Multi-target mechanisms of Creatine in Parkinson's disease: an in-silico and in-vivo investigation.

Abstract

BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative disorder marked by the loss of dopaminergic neurons, resulting in impaired motor control and cognitive decline. Despite current therapies, there remains a need for more effective and multifaceted treatment strategies. OBJECTIVE: This study explores the neuroprotective potential of exogenous Creatine in a Haloperidol-induced PD rat model, with a focus on reducing elevated homocysteine levels and targeting key proteins involved in PD pathology. METHOD: We proposed a multitarget therapeutic approach, aiming to inhibit ADORA2A, alpha-synuclein, and monoamine Oxidase B (MAO-B) using the same bioactive compound. RNA-seq data from publicly available datasets (BioProject: PRJNA608432; GEO: GSE145814) were analyzed to identify dysregulated proteins and pathways associated with neuroactive ligand-receptor interaction, olfactory transduction, and phototransduction. Using computational methods, including RNA Seq analysis, molecular docking, MMGBSA, and ADME/T analyses, we screened for potential common ligand. Creatine showed a higher binding affinity for the target proteins compared to Levodopa (primarily used medication against PD), suggesting its therapeutic potential. In vivo experiments assessed the efficacy of Creatine through behavioural testing, redox status evaluation, biochemical markers, and histological analysis. RESULT: The results potentially suggest that Creatine ameliorates motor deficits, reduces oxidative stress, and protects neuronal integrity in PD rats. Overall, our findings indicate that Creatine acts as a promising multitargeted approach, capable of modulating several PD-associated molecular mechanisms. CONCLUSION: This approach may further be validated and pave the way for more effective, broad-spectrum treatments for Parkinson's disease, addressing both its motor and non-motor symptoms.