Therapeutic Effects of Selenium on Alpha-Synuclein Accumulation in Substantia Nigra Pars Compacta in a Rat Model of Parkinson's Disease: Behavioral and Biochemical Outcomes.

Parkinson's disease (PD) is the second most common progressive neurodegenerative disorder characterized by the accumulation of accumulated alpha-synuclein (α-Syn) in substantia nigra. Research has shown that selenium (Se) can protect neural cells through the actions of selenoproteins, including selenoprotein P (SelP) and selenoprotein S (SelS), which participate in endoplasmic reticulum-associated protein degradation (ERAD). In this study, we investigated the potential protective role of Se in a pre-clinical PD rat model.We aimed to evaluate the therapeutic effects of Se administration in the 6-hydroxydopamine (6-OHDA) induced unilateral rat PD model. Male Wistar rats were utilised for unilateral PD animal model which were subjected to stereotaxic surgery and injected with 20 µg 6-OHDA/5 µl 0.2% ascorbate saline. After confirming the model, the rats were intraperitoneally injected with 0.1, 0.2, and 0.3 mg/kg of sodium selenite for 7 days. We then performed behavioral tests, including apomorphine-induced rotation, hanging, and rotarod tests. Following sacrifice, we analysed the substantia nigra area of the brain and serum for protein quantification, element analysis, and gene expression analysis.Our results indicate that the administration of 0.3 mg/kg of Se improved the motor deficiency in hanging, rotarod, and apomorphine-induced rotational tests. While there was no significant improvement in the expression of α-Syn, Se increased the expression of selenoproteins. Additionally, levels of selenoproteins, Se, and α-Syn both brain and serum were re-established by the treatment, suggesting the role of Se on the α-Syn accumulation. Furthermore, Se improved PD-induced biochemical deficits by increasing the levels of SelS and SelP (p<0.005).In conclusion, our findings suggest that Se may have a protective role in PD. 0.3 mg/kg dosage of Se increased the expression of selenoproteins, reduced the accumulation of α-Syn in the brain, and improved PD-induced motor deficits. These results suggest that Se may be a potential therapeutic option for PD treatment.

One-Year Follow-Up of Subthalamic Nucleus Deep Brain Stimulation in SNCA Mutation Parkinsonism: A Case Report.

Background: Deep brain stimulation (DBS) has shown some efficacy in monogenic Parkinson's disease; however, data about its long-term benefit in SNCA mutations remain scarce. Case report: Subthalamic nucleus DBS was implanted in a 60-year-old female patient with Parkinson's disease due to SNCA duplication. One year later, the patient walked unassisted and was independent for most activities of daily living, without requiring any anti-Parkinson's medication. Discussion: To our knowledge, four cases of bilateral subthalamic DBS have been reported previously. This case report adds an additional body of evidence of improved one-year outcome after DBS surgery in a patient with SNCA mutation. Highlights: This is a case report of a patient with genetic parkinsonism due to SNCA duplication undergoing bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) surgery. The outcome was favorable one year after implantation, with the patient coming off all anti-Parkinson's medications. This further clarifies DBS outcome in monogenic Parkinson's disease.

Roflumilast escalates α-synuclein aggregate degradation in rotenone-induced Parkinson's disease in rats: Modulation of the ubiquitin-proteasome system and endoplasmic reticulum stress.

Perturbation of the protein homeostasis circuit is one of the principal attributes associated with many neurodegenerative disorders, such as Parkinson's disease (PD). This study aimed to explore the neuroprotective effect of roflumilast (ROF), a phosphodiesterase-4 inhibitor, in a rotenone-induced rat model of PD and investigate the potential underlying mechanisms. Interestingly, ROF (1 mg/kg, p.o.) attenuated motor impairment, prevented brain lesions, and rescued the dopaminergic neurons in rotenone-treated rats. Furthermore, it reduced misfolded α-synuclein burden. ROF also promoted the midbrain cyclic adenosine monophosphate level, which subsequently enhanced the 26S proteasome activity and the expression of the 20S proteasome. ROF counteracted rotenone-induced endoplasmic reticulum stress, which was demonstrated by its impact on activating transcription factor 6, glucose-regulated protein 78, and C/EBP homologous protein levels. Moreover, ROF averted rotenone-induced oxidative stress, as evidenced by its effects on the levels of nuclear factor erythroid 2-related factor 2, heme oxygenase-1, reduced glutathione, and lipid peroxides with a significant anti-apoptotic activity. Collectively, this study implies repurposing of ROF as a novel neuroprotective drug owning to its ability to restore normal protein homeostasis.

Rose essential oil diminishes dopaminergic neuron degenerations and reduces α-synuclein aggregation in Caenorhabditis elegans models of Parkinson's disease.

