-synuclein-rich Lewy bodies. The pathogenesis of PD is not caused by any single independent factor. The diversity of these independent factors of PD, such as iron accumulation, oxidative stress, neuroinflammation, mitochondrial dysfunction, age, environment, and heredity, makes the research progress of PD slow. Nrf2 has been well-known to be closely associated with the pathogenesis of PD and could regulate these induced factors development. Nrf2 activation could protect dopaminergic neurons and slow down the progression of PD. This review summarized the role of Nrf2 pathway on the pathogenesis of PD. Regulation of Nrf2 pathway might be one of the promising strategies to prevent and treat PD.

Age-dependent neurodegeneration and neuroinflammation in a genetic A30P/A53T double-mutated α-synuclein mouse model of Parkinson's disease

The pathogenesis of Parkinson's disease (PD) is closely interwoven with the process of aging. Moreover, increasing evidence from human postmortem studies and from animal models for PD point towards inflammation as an additional factor in disease development. We here assessed the impact of aging and inflammation on dopaminergic neurodegeneration in the hm2α-SYN-39 mouse model of PD that carries the human, A30P/A53T double-mutated α-synuclein gene. At 2–3 months of age, no significant differences were observed comparing dopaminergic neuron numbers of the substantia nigra (SN) pars compacta of hm2α-SYN-39 mice with wildtype controls. At an age of 16–17 months, however, hm2α-SYN-39 mice revealed a significant loss of dopaminergic SN neurons, of dopaminergic terminals in the striatum as well as a reduction of striatal dopamine levels compared to young, 2–3 months transgenic mice and compared to 16–17 months old wildtype littermates. A significant age-related correlation of infiltrating CD4+ and CD8+ T cell numbers with dopaminergic terminal loss of the striatum was found in hm2α-SYN-39 mice, but not in wildtype controls. In the striatum of 16–17 months old wildtype mice a slightly elevated CD8+ T cell count and CD11b+ microglia cell count was observed compared to younger aged mice. Additional analyses of neuroinflammation in the nigrostriatal tract of wildtype mice did not yield any significant age-dependent changes of CD4+, CD8+ T cell and B220+ B cell numbers, respectively. In contrast, a significant age-dependent increase of CD8+ T cells, GFAP+ astrocytes as well as a pronounced increase of CD11b+ microglia numbers were observed in the SN of hm2α-SYN-39 mice pointing towards a neuroinflammatory processes in this genetic mouse model for PD. The findings in the hm2α-SYN-39 mouse model strengthen the evidence that T cell and glial cell responses are involved in the age-related neurodegeneration in PD. The slow and age-dependent progression of neurodegeneration and neuroinflammation in the hm2α-SYN-39 PD rodent model underlines its translational value and makes it suitable for studying anti-inflammatory therapies.

Neuromelanins in brain aging and Parkinson's disease: synthesis, structure, neuroinflammatory, and neurodegenerative role.

Neuromelanins are compounds accumulating in neurons of human and animal brain during aging, with neurons of substantia nigra and locus coeruleus having the highest levels of neuromelanins. These compounds have melanic, lipid, peptide, and inorganic components and are contained inside special autolysosomes. Neuromelanins can participate in neuroprotective or toxic processes occurring in Parkinson's disease according to cellular environment. Their synthesis depends on the concentration of cytosolic catechols and is a protective process since it prevents the toxic accumulation of catechols-derived reactive compounds. Neuromelanins can be neuroprotective also by binding reactive/toxic metals to produce stable and non-toxic complexes. Extraneuronal neuromelanin released by dying dopamine neurons in Parkinson's disease activates microglia which generate reactive oxygen species, reactive nitrogen species, and proinflammatory molecules, thus producing still neuroinflammation and neuronal death. Synthetic neuromelanins have been prepared with melanic, protein structure, and metal content closely mimicking the natural brain pigment, and these models are also able to activate microglia. Neuromelanins have different structure, synthesis, cellular/subcellular distribution, and role than melanins of hair, skin, and other tissues. The main common aspect between brain neuromelanin and peripheral melanin is the presence of eumelanin and/or pheomelanin moieties in their structure.

