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Exploration of the Inhibitory Potential of Varespladib for Snakebite Envenomation.
- Source :
-
Molecules (Basel, Switzerland) [Molecules] 2018 Feb 12; Vol. 23 (2). Date of Electronic Publication: 2018 Feb 12. - Publication Year :
- 2018
-
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 <subscript>50</subscript> in vitro and ED <subscript>50</subscript> 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.<br />Competing Interests: The authors declare no conflict of interest.
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1420-3049
- Volume :
- 23
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Molecules (Basel, Switzerland)
- Publication Type :
- Academic Journal
- Accession number :
- 29439513
- Full Text :
- https://doi.org/10.3390/molecules23020391