Neuromodulators in food ingredients: insights from network pharmacological evaluation of Ayurvedic herbs

The global burden of neurological diseases, the second leading cause of death after heart dis-eases constitutes one of the major challenges of modern medicine. Ayurveda, the traditional Indian medicinal systemenrooted in the Vedic literature and considered as a schema for the holistic management of health, characterizes various neurological diseases disorders (NDDs) and prescribes several herbs, formulations, and bio-cleansing regimes for their care and cure. In this work, we examined neuro-phytoregulatory potential of 34,472 phytochemicals among 3,038 herbs (including their varieties) mentioned in Ayurveda using network pharmacology approach and found that 45% of these Ayurvedic phytochemicals (APCs) have regulatory associations with 1,643 approved protein targets. Metabolite interconversion enzymes and protein modifying enzymes were found to be the major target classes of APCs against NDDs. The study further suggests that the actions of Ayurvedic herbs in managing NDDs were majorly via regulating signalling processes, like, G-protein signaling, acetylcholine signaling, chemokine signaling pathway and GnRH signaling. A high confidence network specific to 219 pharmaceutically relevant neuro-phytoregulators (NPRs) from 1,197 Ayurvedic herbs against 102 approved protein-targets involved in NDDs was developed and analyzed for gaining mechanistic insights. The key protein targets of NPRs to elicit their neuro-regulatory effect were highlighted as CYP and TRPA, while estradiol and melatonin were identified as the NPRs with high multi-targeting ability. 32 herbs enriched in NPRs were identified that include some of the well-known Ayurvedic neurological recommendations, like, Papaver somniferum, Glycyrrhiza glabra, Citrus aurantium, Cannabis sativa etc. Herbs enriched in NPRs may be used as a chemical source library for drug-discovery against NDDs from systems medicine perspectives.