Cav1.3 calcium channels are full-range linear amplifiers of firing frequencies in lateral DA SN neurons.

The low-threshold L-type calcium channel Cav1.3 accelerates the pacemaker rate in the heart, but its functional role for the extended dynamic range of neuronal firing is still unresolved. Here, we show that Cav1.3 calcium channels act as unexpectedly simple, full-range linear amplifiers of firing rates for lateral dopamine substantia nigra (DA SN) neurons in mice. This means that they boost in vitro or in vivo firing frequencies between 2 and 50 hertz by about 30%. Furthermore, we demonstrate that clinically relevant, low nanomolar concentrations of the L-type channel inhibitor isradipine selectively reduce the in vivo firing activity of these nigrostriatal DA SN neurons at therapeutic plasma concentrations. Thus, our study identifies the pacemaker function of neuronal Cav1.3 channels and provides direct evidence that repurposing dihydropyridines such as isradipine is feasible to selectively modulate the in vivo activity of highly vulnerable DA SN subpopulations in Parkinson’s disease.

Wnt/β-catenin signaling pathway is involved in early dopaminergic differentiation of trabecular meshwork-derived mesenchymal stem cells.

Permanent degeneration and loss of dopaminergic (DA) neurons in substantia nigra is the main cause of Parkinson's disease. Considering the therapeutic application of stem cells in neurodegeneration, we sought to examine the neurogenic differentiation potential of the newly introduced neural crest originated mesenchymal stem cells (MSCs), namely, trabecular meshwork-derived mesenchymal stem cells (TM-MSCs) compared to two other sources of MSCs, adipose tissue-derived stem cells(ADSCs) and bone marrow-derived mesenchymal stem cells (BM-MSCs). The three types of cells were therefore cultured in the presence and absence of a neural induction medium followed by the analysis of their differentiation potentials. Our results showed that TM-MSCs exhibited enhanced neural morphologies as well as higher expressions of MAP2 as the general neuron marker and Nurr-1 as an early DA marker compared to the adipose tissue-derived mesenchymal stem cells(AD-MSCs) and bone marrow-derived stem cells(BMSCs). Also, analysis of Nurr-1 immunostaining showed more intense Nurr-1 stained nuclei in the neurally induced TM-MSCs compared to those in the AD-MSCs, BMSCs, and noninduced control TM-MSCs. To examine if Wnt/beta-catenin pathway drives TM-MSCs towards a DA fate, we treated them with the Wnt agonist (CHIR, 3 μM) and the Wnt antagonist (IWP-2, 3 μM). Our results showed that the expressions of Nurr-1 and MAP2, as well as the Wnt/beta-catenin target genes, c-Myc and Cyclin D1, were significantly increased in the CHIR-treated TM-MSCs, but significantly reduced in those treated with IWP-2. Altogether, we declare firsta higher neural potency of TM-MSCs compared to the more commonly used MSCs, BMSCs and ADSCs, and secondthat Wnt/beta-catenin activation directs the neurally induced TM-MSCs towards a DA fate.

Respiratory Functional and Neuroanatomical Changes in 6‐OHDA Model of Parkinson’s Disease Require Tumor Necrosis Factor Alpha Receptor 1

