Isolation and pharmacological characterization of α-Elapitoxin-Na1a, a novel short-chain postsynaptic neurotoxin from the venom of the Chinese Cobra (Naja atra)

Liang, Qing; Huynh, Tam Minh; Hodgson, Wayne C.

doi:10.1016/j.bcp.2020.114059

Cited by 6 publications

(12 citation statements)

References 25 publications

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“…The failure to fully reverse the decline in twitch height is likely to be due to a number of factors including the contribution of myotoxins and the lack of reversibility of some neurotoxins. Indeed, we have previously shown that the short-chain post-synaptic neurotoxin α-Elapitoxin-Na1a, which accounts for approximately 9% of N. atra venom, displays pseudo-irreversible antagonism at the skeletal muscle nicotinic acetylcholine receptor and is only partially reversed by antivenom [ 7 ]. Interesting, the Australian polyvalent snake venom displayed similar efficacy against the neurotoxic effects of the venom indicating that the antigenic components in this antivenom, which is raised against a number of venoms from Australian elapid snakes containing postsynaptic and/or presynaptic neurotoxins, are able to recognize the neurotoxic components of N. atra venom.…”

Section: Discussionmentioning

confidence: 99%

“…Although, as indicated above, N. atra venom is highly neurotoxic in vitro, it is only mildly neurotoxic in humans. This is most likely due to the neurotoxic components being short-chain neurotoxins which readily dissociate from human muscle nAChRs [ 7 ]. Interestingly, a recent study found that the post-synaptic α-neurotoxins in N. atra venom bind to the alpha-1 nAChR orthosteric site with selectivity towards the amphibian mimotope over lizard, avian and rodent mimotopes indicative of prey selectivity [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

“…Based on venomic data, Chinese N. atra venom contains a range of toxins, with cardiotoxins and short-chain neurotoxins being the most abundant components [ 3 , 4 , 5 , 6 ]. We have previously isolated a short-chain neurotoxin, α-Elapitoxin-Na1a, from Chinese N. atra venom [ 7 ]. However, it has been previously shown that short-chain neurotoxins dissociate readily from human nicotinic acetylcholine receptors (nAChRs) and are unlikely to contribute substantially to neurotoxicity in humans [ 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

“…We have previously isolated a short-chain neurotoxin, α-Elapitoxin-Na1a, from Chinese N. atra venom [ 7 ]. However, it has been previously shown that short-chain neurotoxins dissociate readily from human nicotinic acetylcholine receptors (nAChRs) and are unlikely to contribute substantially to neurotoxicity in humans [ 7 , 8 ]. The major outcomes of envenoming by Chinese N. atra include severe wound necrosis or chronic necrotic ulceration for which large doses of antivenom are administered.…”

Section: Introductionmentioning

confidence: 99%

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An Examination of the Neutralization of In Vitro Toxicity of Chinese Cobra (Naja atra) Venom by Different Antivenoms

et al. 2020

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The Chinese Cobra (Naja atra) is an elapid snake of major medical importance in southern China. We describe the in vitro neurotoxic, myotoxic, and cytotoxic effects of N. atra venom, as well as examining the efficacy of three Chinese monovalent antivenoms (N. atra antivenom, Gloydius brevicaudus antivenom and Deinagkistrodon acutus antivenom) and an Australian polyvalent snake antivenom. In the chick biventer cervicis nerve-muscle preparation, N. atra venom (1–10 µg/mL) abolished indirect twitches in a concentration-dependent manner, as well as abolishing contractile responses to exogenous acetylcholine chloride (ACh) and carbamylcholine chloride (CCh), indicative of post-synaptic neurotoxicity. Contractile responses to potassium chloride (KCl) were also significantly inhibited by venom indicating myotoxicity. The prior addition of Chinese N. atra antivenom (0.75 U/mL) or Australian polyvalent snake antivenom (3 U/mL), markedly attenuated the neurotoxic actions of venom (3 µg/mL) and prevented the inhibition of contractile responses to ACh, CCh, and KCl. The addition of Chinese antivenom (0.75 U/mL) or Australian polyvalent antivenom (3 U/mL) at the t90 time point after the addition of venom (3 µg/mL), partially reversed the inhibition of twitches and significantly reversed the venom-induced inhibition of responses to ACh and CCh, but had no significant effect on the response to KCl. Venom (30 µg/mL) also abolished direct twitches in the chick biventer cervicis nerve-muscle preparation and caused a significant increase in baseline tension, further indicative of myotoxicity. N. atra antivenom (4 U/mL) prevented the myotoxic effects of venom (30 µg/mL). However, G. brevicaudus antivenom (24 U/mL), D. acutus antivenom (8 U/mL) and Australian polyvalent snake antivenom (33 U/mL) were unable to prevent venom (30 µg/mL) induced myotoxicity. In the L6 rat skeletal muscle myoblast cell line, N. atra venom caused concentration-dependent inhibition of cell viability, with a half maximal inhibitory concentration (IC50) of 2.8 ± 0.48 μg/mL. N. atra antivenom significantly attenuated the cytotoxic effect of the venom, whereas Australian polyvalent snake antivenom was less effective but still attenuated the cytotoxic effects at lower venom concentrations. Neither G. brevicaudus antivenom or D. acutus antivenom were able to prevent the cytotoxicity. This study indicates that Chinese N. atra monovalent antivenom is efficacious against the neurotoxic, myotoxic and cytotoxic effects of N. atra venom but the clinical effectiveness of the antivenom is likely to be diminished, even if given early after envenoming. The use of Chinese viper antivenoms (i.e., G. brevicaudus and D. acutus antivenoms) in cases of envenoming by the Chinese cobra is not supported by the results of the current study.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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An Examination of the Neutralization of In Vitro Toxicity of Chinese Cobra (Naja atra) Venom by Different Antivenoms

