title: Neurotoxicity in Sri Lankan Russell's Viper (Daboia russelii) Envenoming is Primarily due to U1-viperitoxin-Dr1a, a Pre-Synaptic Neurotoxin.
abstract: Russell's vipers are snakes of major medical importance in Asia. Russell's viper (Daboia russelii) envenoming in Sri Lanka and South India leads to a unique, mild neuromuscular paralysis, not seen in other parts of the world where the snake is found. This study aimed to identify and pharmacologically characterise the major neurotoxic components of Sri Lankan Russell's viper venom. Venom was fractionated using size exclusion chromatography and reverse-phase high-performance liquid chromatography (RP-HPLC). In vitro neurotoxicities of the venoms, fractions and isolated toxins were measured using chick biventer and rat hemidiaphragm preparations. A phospholipase A2(PLA2) toxin, U1-viperitoxin-Dr1a (13.6 kDa), which constitutes 19.2 % of the crude venom, was isolated and purified using HPLC. U1-viperitoxin-Dr1a produced concentration-dependent in vitro neurotoxicity abolishing indirect twitches in the chick biventer nerve-muscle preparation, with a t90of 55 ± 7 min only at 1 μM. The toxin did not abolish responses to acetylcholine and carbachol indicating pre-synaptic neurotoxicity. Venom, in the absence of U1-viperitoxin-Dr1a, did not induce in vitro neurotoxicity. Indian polyvalent antivenom, at the recommended concentration, only partially prevented the neurotoxic effects of U1-viperitoxin-Dr1a. Liquid chromatography mass spectrometry analysis confirmed that U1-viperitoxin-Dr1a was the basic S-type PLA2toxin previously identified from this venom (NCBI-GI: 298351762; SwissProt: P86368). The present study demonstrates that neurotoxicity following Sri Lankan Russell's viper envenoming is primarily due to the pre-synaptic neurotoxin U1-viperitoxin-Dr1a. Mild neurotoxicity observed in severely envenomed Sri Lankan Russell's viper bites is most likely due to the low potency of U1-viperitoxin-Dr1a, despite its high relative abundance in the venom.
authors.affiliation: Monash Venom Group, Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, 3800, Australia. anjana.silva@monash.edu.|Department of Parasitology, Faculty of Medicine and Allied Sciences, Rajarata University of Sri Lanka, Saliyapura, 50008, Sri Lanka. anjana.silva@monash.edu.
authors.forename: Anjana
authors.identifier: 0000-0002-9968-3707
authors.initials: A
authors.lastname: Silva
authors.affiliation: Monash Venom Group, Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, 3800, Australia.|Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton Campus, Melbourne, VIC, 3800, Australia.
authors.forename: Sanjaya
authors.initials: S
authors.lastname: Kuruppu
authors.affiliation: Jeffrey Cheah School of Medicine, Monash University Malaysia, Jalan Lagoon Selatan, 47500, Bandar Sunway, Selangor Darul Ehsan, Malaysia.
authors.forename: Iekhsan
authors.initials: I
authors.lastname: Othman
authors.affiliation: Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton Campus, Melbourne, VIC, 3800, Australia.
authors.forename: Robert J A
authors.initials: RJ
authors.lastname: Goode
authors.affiliation: Monash Venom Group, Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, 3800, Australia.
authors.forename: Wayne C
authors.initials: WC
authors.lastname: Hodgson
authors.affiliation: Monash Venom Group, Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, 3800, Australia.|Clinical Toxicology Research Group, Faculty of Health and Medicine, University of Newcastle, Level 5, New Med Building, Calvary Mater Hospital, Edith Street, Waratah, NSW, 2298, Australia.
authors.forename: Geoffrey K
authors.initials: GK
authors.lastname: Isbister
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D000997:Antivenins / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D002645:Chickens; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D009132:Muscles / Q000187:drug effects; D009469:Neuromuscular Junction / Q000187:drug effects; D009498:Neurotoxins / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification / Q000633:toxicity*; D018377:Neurotransmitter Agents / Q000494:pharmacology; D010525:Peripheral Nerves / Q000187:drug effects; D017729:Presynaptic Terminals / Q000187:drug effects; D051381:Rats; D017840:Daboia; D012909:Snake Bites; D046509:Tissue Culture Techniques; D014757:Viper Venoms / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification / Q000633:toxicity*
chemical_list: D000997:Antivenins; D009498:Neurotoxins; D018377:Neurotransmitter Agents; C000621507:U1-viperitoxin-Dr1a, Daboia russelii; D014757:Viper Venoms; D002217:Carbachol; D000109:Acetylcholine
keywords: Neurotoxicity; Phospholipase A2; Pre-synaptic; Russell’s viper