Vitamin D attenuated 6-OHDA-induced behavioural deficits, dopamine dysmetabolism, oxidative stress, and neuro-inflammation in mice.

Background: L-DOPA, the predominant therapy for Parkinson's disease (PD) is associated with motor deficits after prolonged use. The nigrostriatal tract, a primary target of neurodegeneration in PD, contains abundant Vitamin-D receptors, suggesting a potential role for VD in the disease. Therefore, we tested the impact of Vitamin D3 (VD3) in a mouse model of PD.Methods: PD was induced in adult male C57BL6 mice by a single intrastriatal injection of 6-hydroxydopamine. Two weeks post lesion, these mice received injections of a vehicle, VD3, L-DOPA, or a combination of VD3/L-DOPA and compared with sham controls. Treatment lasted three weeks, during which motor-cognitive neurobehaviour was assessed. Five weeks post lesion, brains were collected and striatal levels of the following proteins assessed: tyrosine hydroxylase (TH), dopamine decarboxylase (DDC), monoamine oxidase (MAO-B), Catechol-O-methyl transferase (COMT), dopamine transporter (DAT), brain-derived neurotrophic factor (BDNF), microglia marker (CD11b), inflammation (IL-1ß), apoptotic signaling (BAX) and oxidative stress (p47phox).Results: Treatment with VD3 attenuated behavioural deficits induced by 6-OHDA, protein associated with dopamine metabolism and biomarkers of oxidative stress. VD3 significantly increased contralateral wall touches, exploratory motor and cognitive activities. VD3 significantly enhanced the expression of TH, DAT, BDNF, while significantly reducing expression of MAO-B, CD11b, IL-I ß and p47phox.Conclusion: VD3 reversed some of the 6-OHDA induced changes in proteins involved in modulating the dopamine system, behavioural deficits and oxidative stress biomarkers. The data suggests that VD3 might be beneficial in reducing L-DOPA dosage, thereby reducing problems associated with dosage and prolonged use of L-DOPA in PD management.

Vitamin D attenuates monosodium glutamate-induced behavioural anomalies, metabolic dysregulation, cholinergic impairment, oxidative stress, and astrogliosis in rats.

BACKGROUND: Monosodium glutamate (MSG) is a commonly used flavor enhancer that has raised concerns due to its potential adverse effects on various organs. This study explored the neuroprotective potential of Vitamin D, a beneficial micronutrient, in mitigating MSG-induced neurotoxicity. MATERIALS AND METHODS: Adult male Wistar rats were categorized into five groups: control (2 ml/kg PBS orally for 30 days), MSG (40 mg/kg orally for 30 days), VIT-D (oral cholecalciferol; 500 IU/kg for 30 days), MSG+VIT-D (MSG for 30 days followed by VIT-D for another 30 days), and VIT-D/MSG (concurrent VIT-D and MSG for 30 days). The rats underwent neurobehavioral, histochemical, and biochemical analyses following the treatments. RESULTS: MSG treatment caused a decline in both long and short-term memory, along with reduced exploratory and anxiogenic behavior, mitigated by vitamin D treatment. MSG exposure also induced impaired behavior, dyslipidemia, oxidative stress, lipid peroxidation, altered cholinergic transmission, and increased chromatolysis and neuroinflammation in the frontal cortex, hippocampus, and cerebellum. CONCLUSIONS: VIT-D demonstrated a mitigating effect on MSG-induced adverse outcomes, highlighting its potential to attenuate neurodegenerative cascades. This investigation contributes to understanding MSG-associated neurotoxicity and suggests vitamin D as a valuable and potential intervention for neuroprotection.

African walnut (Tetracarpidium conophorum) extract upregulates glucocerebrosidase activity and circumvents Parkinsonian changes in the Hippocampus via the activation of heatshock proteins.

