Inhibition of Hemorrhagic Activity of Viper Venoms by N-acetyl Cysteine: Involvement of N-acetyl and Thiol Groups

K.      Sunitha; M.      Hemshekhar; M.      Sebastin Santhosh; M.      Suresh Kumar; K.      Kemparaju; K.      S. Girish

doi:10.2174/156802611797633401

Abstract

The mortality rate due to snakebite is reduced markedly by the use of anti-venoms, which are the only medically approved remedial agents available. The anti-venoms effectively neutralize the systemic toxicity but offer no protection towards local tissue degradation. In viperid snake envenomations, SVMPs and SVHYs are the major agents responsible for brutal local tissue damage as they degrade ECM and basement membrane surrounding the blood vessels. Thus, the usage of inhibitor(s) against ECM degrading enzymes in the treatment of viper bites is an affirmative therapeutic choice. The present study assessed the efficacy of N-acetyl cysteine (NAC) to inhibit gelatinase, hyaluronidase, hemorrhagic and defibrinogenating activities of Vipera russelli and Echis carinatus venoms. NAC inhibited these activities dosedependently, but it did not inhibit the PLA2, 5 nucleotidase, procoagulant and edema inducing activities of both the venoms. NAC showed complete inhibition of hemorrhagic activity when incubated with venom prior to testing. Whereas little inhibition was observed when venom and NAC were injected independently. Inhibition of the basement membrane degradation and accumulation of inflammatory leukocytes at the site of venom injection in histological sections further corroborate the inhibitory property of NAC. The observed inhibition of hemorrhage was likely due to zinc chelation as supported by spectral studies. Further, docking predictions suggested the role of -SH and -NH-CO-CH3 groups of NAC in the inhibition of SVMPs and SVHYs. Future studies related to the protective role of NAC against the venom induced systemic hemorrhage and secondary complications are highly exciting.

Keywords: Viper venom, snake venom metalloproteases, snake venom hyaluronidases, hemorrhagins, extracellular matrix, Nacetyl cysteine, hyaluronic acid, spreading factors, SVMPs and SVHYs, efficacy