, 2003) and the MAJar3 monoclonal antibody was shown to be capable of binding to a number of venoms from snakes of different genera or families ( Tanjoni et al., 2003b). The observations that antibodies that selectively

recognize non-catalytic domains of jararhagin bind to a distinct number of different SVMPs and neutralize venom-induced hemorrhage raise important issues about the role of non-catalytic domains for SVMPs selleck chemicals mechanism of action (discussed below) and present their epitopes as candidates for alternative protocols to produce recombinant antivenoms. Another interesting approach is the search of endogenous inhibitors for SVMPs in the serum of certain mammals and reptiles naturally resistant to snake venom that prey on venomous snakes. Two antihemorrhagic proteins belonging to the immunoglobulin supergene family have been isolated from the serum of the opossum Didelphis aurita: DM40 and DM43, ( Neves-Ferreira et al., 2000). DM43 inhibited the in vitro proteolytic activity and the in vivo hemorrhagic effect of jararhagin ( Neves-Ferreira et al., 2000, 2002). Additionally, when tested in vivo against crude B. jararaca venom, DM43 showed anti-lethal, anti-edematogenic and anti-hyperalgesic properties

( Neves-Ferreira et al., 2000). Similarly, BJ46a was isolated from the serum of B. jararaca snake and characterized as an SVMP inhibitor similar to members of the cystatin protein superfamily, which forms a non-covalent complex with jararhagin thus inhibiting its hemorrhagic and catalytic activities ( Valente et al., 2001). Chelating agents are also SVMP AZD6738 inhibitors and promising agents to control venom-induced local tissue damage when administered together with serumtherapy. They have been successfully used for inhibiting most in vitro and in vivo metalloproteinase activities. The injection of a peptidomimetic

MMP inhibitor (Batimastat) and the chelating agent CaNa2EDTA in the same local site as the venom resulted in reduction of the local see more hemorrhagic and dermonecrotic effects in mice injected with Bothrops asper snake venom ( Rucavado et al., 2000). The pathogenesis induced by jararhagin is largely reliant on its Zn2+-dependent catalytic activity. The molecular and cellular events associated with microvessel disruption resulting in hemorrhage depend on proteolytic degradation of vascular basement membrane components (Baldo et al., 2010; Escalante et al., 2006). Proteolysis is also essential for the disruption of endothelial cell survival signals promoted by matrix anchorage leading these cells to apoptosis by anoikis (Tanjoni et al., 2005). Proteolysis of β1 subunit of the integrin receptor is a key factor for jararhagin effects on platelets, which then fails to recognize native collagens for aggregation (Kamiguti et al., 1996b). Besides, jararhagin pro-inflammatory activity is reduced after enzyme inactivation by chelating agents as EDTA or o-phenanthroline (Costa et al., 2002).