BACKGROUND: Neurodegenerative illnesses like Parkinson's and Alzheimer's are largely caused by the accumulation of aggregated proteins. Heat shock proteins (HSPs), which are molecular chaperons, have been linked with the modulation of ß-glucocerebrosidase (GCase) function encoded by GBA1 and Synucleinopathies. Herein, the chaperonic properties of African walnut ethanolic extract (WNE) in manganese-induced Parkinsonian neuropathology in the hippocampus was examined. METHODOLOGY: 48 adult male rats weighing 185 g ± 10 g were randomly assigned into 6 (A - F) groups (n = 8) and treated orally as follows: A-PBS (1 ml daily for 28 days), B-WNE (200 mg/kg daily for 28 days), C- WNE (400 mg/kg daily for 28 days), D-Mn (100 mg/kg daily for 28 days), E-Mn plus WNE (100 mg/kg Mn + 200 mg/kg WNE daily concomitantly for 28 days), F-Mn plus WNE (100 mg/kg Mn + 400 mg/kg WNE daily concomitantly for 28 days). RESULTS: Rats treated with WNE showed increased levels of HSP70 and HSP90 in comparison with the Mn-intoxicated group. GCase activity also increased significantly in animals treated with WNE. Our results further revealed the therapeutic tendencies of WNE against Mn toxicity by modulating oligomeric α-synuclein levels, redox activity, and glucose bioenergetics. Furthermore, immunohistochemical evaluation revealed reduced expression of neurofibrillary tangles, and reactive astrogliosis following WNE treatment. CONCLUSION: The ethanolic extract of African Walnut induced the activation of HSPs and increased the expression of GBA1 gene in the hippocampus. Activated heat shock proteins suppressed neurodegenerative changes due to Manganese toxicity. WNE was also shown to modulate neuroinflammatory, bioenergetics and neural redox balance in Parkinson-like neuropathology. This study was limited to the use of crude walnut extract and the evaluation of non-motor cascades of Parkinson's disease.

Cholecalciferol (VD3) Attenuates L-DOPA-Induced Dyskinesia in Parkinsonian Mice Via Modulation of Microglia and Oxido-Inflammatory Mechanisms.

L-DOPA, the gold standard for managing Parkinson's disease (PD) is fraught by motor fluctuations termed L-Dopa-Induced Dyskinesia (LID). LID has very few therapeutic options. Hence, the need for preclinical screening of new interventions. Cholecalciferol (VD3) treatment reportedly improves motor deficit in experimental Parkinsonism. Therefore, the novel anti-dyskinetic effect of VD3 and its underlying mechanisms in LID was investigated. Dyskinesia was induced by chronic L-DOPA administration in parkinsonian (6-OHDA- lesioned) mice. The experimental groups: Control, Dyskinesia, Dyskinesia/VD3, and Dyskinesia/Amantadine were challenged with L-DOPA to determine the abnormal involuntary movements (AIMs) score during 14 days of VD3 (30 mg/kg) or Amantadine (40 mg/kg) treatment. Behavioral Axial, Limb & Orolingual (ALO) AIMs were scored for 1 min at every 20 mins interval, over a duration of 100 mins on days 1,3,7,11 and 14. Using western blot, striatum was assessed for expression of dopamine metabolic enzymes: Tyrosine Hydroxylase (TH) and Monoamine Oxidase-B (MAO-B); CD11b, BAX, P47phox, and IL-1ß. Cholecalciferol significantly attenuated AIMs only on days 11 & 14 with maximal reduction of 32.7%. Expression of TH and MAO-B was not altered in VD3 compared with dyskinetic mice. VD3 significantly inhibited oxidative stress (P47phox), apoptosis (BAX), inflammation (IL-1ß) and microglial activation (CD11b). VD3 showed anti-dyskinetic effects behaviorally by attenuating abnormal involuntary movements, modulation of striatal oxidative stress, microglial responses, inflammation, and apoptotic signaling; without affecting dopamine metabolic enzymes. Its use in the management of dyskinesia is promising. More studies are required to further evaluate these findings. Keywords: Cholecalciferol; L-DOPA-Induced Dyskinesia; Parkinson's Disease; Microglial; Oxidative stress; Inflammation.