title: Geographical venom variations of the Southeast Asian monocled cobra (Naja kaouthia): venom-induced neuromuscular depression and antivenom neutralization.
abstract: The Southeast Asian monocled cobras (Naja kaouthia) exhibit geographical variations in their venom proteomes, especially on the composition of neurotoxins. This study compared the neuromuscular depressant activity of the venoms of N. kaouthia from Malaysia (NK-M), Thailand (NK-T) and Vietnam (NK-V), and the neutralization of neurotoxicity by a monospecific antivenom. On chick biventer cervicis nerve-muscle preparation, all venoms abolished the indirect twitches, with NK-T venom being the most potent (shortest t90, time to 90% twitch inhibition), followed by NK-V and NK-M. Acetylcholine and carbachol failed to reverse the blockade, indicating irreversible/pseudo-irreversible post-synaptic neuromuscular blockade. KCl restored the twitches variably (NK-M preparation being the least responsive), consistent with different degree of muscle damage. The findings support that NK-T venom has the most abundant curarimimetic alpha-neurotoxins, while NK-M venom contains more tissue-damaging cytotoxins. Pre-incubation of tissue with N. kaouthia monovalent antivenom (NKMAV) prevented venom-induced twitch depression, with the NK-T preparation needing the largest antivenom dose. NKMAV added after the onset of neuromuscular depression could only halt the inhibitory progression but failed to restore full contraction. The findings highlight the urgency of early antivenom administration to sequester as much circulating neurotoxins as possible, thereby hastening toxin elimination from the circulation. In envenomed mice, NKMAV administered upon the first neurological sign neutralized the neurotoxic effect, with the slowest full recovery noticed in the NK-T group. This is consistent with the high abundance of neurotoxins in the NK-T venom, implying that a larger amount or repeated dosing of NKMAV may be required in NK-T envenomation.
authors.affiliation: Department of Molecular Medicine, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.
authors.forename: Kae Yi
authors.initials: KY
authors.lastname: Tan
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia. Electronic address: tanchoohock@gmail.com.
authors.forename: Choo Hock
authors.initials: CH
authors.lastname: Tan
authors.affiliation: Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.
authors.forename: Si Mui
authors.initials: SM
authors.lastname: Sim
authors.affiliation: Department of Molecular Medicine, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.
authors.forename: Shin Yee
authors.initials: SY
authors.lastname: Fung
authors.affiliation: Department of Molecular Medicine, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.
authors.forename: Nget Hong
authors.initials: NH
authors.lastname: Tan
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000997:Antivenins / Q000494:pharmacology*; D002645:Chickens; D018679:Cholinergic Agonists / Q000494:pharmacology; D003039:Cobra Neurotoxin Proteins / Q000378:metabolism / Q000633:toxicity*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004546:Elapid Venoms / Q000378:metabolism / Q000633:toxicity*; D017815:Elapidae / Q000378:metabolism*; D008296:Malaysia; D008297:Male; D008813:Mice, Inbred ICR; D009119:Muscle Contraction / Q000187:drug effects*; D009469:Neuromuscular Junction / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D020127:Recovery of Function; D012909:Snake Bites / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D013785:Thailand; D013997:Time Factors; D014744:Vietnam
chemical_list: D000997:Antivenins; D018679:Cholinergic Agonists; D003039:Cobra Neurotoxin Proteins; D004546:Elapid Venoms; C521753:Naja kaouthia venom
keywords: Antivenom; Challenge-rescue assay; Chick biventer-cervicis nerve-muscle preparation; Naja kaouthia; Reversibility; Venom-induced neurotoxicity