1. Exploration of the Inhibitory Potential of Varespladib for Snakebite Envenomation.
- Author
-
Wang Y, Zhang J, Zhang D, Xiao H, Xiong S, and Huang C
- Subjects
- Alanine Transaminase antagonists & inhibitors, Alanine Transaminase blood, Animals, Aspartate Aminotransferases antagonists & inhibitors, Aspartate Aminotransferases blood, Creatine Kinase blood, Crotalinae physiology, Ecchymosis prevention & control, Edema prevention & control, Female, Isoenzymes antagonists & inhibitors, Isoenzymes blood, Keto Acids, L-Lactate Dehydrogenase antagonists & inhibitors, L-Lactate Dehydrogenase blood, Mice, Muscle, Skeletal blood supply, Muscle, Skeletal drug effects, Muscle, Skeletal physiopathology, Snake Bites metabolism, Snake Bites physiopathology, Acetates pharmacology, Antivenins pharmacology, Crotalid Venoms toxicity, Indoles pharmacology, Phospholipase A2 Inhibitors pharmacology, Phospholipases A2 metabolism, Snake Bites drug therapy
- Abstract
Phospholipase A₂s (PLA₂) is a major component of snake venom with diverse pathologic toxicities and, therefore, a potential target for antivenom therapy. Varespladib was initially designed as an inhibitor of mammal PLA₂s, and was recently repurposed to a broad-spectrum inhibitor of PLA₂ in snake venom. To evaluate the protective abilities of varespladib to hemorrhage, myonecrosis, and systemic toxicities that are inflicted by different crude snake venoms, subcutaneous ecchymosis, muscle damage, and biochemical variation in serum enzymes derived from the envenomed mice were determined, respectively. Varespladib treatment showed a significant inhibitory effect to snake venom PLA₂, which was estimated by IC
50 in vitro and ED50 in vivo. In animal models, the severely hemorrhagic toxicity of D. acutus and A. halys venom was almost fully inhibited after administration of varespladib. Moreover, signs of edema in gastrocnemius muscle were remarkably attenuated by administration of varespladib, with a reduced loss of myonecrosis and desmin. Serum levels of creatine kinase, lactate dehydrogenase isoenzyme 1, aspartate transaminase, and alanine transaminase were down-regulated after treatment with varespladib, which indicated the protection to viscera injury. In conclusion, varespladib may be a potential first-line drug candidate in snakebite envenomation first aid or clinical therapy., Competing Interests: The authors declare no conflict of interest.- Published
- 2018
- Full Text
- View/download PDF