Abstract
The King Cobra (Ophiophagus hannah) is the world’s largest venomous snake and has a widespread geographical distribution throughout Southeast Asia. Despite proteomic studies indicating the presence of postsynaptic neurotoxins in O. hannah venom, there are few pharmacological investigations of these toxins. We isolated and characterized α-elapitoxin-Oh3a (α-EPTX-Oh3a; 7,938 Da), a long-chain postsynaptic neurotoxin, which constitutes 5% of O. hannah venom. α-EPTX-Oh3a (100–300 nM) caused concentration-dependent inhibition of indirect twitches and inhibited contractile responses of tissues to exogenous acetylcholine and carbachol, in the chick biventer cervicis nerve-muscle preparation. The prior incubation of tissues with Thai Red Cross Society King Cobra antivenom (1 ml/0.8 mg) prevented the in vitro neurotoxic effects of α-EPTX-Oh3a (100 nM). The addition of Thai Red Cross Society King Cobra antivenom (1 ml/0.8 mg), at the t90 time point partially reversed the in vitro neurotoxicity of α-EPTX-Oh3a (100 nM). Repeatedly washing the tissue did not allow significant recovery from the in vitro neurotoxic effects of α-EPTX-Oh3a (100 nM). α-EPTX-Oh3a demonstrated pseudo-irreversible antagonism of concentration-response curves to carbachol, with a pA2 of 8.99. De novo sequencing of α-EPTX-Oh3a showed a long-chain postsynaptic neurotoxin with 72 amino acids, sharing 100% sequence identity with Long neurotoxin OH-55. In conclusion, the antivenom is useful for reversing the clinically important long-chain α-neurotoxin-mediated neuromuscular paralysis.
Highlights
The King Cobra (Ophiophagus hannah) is widely distributed in Southeast Asia, some parts of the Indian subcontinent and Southern China (O’Shea, 2008)
This study aimed to isolate the main neurotoxins from O. hannah venom and identify the mode of action, as well as determine the in vitro efficacy of Thai Red Cross Society King Cobra antivenom in neutralizing them
Fractionation of Venom via Reverse-phase high-performance liquid chromatography (HPLC) and Ion-Exchange Chromatography α-Elapitoxin-Oh3a was isolated from O. hannah venom using reverse-phase HPLC followed by ion-exchange chromatography
Summary
The King Cobra (Ophiophagus hannah) is widely distributed in Southeast Asia, some parts of the Indian subcontinent and Southern China (O’Shea, 2008). Few pharmacological studies have investigated the mechanism of action of O. hannah venom, and isolated neurotoxins, at the skeletal neuromuscular junction. Proteomic studies of the venom of O. hannah have indicated a large relative abundance of “postsynaptic” neurotoxins (Petras et al, 2015; Tan et al, 2015), which inhibit neurotransmission by acting as antagonists at the skeletal nicotinic acetylcholine receptor (nAChR) (Barber et al, 2013). Postsynaptic neurotoxins are further classified as short-chain or long-chain neurotoxins, and their structural and functional differences have been previously described in detail (Barber et al, 2013; Utkin, 2019). Recent research has shown that long-chain α-neurotoxins are more clinically important in human envenoming, compared to short-chain α-neurotoxins, due to their higher potency and poor reversibility on the human nAChR (Silva et al, 2018)
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