Unraveling Druggable Targets in Epileptogenesis: Recent Advances.

INTRODUCTION: Afflicting 50 million people worldwide, epilepsy accounts for a sizeable burden among neurological diseases. Its progression, termed epileptogenesis, and the sole availability of medications with negligible effects against its clinical course in the market render epilepsy largely incurable. As studies illuminate the anti-epileptogenic properties of natural compounds and repurposed drugs in recent decades, the treatable potential of epilepsy is increasingly speculated. METHODS: In this review, mechanistic roles of prospective anti-epileptogenic targets in driving disease progression are clarified through the lens of neuroinflammation, neural remodeling, and neuronal death. This discussion integrates in vivo, in vitro, and clinical therapeutic evidence from the last two decades of epilepsy research, spanning pharmacoresistant to traumatic subtypes. Drug efficacies and limitations are also evaluated. RESULTS: Apart from the IL-1β/IL-1R1 and TLR4/HMGB1 axes, tight junction proteins are emerging as areas of growing attention in neuroinflammation. While mTOR and Wnt/β-catenin cascades are prime targets for neural remodeling, modulating genetic hypermethylatory patterns and extracellular matrix expression alleviates convulsive phenotypes. Apoptotic and endoplasmic reticulum-mediated cell deaths are also responsive to respective pharmacological treatments. Several drugs exemplify synergistic effects spanning multiple epileptogenic processes, but adverse complications accompany some. DISCUSSION: The adoption of anti-epileptogenic drugs (AEGDs) in place of anti-seizure medications (ASMs) offers a substantial window of disease-modifying action during the latency period, providing a golden opportunity to delay disease progression and thereby optimize patients' care. Because observations are still largely preclinical, examples could serve as a launching point for translational research to enable timely delivery of anti-epileptogenic regimens. CONCLUSION: Neuroinflammation, neural remodeling, and neuronal death are key processes of epileptogenesis, providing a druggable framework for future anti-epileptogenic treatments.