Most deaths of Parkinson’s Disease (PD) patients are due to respiratory complications which appears in the late stages of this disease. Previous studies have shown brainstem degeneration which is probably linked to respiratory function impairment in a rat model of PD induced by 6‐hydroxydopamine (6‐OHDA) injection in caudate‐putamen (CPu). One of the hypotheses that explains why neurons die in this PD model is neuroinflammation mediated by a cytokine called tumor necrosis factor alpha (TNF‐α). So, this study aims to investigate the role of TNF‐α in respiratory functional and neuroanatomical deficits in the animal model of PD induced by 6‐OHDA. C57BL/6 or TNF‐α receptor 1 knockout mice (TNFR1‐/‐) were anesthetized with isoflurane 2.5% and received bilateral injection of 6‐OHDA (10 µg/µl) or vehicle in CPu through stereotaxic surgery. 20 days after surgery, mice were submitted to whole body plethysmography under normal and hypercapnic conditions (7% CO2). Animals were perfused and the brains were removed to neuroanatomical analysis. 6‐OHDA destroyed TH+ neurons in Substantia nigra (SNc) in all groups analyzed (6‐OHDA WT: 77%; 6‐OHDA TNFR1‐/‐: 79%). Degeneration was observed in preBötzinger complex (preBötC) and in retrotrapezoid nucleus (RTN) in 6‐OHDA WT group, but not in 6‐OHDA TNFR1‐/‐ group (preBötC: 6‐OHDA WT: 43%, 6‐OHDA TNFR1‐/‐: 22%; RTN: 6‐OHDA WT: 52%; 6‐OHDA TNFR1‐/‐: 15%). Astrocyte’s density in SNc is enhanced in 6‐OHDA WT group but not in 6‐OHDA TNFR1‐/‐ group (6‐OHDA WT: 122%) and is reduced in preBötC in all groups analyzed (p<0.05), while in RTN, no change was observed. Microglia analysis indicates neuroinflammation in SNc and RTN in all groups. Respiratory assessment reveals reduction in basal respiratory rate in 6‐OHDA WT group but not in 6‐OHDA TNFR1‐/‐ group (6‐OHDA WT: 25%; 6‐OHDA TNFR1‐/‐: 17%). No change was observed between groups in respiratory parameters under hypercapnia. Considering all results presented here we can state that in this model of PD, respiratory deficits are associated with neurodegeneration in respiratory brainstem areas. Abolishing TNF‐α inflammation pathway, reduction in respiratory rate and degeneration of brainstem areas involved with neural control of breathing are prevented indicating the involvement of this pathway in the respiratory changes found in the 6‐OHDA model of PD.

Alpha-synuclein peptides presented on chimeric MHC class Ib molecules prevent loss of substantia nigra neurons in an animal model for Parkinson’s disease

Abstract Aim An accumulating body of evidence suggests the involvement of alpha-synuclein (aSyn) specific autoreactive T cells in Parkinson’s disease (PD). Here, we investigate whether novel antigen-specific tolerance-inducing biomolecules, that present peptide antigens on MHC class Ib-related molecules, can inhibit neurodegeneration and prevent PD in vivo. Methods The alpha3 domain of the human MHC class Ib molecule HLA-G inhibits T cells via the human ILT-2 or the murine PIRB receptor. We fused this HLA-G alpha3 domain to MHC class I alpha1-alpha2 antigen presenting domains, antigenic peptides and beta2-microglobulin. These single-chain AutoImmunity Modifying Biologicals (AIM Bios) induce antigen-specific tolerogenic CD8+ Treg cells in human cells in vitro and in mice in vivo. We used this platform to prevent autoimmune disease symptoms in mouse models for autoimmune diseases, including an aSynA53T-AAV driven model for PD. Results Single-chain model AIM Bios with MHC-derived antigen-presenting domains and antigenic peptides polarize cognate CD8+ T cells towards a CD8+CD122+ IL-10 secreting Treg phenotype. Such antigen-specific Treg can also be induced in mice in vivo. Disease-associated aSyn CD8+ epitopes were identified in aSynA53T-AAV PD mice. Corresponding AIM Bios prevented mobility impairments. Post mortem histopathological assessment confirmed the induction a favorable in-situ immune cell composition and the rescue of substantia nigra neurons. The translational potential of this approach deserves further exploration. Supported by grants from the IZKF Wuerzburg A421 and by Aeterna Zentaris Inc.

