Neuroprotective potential of polydatin in combating Parkinson’s disease through the inhibition of Monoamine Oxidase-B and Catechol-o-Methyl Transferase

This study aims to deduce the plausible contribution of polydatin in dopamine replenishment and dopaminergic neuroprotection to unveil its potential as a drug candidate for PD. Available therapies for the management of dopaminergic degradation in Parkinson’s disease (PD) provide only symptomatic relief and are associated with various adverse effects. Levodopa (L-DOPA) is an age-old therapy in the treatment paradigm of PD, either used as mono-therapy or in combination with the inhibitors of the dopamine catabolising enzymes monoamine oxidase-B (MAO-B) and catechol O-methyltransferase (COMT) for replenishing the levels of the neurotransmitter. The discovery of plant-based novel drug therapies would help to target multiple pathways underlying the disease pathogenesis and are associated with minimal side effects. Polydatin, the precursor of resveratrol, has been explored recently to possess neuroprotective efficacy, however, the molecular mechanisms that underlie the Parkinsonism-associated neurobehavioral recovery as well as the neurorescue potential of polydatin has not been illustrated yet. The present study aimed to unveil the role of polydatin in dopamine upregulation in PD, by determining its dual inhibitory potential on the enzymes responsible for its breakdown, MAO-B and COMT. The study further aimed to elucidate the role of this molecule in regulating the enzymatic activity of Cytosolic Phospholipase A2 (cPLA2), the crucial enzyme underlying several pathogenic pathways leading to neurodegeneration. Molecular docking simulation of polydatin with the dopamine catabolizing enzymes MAO-B and COMT, as well as cPLA2, along with their respective known inhibitors was performed using the Molegro Virtual Docker (MVD) 2.1 package. In-silico analyses revealed that polydatin could significantly inhibit the activities of this dopamine catabolizing enzyme, MAO-B, and COMT with comparable docking scores and more numbers of hydrogen bonds, and weaker interactions as that of their respective available synthetic inhibitors. Moreover, it was found that polydatin could regulate the activity of cPLA2 comparable to its known inhibitors. Polydatin exhibited efficacy as a potent dopamine replenishing agent by inhibiting its metabolizing enzymes as well as found to have efficacy against neuroinflammation, thereby highlighting the significance of designing novel phyto drugs for combating dopamine deficiency in PD.