The underlying mechanism of scorpion venom peptide BmK AS in reducing epilepsy seizures: mediated through dual modulation of Nav1.6 and the inflammasome pathway

Introduction: Voltage-gated sodium channel (VGSC) dysregulation, particularly of the Nav1.6 subtype, is a core mechanism underlying epileptogenesis and its associated neuropsychiatric comorbidities. The scorpion venom peptide BmK AS has demonstrated anticonvulsant potential, but its efficacy in chronic epilepsy and the precise mechanisms of action remain undefined. Methods: Here, we show that BmK AS exerts robust anti-epileptic and neuroprotective effects through converging mechanisms. In a kainic acid-induced mouse model, BmK AS treatment reduced mortality and seizure parameters. Electrophysiological studies assessed BmK AS modulation of VGSC subtypes. The functional relevance of Nav1.6 targeting was confirmed by the loss of BmK AS's anti-seizure efficacy upon its pharmacological blockade in a PTZ-induced model. Furthermore, in both KA-induced chronic epilepsy models and native hippocampal neurons, BmK AS was evaluated for neuronal hyperexcitability and NLRP1 inflammasome-mediated pyroptosis. Results: BmK AS reduced mortality to 0% (vs. 40% in the model group) and significantly reduced seizure duration by 10.5% and the frequency of severe (stages 4 and 5) seizures by 68.8%. It also improved cognitive and psychiatric outcomes, significantly reversing epilepsy-associated spatial memory deficits and anxiety-/depression-like behaviors. Electrophysiological studies show that BmK AS nonlinearly inhibited multiple VGSC subtypes, with pronounced potency against Nav1.6, reducing the peak sodium current to 43% of control at 5 nM. BmK AS attenuated neuronal hyperexcitability and suppressed neuroinflammation by inhibiting the NLRP1 inflammasome pathway and the associated pyroptosis. Discussion: Our findings establish BmK AS as a promising multimechanistic therapeutic candidate, highlighting the strategic value of dual therapeutic actions, namely, Nav1.6 modulation and neuroinflammation inhibition, for epilepsy treatment.