Wuzi Yanzong pill attenuates MPTP-induced Parkinson’s Disease via PI3K/Akt signaling pathway

Wuzi Yanzong Pill (WYP) was found to play a protective role on nerve cells and neurological diseases, however the molecular mechanism is unclear. To understand the molecular mechanisms that underly the neuroprotective effect of WYP on dopaminergic neurons in Parkinson's disease (PD). PD mouse model was induced by the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Gait and hanging tests were used to assess motor behavioral function. Immunofluorescence assay was used to determine TH-positive neurons in substantia nigra (SN). Apoptosis, dopamine and neurotrophic factors as well as expression of PI3K/Akt pathway were detected by TUNEL staining, ELISA and western blotting, respectively. First, it was observed that WYP intervention improved abnormal motor function in MPTP-induced PD model, alleviated the loss of TH+ neurons in SN, and increased dopamine content in brain, revealing a potential protective effect. Second, network pharmacology was used to analyze the possible targets and pathways of WYP action in the treatment of PD. A total of 126 active components related to PD were screened in WYP, and the related core targets included ALB, GAPDH, Akt1, TP53, IL6 and TNF. Particularly, the effect of WYP on PD may be medicate through PI3K/Akt signaling pathway and apoptotic regulation. The WYP treated PD mice had higher expression of p-PI3K, p-Akt and Bcl-2 but lower expression of Bax and cleaved caspase-3 than the non-WYP treated PD mice. Secretion of brain-derived neurotrophic factor (BDNF) and cerebral dopamine neurotrophic factor (CDNF) were also increased in the treated mice. WYP may inhibit apoptosis and increase the secretion of neurotrophic factor via activating PI3K/ Akt signaling pathway, thus protecting the loss of dopamine neurons in MPTP-induced PD mice.

Parkinsonism Attenuation by Antihistamines via Downregulating the Oxidative Stress, Histamine, and Inflammation.

Parkinson disease (PD) is a neurodegenerative disorder of the motor activity of the brain, regulated by dopaminergic neurons of substantia nigra, resulting in an increased density of histaminergic fibers. This study was aimed to evaluate the effects of H1 antagonist’s ebastine and levocetirizine in PD per se and in combination. Animals were divided into 9 groups (n = 10). Group 1 received carboxymethyl cellulose CMC (1 mL/kg). Group II was treated with haloperidol (1 mg/kg) (diseased group). Group III was treated with levodopa/carbidopa (levo 20 mg/kg). Groups IV and V were treated with ebastine at dose levels of 2 and 4 mg/kg, respectively. Groups VI and VII were treated with levocetirizine at dose levels of 0.5 and 1 mg/kg, respectively. Group VIII was treated with ebastine (4 mg/kg) + levo (20 mg/kg) in combination. Group IX was treated with levocetirizine (1 mg/kg) + levo (20 mg/kg). PD was induced with haloperidol (1 mg/kg iv, once daily for 23 days) for a duration of 30 min. Behavioral tests like rotarod, block and triple horizontal bars, actophotometer, and open field were performed. Biochemical markers of oxidative stress, i.e., SOD, CAT, GSH, MDA, dopamine, serotonin, and nor-adrenaline and nitrite, were determined. Histamine, mRNA expression of α-synuclein, and TNF-α level in the serum and brain of mice were analyzed. Endogenous biochemical markers were increased except mRNA expression of α-synuclein, which was reduced. In combination therapy with the standard drug, ebastine (4 mg/kg) significantly improved the cataleptic state and dopamine levels, but no significant difference in the renal and liver functioning tests was observed. This study concluded that ebastine (4 mg/kg) might work in the treatment of PD as it improves the cataleptic state in haloperidol-induced catalepsy.

Tracing brain genotoxic stress in Parkinson's disease with a novel single-cell genetic sensor.

To develop an in vivo tool to probe brain genotoxic stress, we designed a viral proxy as a single-cell genetic sensor termed PRISM that harnesses the instability of recombinant adeno-associated virus genome processing and a hypermutable repeat sequence–dependent reporter. PRISM exploits the virus-host interaction to probe persistent neuronal DNA damage and overactive DNA damage response. A Parkinson’s disease (PD)–associated environmental toxicant, paraquat (PQ), inflicted neuronal genotoxic stress sensitively detected by PRISM. The most affected cell type in PD, dopaminergic (DA) neurons in substantia nigra, was distinguished by a high level of genotoxic stress following PQ exposure. Human alpha-synuclein proteotoxicity and propagation also triggered genotoxic stress in nigral DA neurons in a transgenic mouse model. Genotoxic stress is a prominent feature in PD patient brains. Our results reveal that PD-associated etiological factors precipitated brain genotoxic stress and detail a useful tool for probing the pathogenic significance in aging and neurodegenerative disorders.

