MULTI TARGET MODULATION OF EPILEPTOGENIC PATHWAYS BY PLANT-DERIVED COMPOUNDS: A MECHANISTIC REVIEW FOR DRUG-RESISTANT EPILEPSY

Abstract

Epilepsy represents a major neurological burden affecting approximately 100 million individuals worldwide, with one-third of cases remaining drug resistant despite available antiseizure medications. This resistance stems from the multifactorial nature of epileptogenesis, involving interconnected pathological processes including neurotransmitter imbalances (glutamate/GABA dysregulation), chronic neuroinflammation (astrocyte and microglia activation), mTOR pathway hyperactivation, and ion channel dysfunction. Current pharmacotherapies predominantly target single mechanisms, underscoring the need for multi target approaches. This review evaluates six plant derived compounds Cannabis sativa (cannabidiol, Δ⁹-THC), Curcuma longa (curcumin), Acorus tatarinowii (asarones), Valeriana officinalis (valerenic acid), Citrus sinensis (hesperidin, nobiletin), and Cymbopogon winterianus (citronellal, geraniol) for their polypharmacological potential against these epileptogenic pathways. These botanicals demonstrate simultaneous modulation of multiple targets, offering a promising strategy for developing disease-modifying therapies. However, translational challenges including poor bioavailability, standardization issues, and limited clinical evidence must be addressed through advanced formulation strategies, systems pharmacology approaches, and mechanistically-informed clinical trials. Integrating ethnopharmacological knowledge with contemporary neuroscience may yield novel therapeutic avenues for drug resistant epilepsy.