Unveiling Neuroelectrophysiological Mechanisms of Combined Antiepileptic Drug Therapy for Refractory Epilepsy: Synergistic Effects of NaV channels and GABAA Receptors
Abstract
ABSTRACT Background and Purpose: Clinical studies suggest that combining GABA A R agonists with Na V blockers enhances antiseizure effects, although the mechanisms remain unclear. This study aims to demonstrate that dual modulation of GABA A Rs and Na V s can synergistically suppresses neuronal hyperexcitability and cortical spreading depolarization (CSD), and to highlight the therapeutic potential of 5-But-1-enyl-1,2,3-trimethoxybenzene (BETMB), a dual-target compound. Experimental Approach: Whole-cell patch-clamp recordings in Mg 2+ -free neuronal cultures revealed that GABA A R and Na V synergistically suppress epileptiform discharges. Computational modeling simulated CSD dynamics. BETMB’s impact on GABA A R currents and Na V kinetics was evaluated through patch-clamp recordings. Antiseizure effects were tested using maximal electroshock, pentylenetetrazole, and kainic acid (KA) models. In the chronic KA model, cognitive function in mice was assessed with novel object recognition and Morris water maze tests. Neuroprotective mechanisms were investigated using histopathological, immunohistochemical, and western blot analyses. Key Results: Co-application of GABA A R and Na V modulators suppressed ictal-like discharges more effectively than either agent alone (p < 0.01). Computational analysis indicated synergistic inhibition of CSD. BETMB showed dual mechanisms: (1) positive allosteric modulation of GABA A Rs (EC 50 = 93.2 µM), and (2) state-dependent Na V inhibition (Kd=1.9…
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