Effect of the metalloproteinase inhibitor batimastat in the systemic toxicity induced by Bothrops asper snake venom: understanding the role of metalloproteinases in envenomation.

Abstract

The peptidomimetic hydroxamate metalloproteinase inhibitor batimastat (BB-94) was assessed for its ability to neutralize the systemic effects (lethality, hemorrhage and coagulopathy) induced by the venom of Bothrops asper, the most important snake from a medical standpoint in Central America. Batimastat inhibited lethality when a venom challenge dose of two LD(50)s was used by intraperitoneal and intravenous routes, with ED(50)s of 250 and 22 microM, respectively. With a challenge dose of three LD(50)s, lethality was not abrogated, but a conspicuous and dose-dependent delay in the time of death was observed in mice injected with mixtures of venom plus batimastat. Upon incubation with 500 microM batimastat, venom LD(50) increased 2.86-fold (intraperitoneal route) and 2.37-fold (intravenous route), when compared with LD(50) of venom alone. Batimastat also inhibited the hemorrhagic effect induced by venom in the lungs after intravenous injection. Moreover, batimastat exerted a significant inhibition of in vitro coagulant and in vivo defibrinogenating effects of venom, evidencing that metalloproteinases play a key role in the coagulopathy characteristic of B. asper envenomation. The remaining uninhibited coagulant effect is due to serine proteinases, i.e. thrombin-like enzymes, since this effect was completely abrogated by the combination of batimastat and PMSF. Our results stress the view that metalloproteinases play a relevant role in the systemic pathophysiology of B. asper envenomation and that metalloproteinase inhibitors may become a therapeutic alternative in this pathology.

• Authors: Alexandra Rucavado, Teresa Escalante, José María Gutiérrez
• Journal: Toxicon : official journal of the International Society on Toxinology (Toxicon) Vol. 43 Issue 4 Pg. 417-24 (Mar 15 2004) ISSN: 0041-0101 [Print] England
• PMID: 15051405 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Crotalid Venoms
• Thiophenes
• Phenylalanine
• Prothrombin
• Factor X
• batimastat
• Metalloendopeptidases

Topics

• Animals
• Blood Coagulation (drug effects)
• Bothrops
• Costa Rica
• Crotalid Venoms (antagonists & inhibitors, metabolism, toxicity)
• Dose-Response Relationship, Drug
• Drug Interactions
• Factor X (drug effects, metabolism)
• Hemorrhage (chemically induced, prevention & control)
• Histological Techniques
• Lethal Dose 50
• Lung (pathology)
• Metalloendopeptidases (antagonists & inhibitors)
• Mice
• Phenylalanine (analogs & derivatives, metabolism, pharmacology)
• Prothrombin (drug effects, metabolism)
• Snake Bites (mortality, physiopathology)
• Thiophenes (metabolism, pharmacology)
• Time Factors