ABSTRACT Aims This study aims to evaluate 5‐(but‐1‐en‐1‐yl)‐1,2,3‐trimethoxybenzene (BETMB) as a novel dual‐target anti‐seizure agent for refractory epilepsy and elucidate the synergistic neuroelectrophysiological mechanism between Na V channels and GABA A receptors. Methods Whole‐cell patch‐clamp recordings characterized BETMB's dual‐target activity. Antiseizure efficacy was assessed in maximal electroshock (MES), pentylenetetrazole (PTZ), and kainic acid (KA) models. Cognitive function in chronic KA mice was evaluated using the Morris water maze (MWM). Histopathological, immunohistochemical, and Western blot analyses explored neuroprotection. Synergy between Na V and GABA A R modulation was systematically investigated using both an in vitro Mg 2+ ‐free model of neuronal hyperexcitability and an in silico model of cortical spreading depolarization (CSD). Results BETMB acted as a GABA A R positive allosteric modulator (EC 50 = 93.2 μM) and a state‐dependent Na V blocker (K I = 1.9 μM). It significantly suppressed seizures across models, improved cognition in chronic epilepsy, and modulated downstream expression of GABRA1, NR2B, and BDNF‐pAKT‐CREB signaling. Synergistic Na V and GABA A R modulation completely abolished ictal‐like discharges in Mg 2+ ‐free cellular models and prevented CSD initiation in computational simulations. Conclusion BETMB is a promising dual‐target therapy for refractory epilepsy, supported by the first electrophysiological evidence that dual modulation of GABA A R and Na V synergistically suppresses neuronal hyperexcitability. Beyond epilepsy, this finding may also extend to CSD‐related conditions such as stroke, traumatic brain injury, and migraine.
Zhang et al. (Thu,) studied this question.