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

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

In vitro-in vivo discord: a preclinical study of AZD2716 and its racemate with comparison to varespladib for the development of snake venom sPLA2 inhibitors

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In vitro-in vivo discord: a preclinical study of AZD2716 and its racemate with comparison to varespladib for the development of snake venom sPLA2 inhibitors

Abstract

We evaluated a family of repurposed sPLA2 inhibitors as novel candidate snakebite envenoming therapeutics. Stereospecific (R)-7 AZD2716 and its racemic mixture were compared to varespladib in an in vitro sPLA2 assay against a sample of 26 venoms from medically important snake species from five continents. All compounds demonstrated potent nano- to picomolar IC50 values, comparable to the benchmark inhibitory profile of varespladib. Surprisingly, however, this in vitro efficacy did not translate to survival in an in vivo mouse model under GLP standard conditions at an independent third party laboratory. In animal rescue studies evaluating both oral and IV dosing against the same four high sPLA2 venoms, varespladib demonstrated more consistent survival duration versus the chirally separated AZD2716 enantiomer and racemate following single-dose intravenous or two-dose oral drug administration. Additionally, the stereospecific AZD2716 did not provide the same survival advantage as the racemic mixture and neither molecule resulted in the same survival advantage as varespladib in vivo (p < 0.05), despite similar in vitro potency. These findings highlight the importance of following in vitro inhibition assays with preclinical studies in drug candidate selection for lead compounds and advancement to clinical development.
Hearth, J. L., Surovtseva, Y., Karjala, Z., Casewell, N. R., Giang, K., & Lewin, M. R. (2026). In vitro-in vivo discord: A preclinical study of AZD2716 and its racemate with comparison to varespladib for the development of snake venom sPLA2 inhibitors. Toxicon: X, 100243. https://doi.org/10.1016/j.toxcx.2026.100243