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Oxidative stress‐induced methemoglobinemia is the silent killer during snakebite: a novel and strategic neutralization by melatonin
Author(s) -
Sharma Rachana D.,
Katkar Gajanan D.,
Sundaram Mahalingam S.,
Paul Manoj,
NaveenKumar Somanathapura K.,
Swethakumar Basavarajaiah,
Hemshekhar Mahadevappa,
Girish Kesturu S.,
Kemparaju Kempaiah
Publication year - 2015
Publication title -
journal of pineal research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.881
H-Index - 131
eISSN - 1600-079X
pISSN - 0742-3098
DOI - 10.1111/jpi.12256
Subject(s) - methemoglobin , methemoglobinemia , venom , antivenom , envenomation , oxidative stress , pharmacology , medicine , immunology , hemoglobin , chemistry , endocrinology , anesthesia , biochemistry
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 Naja naja > Ophiophagus hannah > Echis carinatus > Daboia russellii > Apis mellifera > Mesobuthus tamulus > Hippasa partita . Being highly potential, N . naja venom was further studied to observe methemoglobin formation in RBC s and in combinations with PMN s and PBMC s, where maximum effect was observed in RBC s + PMN s combination. Naja naja venom/externally added methemoglobin‐induced methemoglobin formation was in parallel with ROS generation in whole blood/ RBC s/ RBC s + PMN s/ RBC s + PBMC s. 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‐3 α . 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‐3 α . 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 translating the combined therapy towards the bed side.