Investigating the Neuroprotective Effect of Withaferin-A in a Parkinsonian Mouse Model

Abstract

Parkinson's disease (PD) is an enduring and advancing neurodegenerative disorder that impacts millions worldwide. While options to manage its symptoms are available, a definitive cure remains elusive. To enhance the quality of life for PD patients and to alleviate symptoms, various classes of medications are employed including Levodopa (L-Dopa), Dopamine Agonists and Dopamine Agonists. Within this investigation, we investigated the neuroprotective potential of Withaferin-A within a mouse model of Parkinsonism, utilizing a proteomics methodology. Withaferin A, a natural compound extracted from the plant Withania somnifera, colloquially known as ashwagandha, has been explored for its therapeutic attributes across several conditions including PD. To assess the neuroprotective capacity of Withaferin A (WA), we employed a quantitative proteomics strategy to pinpoint proteins with distinct expression patterns in mouse models of Parkinson's disease (PD) treated with WA and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The experimental setup encompassed four groups of mice: Group I as control, group II administered MPTP, group III treated with Withaferin A and group IV receiving Withaferin A treatment. After humane termination and intracardial infusion, the substantia nigra (SN) region of the mice brains was collected. Employing tandem mass tags, quantitative proteomics was executed on the obtained brain samples through an Orbitrap Fusion Mass spectrometer (MS). The subsequent analysis of LC-MS/MS data was conducted via Proteome Discoverer and NCBI's mouse protein database using the MASCOT search engine. This comprehensive exploration unveiled a list of 6044 proteins among which alpha-synuclein was identified. Notably, 133 proteins exhibited differential expression. These differentially expressed proteins played pivotal roles in significant biological processes including cellular processes (signal transduction), metabolic processes (NADP metabolic process) and signaling (dopamine receptor signaling). Crucial pathways uncovered encompass Parkinson's disease and the dopamine receptor-mediated signaling pathway. It is our belief that the insights gleaned from this study provide a foundation for formulating targeted treatment strategies to combat Parkinson's disease, thus potentially enhancing the therapeutic landscape for individuals affected by this condition.