Toxicon 49 (2007) 670–677 Role of cyclooxygenases in oedema-forming activity of bothropic venoms Renata do A. Olivo a , Catarina F.P. Teixeira a , John L. Wallace b , Jose M. Gutierrez c , Stella R. Zamuner a,b,à a Laboratory of Pharmacology, Butantan Institute, Avenida Vital Brazil 1500, 05503-900 Sa˜o Paulo, SP, Brazil b Mucosal Inflammation Research Group, University of Calgary, Calgary, Alberta T2N 4N1, Canada c Clodomiro Picado Institute, Faculty of Microbiology, University of Costa Rica, San Jose´, Costa Rica Received 2 June 2006; received in revised form 8 November 2006; accepted 13 November 2006 Available online 21 November 2006 Abstract The venoms of Bothrops asper (BaV) and Bothrops jararaca (BjV), two of the most medically important poisonous snakes of Latin America, cause pronounced oedema in the victims through poorly understood mechanisms. In the present study, we examined the possible role of cyclooxygenases (COX) in the genesis of mouse paw oedema caused by BaV and BjV injections. BaV at 2.5 mg/paw and BjV at 0.75 mg/paw induced significant oedema that persisted for up to 6 h following subplantar injection. Treatment with indomethacin (2 mg/kg), rofecoxib, (10 mg/kg), or dexamethasone (2 mg/kg) significantly reduced the BaV- and BjV-induced oedema formation. Treatment with SC-560 (30 mg/kg) significantly reduced the oedema formation induced by BjV but had no effect on that induced by BaV. Both venoms induced significant increases in the levels of prostaglandin E 2 (PGE 2 ) and the expression of COX-1 and COX-2 in paw tissue. The peak of oedema formation and PGE 2 release correlated with marked expression of COX-2 in the paw tissue. These results demonstrate that injection of BaV and BjV results in a rapid increase in oedema formation that is, at least partially, mediated by arachidonic acid metabolites formed by COX-2. In the case of BjV, COX-1-derived prostanoids also appear to contribute significantly to the inflammatory changes. r 2006 Elsevier Ltd. All rights reserved. Keywords: Bothrops asper; Bothrops jararaca; Cyclooxygenase; Inflammation; COX-2; PGE 2 1. Introduction Snake venoms are rich sources of enzyme- generating factors and enzymes capable of mediat- ing, directly or indirectly, the early events of the hemorrhagic and inflammatory processes (Rodri- gues et al., 2004). Envenomation by snakes of the genus Bothrops induces both local and systemic pathological alterations, which are due to the additive or synergistic effects of the different toxins and enzymes present in the venoms (Ownby et al., 1982; Gutierrez and Lomonte, 1995; Trebien and Calixto, 1989). Bothrops asper (BaV) and Bothrops jararaca (BjV) venoms are responsible for most snake poisonings in Costa Rica and Brazil, ARTICLE IN PRESS www.elsevier.com/locate/toxicon 0041-0101/$ - see front matter r 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.toxicon.2006.11.006 Abbreviations: BaV, Bothrops asper venom; BjV, Bothrops jararaca venom; COX, cyclooxygenase; PG, prostaglandin à Corresponding author. Universidade do Vale do Paraı´ba- UNIVAP, Instituto de Pesquisa e Desenvolvimento—IP&D, Av. Shishima Hifumi, 2911 Bairro Urbanova, CEP 12244-000 Sa˜o Paulo, Brazil. Tel.: +55 1239471106. E-mail address: szamuner@univap.br (S.R. Zamuner).