Parkinson's disease (P.D.) is the second most progressive neurodegenerative disorder in the elderly. Degeneration of dopaminergic (DA) neurons and α-synuclein (α-Syn) accumulated toxicity is the major contributor to this disease. At present, the disease has no effective treatment. Many recent studies focus on identifying novel therapeutics that provide benefits to stop the disease progression in P.D. patients. Screening novel and effective drugs in P.D. animal models is time- and cost-consuming. Rose Essential Oil (REO) extracted from Rosa Rugosa species (R. Setate × R. Rugosa). REO contains Citronellol, Geraniol, and Octadiene that possess anti-Aß, anti-oxidative, and anti-depression-like properties, but no reports have defined the REO effect on P.D. yet. The present study examines the REO neuroprotective potential in transgenic Caenorhabditis elegans P.D. models. We observed that REO reduced α-Syn aggregations and diminished DA neuron degenerations induced by 6-OHDA, reduced food-sensing behavioural disabilities, and prolonged the lifespan of the nematode. Moreover, REO augmented the chymotrypsin-like proteasome and SOD-3 activities. Further, we observed the anti-oxidative role of REO by reducing internal cells ROS. Together, these findings supported REO as an anti-PD drug and may exert its effects by lowering oxidative stress via the anti-oxidative pathway.

Protective Effects of Ursodeoxycholic Acid Against Oxidative Stress and Neuroinflammation Through Mitogen-Activated Protein Kinases Pathway in MPTP-Induced Parkinson Disease.

OBJECTIVES: Parkinson disease (PD) is the second most common neurodegenerative disorder, and no disease-modifying medications are available. Ursodeoxycholic acid (UDCA) has been shown to prevent neuronal damage; however, the effect of UDCA on PD is unclear. This study aimed to the role of UDCA on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. METHODS: Mice were divided into 3 experimental groups: the control group, MPTP group, and UDCA-treat group. Mice were tested for behavioral impairments, and slices at the level of the ventral midbrain were collected to perform hematoxylin and eosin and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining and immunohistochemistry. To evaluate the levels of dopamine (DA), serotonin (5-HT), antioxidant markers, and inflammatory cytokines, enzyme-linked immunoassays were carried out. The protein (α-synuclein, p38, phospho-p38, c-Jun N-terminal kinase [JNK], and phospho-JNK) expression was examined adopting Western blot. RESULTS: We found that UDCA reduced the MPTP-induced degeneration of DA neurons, improved behavioral impairments, and decreased the protein level of α-synuclein, accompanied with increases of DA and 5-HT. In the present study, UDCA prevented DA neurons from MPTP toxicity with increased superoxide dismutase, catalase, glutathione, and decreased malondialdehyde levels. Ursodeoxycholic acid prevented DA neurons from MPTP toxicity with decreased levels of tumor necrosis factor α, interferon γ, and interleukin (IL)-1ß, IL-6, and IL-10. Our results demonstrated that UDCA inhibited the phosphorylation of JNK and p38MAPK. CONCLUSIONS: This study revealed protective effects of UDCA against oxidative stress and neuroinflammation through mitogen-activated protein kinases pathways in MPTP-induced PD, suggesting that UDCA may be a novel therapeutic candidate for PD.

Progressive neurodegeneration or endogenous compensation in an animal model of Parkinson's disease produced by decreasing doses of alpha-synuclein.

The pathological hallmarks of Parkinson's disease (PD) are degeneration of dopamine (DA) neurons of the substantia nigra (SN) and the presence of alpha-synuclein (α-syn)-rich Lewy bodies in DA cells that remain. To model these aspects of the disease, we previously showed that high titer (5.1×10exp12 gp/ml) AAV1/2 driven expression of A53T α-syn in the SN of rats caused nigrostriatal pathology including a loss of DA neurons, but also with toxicity in the GFP control group. In the current study, we evaluate the effects of two lower titers by dilution of the vector (1∶3 [1.7×10exp12] and 1∶10 [5.1×10exp11]) to define a concentration that produced pathology specific for α-syn. In GFP and empty vector groups there were no behavioural or post-mortem changes at 3 or 6 weeks post-administration at either vector dose. Dilution of the AAV1/2 A53T α-syn (1:3) produced significant paw use asymmetry, reductions in striatal tyrosine hydroxylase (TH), and increases in DA turnover at 3 weeks in the absence of overt pathology. By 6 weeks greater evidence of pathology was observed and included, reductions in SN DA neurons, striatal DA, TH and DA-transporter, along with a sustained behavioural deficit. In contrast, the 1:10 AAV1/2 A53T α-syn treated animals showed normalization between 3 and 6 weeks in paw use asymmetry, reductions in striatal TH, and increased DA turnover. Progression of dopaminergic deficits using the 1:3 titer of AAV1/2 A53Tα-syn provides a platform for evaluating treatments directed at preventing and/or reversing synucleinopathy. Use of the 1:10 titer of AAV1/2 A53T α-syn provides an opportunity to study mechanisms of endogenous compensation. Furthermore, these data highlight the need to characterize the titer of vector being utilized, when using AAV to express pathogenic proteins and model disease process, to avoid producing non-specific effects.