Exploration of the Inhibitory Potential of Varespladib for Snakebite Envenomation

Molecules. 2018 Feb 12;23(2):391. doi: 10.3390/molecules23020391.

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 IC50 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.

Keywords: antivenom; myotoxicity; phospholipase A2; varespladib.

MeSH terms

  • Acetates / pharmacology*
  • Alanine Transaminase / antagonists & inhibitors
  • Alanine Transaminase / blood
  • Animals
  • Antivenins / pharmacology*
  • Aspartate Aminotransferases / antagonists & inhibitors
  • Aspartate Aminotransferases / blood
  • Creatine Kinase / blood
  • Crotalid Venoms / toxicity*
  • Crotalinae / physiology
  • Ecchymosis / prevention & control
  • Edema / prevention & control
  • Female
  • Indoles / pharmacology*
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / blood
  • L-Lactate Dehydrogenase / antagonists & inhibitors
  • L-Lactate Dehydrogenase / blood
  • Mice
  • Muscle, Skeletal / blood supply
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / physiopathology
  • Phospholipase A2 Inhibitors / pharmacology*
  • Phospholipases A2 / metabolism*
  • Snake Bites / drug therapy*
  • Snake Bites / metabolism
  • Snake Bites / physiopathology

Substances

  • Acetates
  • Antivenins
  • Crotalid Venoms
  • Indoles
  • Isoenzymes
  • Phospholipase A2 Inhibitors
  • varespladib
  • L-Lactate Dehydrogenase
  • lactate dehydrogenase 1
  • Aspartate Aminotransferases
  • Alanine Transaminase
  • Creatine Kinase
  • Phospholipases A2