Inhibitory potential of plant secondary metabolites on anti-Parkinsonian drug targets: Relevance to pathophysiology, and motor and non-motor behavioural abnormalities

Abstract

Parkinson’s disease (PD), a progressive neurodegenerative motor disorder, is caused due to the loss of dopaminergic neurons in the substantia nigra pars compacta region of mid-brain and the resultant depletion of the levels of the neurotransmitter dopamine. Although the pathophysiology of the disease is least understood, studies in animal models revealed oxidative stress, mitochondrial dysfunction and inflammation to be the major contributors. Dopamine replenishment therapy by oral administration of L-DOPA, the precursor of dopamine remains to be the therapeutic gold-standard for symptomatic treatment of PD. In addition, use of inhibitors of dopamine metabolizing enzymes (viz. monoamine oxidase-B: MAO-B; and catechol-O-methyltransferase: COMT) are the other strategies for amelioration of the motor abnormalities. Further, PD is associated with non-motor behavioural abnormalities as well, including cognitive impairment and mood disorders, which are caused due to cholinergic neurodegeneration, and thus inhibition of Acetylcholinesterase (AChE) is suggested. However, the currently used drugs against the three crucial enzymes (MAO-B, COMT and AChE) elicit several side effects, and thus the search for novel compounds continues, and plant-based compounds have promising potential in this regard. In the present study, we have used computational modeling to determine the efficiency of 40 plant-based natural products in inhibiting the three anti-Parkinsonian drug targets. Further, statistical analysis was performed to identify the properties of the compounds which are crucial for inhibition of the enzymes. While all the phytochemicals showed potential in inhibiting the enzymes, Rutin, Demethoxycurcumin and Acteoside were found to be most effective inhibitors of MAO-B, COMT and AChE respectively. Since most of the compounds are established anti-oxidant and anti-inflammatory molecules, they are surmised to confer neuroprotection in PD, and prevent progression of the disease.