Effect of the metalloproteinase inhibitor batimastat in the systemic toxicity induced by Bothrops asper snake venom: understanding the role of metalloproteinases in envenomation.
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.
Rucavado
Alexandra
A
Facultad de Microbiología, Instituto Clodomiro Picado, Universidad de Costa Rica, San José, Costa Rica. arucavad@cariari.ucr.ac.cr
Escalante
Teresa
T
Gutiérrez
José María
JM
D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects*; D017837:Bothrops; D003364:Costa Rica; D003435:Crotalid Venoms / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005170:Factor X / Q000187:drug effects / Q000378:metabolism; D006470:Hemorrhage / Q000139:chemically induced / Q000517:prevention & control*; D006652:Histological Techniques; D007928:Lethal Dose 50; D008168:Lung / Q000473:pathology; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D051379:Mice; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D011516:Prothrombin / Q000187:drug effects / Q000378:metabolism; D012909:Snake Bites / Q000401:mortality / Q000503:physiopathology*; D013876:Thiophenes / Q000378:metabolism / Q000494:pharmacology*; D013997:Time Factors
D003435:Crotalid Venoms; D013876:Thiophenes; D010649:Phenylalanine; D011516:Prothrombin; D005170:Factor X; C080985:batimastat; D008666:Metalloendopeptidases