Varespladib (LY315920) rescued mice from fatal neurotoxicity caused by venoms of five major Asiatic kraits (Bungarus spp.) in an experimental envenoming and rescue model

The venoms of Asiatic kraits (Bungarus spp.) contain various neurotoxic phospholipases A2 (beta-bungarotoxins) which can irreversibly damage motor nerve terminals, resulting in rapidly fatal suffocation by respiratory muscle paralysis or oral airway obstruction. Hence, there is a need of adjunct therapy at the pre-hospital stage to prevent or delay the onset of neurotoxicity, so that antivenom can be given within golden hour before the envenoming becomes antivenom-resistant. This study investigated the efficacy of varespladib, a small molecule PLA2 (phospholipase A2) inhibitor, given as a bolus subcutaneously upon the onset of krait venom-induced paralysis in a mouse experimental envenoming and rescue model, where the severity of neurotoxicity was scored and the survival rate was monitored over 24 h. Varespladib at 10 mg/kg effectively alleviated the neurotoxicity of Bungarus sindanus, Bungarus multicinctus and Bungarus fasciatus venoms, and rescued all mice from venom-induced lethality (100% survival). Varespladib at this dose, however, only partially reduced the neurotoxicity of Bungarus caeruleus and Bungarus candidus venoms, while all challenged mice were dead by 23 h (B. caeruleus) and 12 h (B. candidus). An increased dose of varespladib at 20 mg/kg markedly abated the venom neurotoxicity past 8 h of envenoming, and protected the mice from venom lethality (B. caeruleus: 75% survival; B. candidus: 100% survival). The finding is consistent with previous studies which demonstrated varespladib's inhibitory effect against some snake venoms. The findings suggest varespladib could be repurposed as an emergency drug for prevention or rescue (if given early enough) from the acute, neurotoxic envenoming syndromes caused by various major krait species in Asia.