Inflammation and immunopharmacologyEffectiveness of batimastat, a synthetic inhibitor of matrix metalloproteinases, in neutralizing local tissue damage induced by BaP1, a hemorrhagic metalloproteinase from the venom of the snake Bothrops asper
Section snippets
Metalloproteinase and inhibitor
BaP1 was isolated from a venom pool of more than 40 adult specimens of B. asper collected in the Pacific region of Costa Rica. Purification was performed by ion-exchange chromatography on Carboxymethyl Sephadex C-50, gel filtration in Sephacryl S-200, and affinity chromatography on Affi-Gel Blue, as previously described 15, 20. Homogeneity was demonstrated by SDS–PAGE run under reducing conditions [26], using 12% acrylamide gels. Batimastat (also known as BB-94; [4-(N-hydroxyamino)-2R-isobutyl-3
Assays with preincubation of BaP1 and batimastat
Batimastat inhibited, in a concentration-dependent way, the proteolytic activity of BaP1 on biotinylated casein, with an ic50 of 80 nM (Fig. 1). A concentration of 400 nM batimastat totally inhibited caseinolytic activity. Moreover, batimastat was effective in inhibiting the hemorrhagic activity of BaP1 in skin and muscle (Fig. 2). When hemorrhage inhibition was assessed in the skin, the ic50 was 1.95 μM. Batimastat concentrations of 5.71 and 12.6 μM abrogated hemorrhagic activity totally in
Discussion
Venom metalloproteinases play a relevant role in the pathogenesis of local tissue damage characteristic of pit viper envenomations 3, 21. In the case of B. asper venom, metalloproteinases induce hemorrhage 17, 27, myonecrosis 18, 19, dermonecrosis, blister formation [15], and edema [20]. Neutralization of these activities by antivenoms is a difficult task, due to the time lapse between envenomation and antivenom administration in hospitals [9]. The use of synthetic metalloproteinase inhibitors
Acknowledgements
The authors thank British Biotech Pharmaceuticals Ltd. for supplying batimastat, and Javier Núñez, Marcos Méndez, Rodrigo Mora, and Rodrigo Chaves for their collaboration in the laboratory work. This study was supported by the International Foundation for Science (project F/2707–1), by the Consejo Nacional para Investigaciones Cientı́ficas y Tecnológicas (CONICIT) of Costa Rica (project 98–012-F0), and by Vicerrectorı́a de Investigación, Universidad de Costa Rica (project 741–98-202).
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