Intraperitoneal Administration of Forskolin Reverses Motor Symptoms and Loss of Midbrain Dopamine Neurons in PINK1 Knockout Rats.

Background:Parkinson’s disease (PD) is a relentless, chronic neurodegenerative disease characterized by the progressive loss of substantia nigra (SN) neurons that leads to the onset of motor and non-motor symptoms. Standard of care for PD consists of replenishing the loss of dopamine through oral administration of Levodopa; however, this treatment is not disease-modifying and often induces intolerable side effects. While the etiology that contributes to PD is largely unknown, emerging evidence in animal models suggests that a significant reduction in neuroprotective Protein Kinase A (PKA) signaling in the SN contributes to PD pathogenesis, suggesting that restoring PKA signaling in the midbrain may be a new anti-PD therapeutic alternative.Objective:We surmised that pharmacological activation of PKA via intraperitoneal administration of Forskolin exerts anti-PD effects in symptomatic PTEN-induced kinase 1 knockout (PINK1-KO), a bona fide in vivo model of PD.Methods:By using a beam balance and a grip strength analyzer, we show that Forskolin reverses motor symptoms and loss of hindlimb strength with long-lasting therapeutic effects (> 5 weeks) following the last dose.Results:In comparison, intraperitoneal treatment with Levodopa temporarily (24 h) reduces motor symptoms but unable to restore hindlimb strength in PINK1-KO rats. By using immunohistochemistry and an XF24e BioAnalyzer, Forskolin treatment reverses SN neurons loss, elevates brain energy production and restores PKA activity in SN in symptomatic PINK1-KO rats.Conclusion:Overall, our collective in vivo data suggest that Forskolin is a promising disease-modifying therapeutic alternative for PD and is superior to Levodopa because it confers long-lasting therapeutic effects.

Picornavirus May Be Linked to Parkinson's Disease through Viral Antigen in Dopamine-Containing Neurons of Substantia Nigra.

Parkinson’s disease (PD) is a neurodegenerative disease linked with the loss of dopaminergic neurons in the brain region called substantia nigra and caused by unknown pathogenic mechanisms. Two currently recognized prominent features of PD are an inflammatory response manifested by glial reaction and T-cell infiltration, as well as the presence of various toxic mediators derived from activated glial cells. PD or parkinsonism has been described after infection with several different viruses and it has therefore been hypothesized that a viral infection might play a role in the pathogenesis of the disease. We investigated formalin-fixed post-mortem brain tissue from 9 patients with Parkinson’s disease and 11 controls for the presence of Ljungan virus (LV) antigen using a polyclonal antibody against the capsid protein of this recently identified picornavirus with neurotropic properties, suspected of being both a human and an animal pathogen. Evidence of viral antigen was found in 7 out of 9 Parkinson’s disease cases and in only 1 out of 11 controls (p = 0.005). The picornavirus antigen was present in dopamine-containing neurons of the substantia nigra. We propose that LV or an LV-related virus initiates the pathological process underlying sporadic PD. LV-related picornavirus antigen has also been reported in patients with Alzheimer’s disease. Potentially successful antiviral treatment in Alzheimer’s disease suggests a similar treatment for Parkinson's disease. Amantadine, originally developed as an antiviral drug against influenza infection, has also been used for symptomatic treatment of patients with PD for more than 50 years and is still commonly used by neurologists today. The fact that amantadine also has an antiviral effect on picornaviruses opens the question of this drug being re-evaluated as potential PD therapy in combination with other antiviral compounds directed against picornaviruses.

