Oxidative stress induced methemoglobinemia is the silent killer during snakebite: a novel and strategic neutralization by melatonin.
J Pineal Res. 2015 Jun 23. Epub 2015 Jun 23. PMID: 26103459
Rachana D Sharma
Oxidative stress induced methemoglobinemia remained an untouched area in venom pharmacology till date. This study for the first time explored the potential of animal venoms to oxidize hemoglobin to methemoglobin. In in vitro whole blood assay, methemoglobin forming ability of venoms varied as, N. naja>O. hannah>E. carinatus>D. russellii>A. mellifera>M. tamulus>H. partita. Being highly potential, N. naja venom was further studied to observe methemoglobin formation in RBCs and in combinations with PMNs and PBMCs, where maximum effect was observed in RBCs + PMNs combination. N. naja venom/externally added methemoglobin induced methemoglobin formation was in parallel with ROS generation in whole blood/ RBCs/ RBCs + PMNs/ RBCs + PBMCs. In in vivo studies, the lethal dose (1 mg/kg body weight, i.p.) of N. naja venom readily induced methemoglobin formation, ROS generation, expression of inflammatory markers, and hypoxia inducible factor-3α. Although the mice administered with three effective doses of antivenom recorded zero mortality; the methemoglobin and ROS levels remained high. However, one effective dose of antivenom when administered along with melatonin (1:50; venom/melatonin, w/w), not only offered 100% survival of experimental mice, but also significantly reduced methemoglobin level, and oxidative stress markers including hypoxia inducible factor-3α. This study provides strong drive that, complementing melatonin would not only reduce the antivenom load, but for sure greatly increase the success rate of antivenom therapy and drastically minimize the global incidence of snakebite deaths. However, further detailed investigations are needed before transferring the combined therapy towards the bed side. This article is protected by copyright. All rights reserved.