β-carotene Has the Neuroprotective Effects in Parkinson's Disease by Regulating Mitochondrial Apoptotic Pathway Genes

Background: Parkinson's disease (PD) is one of the most common neurodegenerative diseases that cause disability. Finding treatment options that have no side effects can be very important. Objectives: Therefore, in this study, the effect of β-carotene administration was investigated in the PD model of rats. Methods: Induction of Parkinson's disease in rats was done by injection of 6-hydroxydopamine (6-OHDA) into the substantia nigra (SN). After induction rat behaviour was studied using an apomorphine-induced rotation test. The SN cells' viability was evaluated by MTT assay and apoptosis and necrosis were measured by flow cytometry. The expressions of bax and bcl-2 genes were also studied using RT-PCR technique. Data analysis was done by GraphPad Prism V.8 software. Results: The results showed a positive effect of β-carotene administration in PD rats, which led to improvement in apomorphine-induced rotation test, increased viability, and decreased apoptosis and necrosis of SN neurons. It also downregulated bax and overexpressed bcl-2 gene expressions (P < 0.01). Conclusions: β-carotene has therapeutic effects in PD conditions and its mechanism of action was attributed to regulating the expressions of genes involved in mitochondrial apoptosis. Therefore, its study in a clinical setting is recommended.

Pathological Study of Pure Autonomic Failure

Pure autonomic failure (PAF) is a subtype of Lewy body disease whose main target is the peripheral autonomic nervous system. The differential diagnosis includes multiple system atrophy and small fiber neuropathy like amyloidosis. Low uptake of 123I- metaiodebenzyl guanidine (MIBG) cardiac scintigraphy is of diagnosis use. Biopsy of skins affected with decreased sweating could prove Lewy pathology in the peripheral autonomic nerves. Among more than 10,000 autopsy cases in BBAR (Brain Bank for Aging Research), representing an aging cohort in Tokyo metropolitan suburban area, only two cases had clinical diagnosis of PAF. Orthostatic hypotension without parkinsonism is common clinical features. Both presented with diffuse Lewy body pathology involving the peripheral autonomic nervous system, brain stem, limbic system and neocortex with mild loss of pigmented neurons in substantia nigra. Other senile changes like Alzheimer pathology, argyrophlic grains and TDP43 (TAR DNA- binding protein of 43kDa) proteinopathy were mild. Neuropathological features fulfilled morphological criteria of dementia with Lewy bodies (DLB) pure neocortical form, suggesting dementia as one of the late clinical complications. About one third of autopsy cases registered to BBAR contained Lewy pathology in the body, among whom, 5% had Lewy pathology only in the peripheral autonomic nervous system. These cases may be the earliest stage of PAF.

Melanocortin 1 receptor activation protects against alpha-synuclein pathologies in models of Parkinson\u2019s disease

BackgroundEpidemiological studies suggest a link between the melanoma-related pigmentation gene melanocortin 1 receptor (MC1R) and risk of Parkinson’s disease (PD). We previously showed that MC1R signaling can facilitate nigrostriatal dopaminergic neuron survival. The present study investigates the neuroprotective potential of MC1R against neurotoxicity induced by alpha-synuclein (αSyn), a key player in PD genetics and pathogenesis.MethodsNigral dopaminergic neuron toxicity induced by local overexpression of aSyn was assessed in mice that have an inactivating mutation of MC1R, overexpress its wild-type transgene, or were treated with MC1R agonists. The role of nuclear factor erythroid 2-related factor 2 (Nrf2) in MC1R-mediated protection against αSyn was characterized in vitro. Furthermore, MC1R expression was determined in human postmortem midbrain from patients with PD and unaffected subjects.ResultsTargeted expression of αSyn in the nigrostriatal pathway induced exacerbated synuclein pathologies in MC1R mutant mice, which were accompanied by neuroinflammation and altered Nrf2 responses, and reversed by the human MC1R transgene. Two MC1R agonists were neuroprotective against αSyn-induced dopaminergic neurotoxicity. In vitro experiments showed that Nrf2 was a necessary mediator of MC1R effects. Lastly, MC1R was present in dopaminergic neurons in the human substantia nigra and appeared to be reduced at the tissue level in PD patients.ConclusionOur study supports an interaction between MC1R and αSyn that can be mediated by neuronal MC1R possibly through Nrf2. It provides evidence for MC1R as a therapeutic target and a rationale for development of MC1R-activating strategies for PD.