et al. 2020

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“…in their venoms, such as the sea snake Hydrophis schistosus (<14% LC-α-3FNTxs), Chinese cobra Naja atra (< 3% LC-α-3FNTxs) and Australian red-bellied black snake Pseudechis porphyriacus (no LC-α-3FNTxs detected), do not cause significant neuromuscular paralysis [185,231].…”

Section: Role Of α-Neurotoxins In Snakebite Envenomation and Implications For Treatmentmentioning

confidence: 99%

Scope of practice and educational needs of infection prevention and control professionals in Australian residential aged care facilities

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Sotomayor-Castillo

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et al. 2020

Infection, Disease & Health

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Snake venom three-finger α-neurotoxins (α-3FNTx) act on postsynaptic nicotinic acetylcholine receptors (nAChRs) at the neuromuscular junction (NMJ) to produce skeletal muscle paralysis.The discovery of the archetypal α-bungarotoxin (α-BgTx), almost six decades ago, exponentially expanded our knowledge of membrane receptors and ion channels. This included the localisation, isolation and characterization of the first receptor (nAChR); and by extension, the pathophysiology and pharmacology of neuromuscular transmission and associated pathologies such as myasthenia gravis, as well as our understanding of the role of α-3FNTxs in snakebite envenomation leading to novel concepts of targeted treatment. Subsequent studies on a variety of animal venoms have yielded a plethora of novel toxins that have revolutionized molecular biomedicine and advanced drug discovery from bench to bedside. This review provides an overview of nAChRs and their subtypes, classification of α-3FNTxs and the challenges of typifying an increasing arsenal of structurally and functionally unique toxins, and the three-finger protein (3FP) fold in the context of the uPAR/Ly6/CD59/snake toxin superfamily. The pharmacology of snake α-3FNTxs including their mechanisms of neuromuscular blockade, variations in reversibility of nAChR interactions, specificity for nAChR subtypes or for distinct ligand-binding interfaces within a subtype and the role of α-3FNTxs in neurotoxic envenomation are also detailed. Lastly, a reconciliation of structure-function relationships between α-3FNTx and nAChRs, derived from historical mutational and biochemical studies and emerging atomic level structures of nAChR models in complex with α-3FNTxs is discussed.

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In Vitro neurotoxicity and myotoxicity of Malaysian Naja sumatrana and Naja kaouthia venoms: Neutralization by monovalent and Neuro Polyvalent Antivenoms from Thailand

et al. 2022

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Naja sumatrana and Naja kaouthia are medically important elapids species found in Southeast Asia. Snake bite envenoming caused by these species may lead to morbidity or mortality if not treated with the appropriate antivenom. In this study, the in vitro neurotoxic and myotoxic effects N. sumatrana and N. kaouthia venoms from Malaysian specimens were assessed and compared. In addition, the neutralizing capability of Cobra Antivenom (CAV), King Cobra Antivenom (KCAV) and Neuro Polyvalent Antivenom (NPAV) from Thailand were compared. Both venoms produced concentration-dependent neurotoxic and myotoxic effects in the chick biventer cervicis nerve-muscle preparation. Based on the time to cause 90% inhibition of twitches (i.e. t90) N. kaouthia venom displayed more potent neurotoxic and myotoxic effects than N. sumatrana venom. All three of the antivenoms significantly attenuated venom-induced twitch reduction of indirectly stimulated tissues when added prior to venom. When added after N. sumatrana venom, at the t90 time point, CAV and NPAV partially restored the twitch height but has no significant effect on the reduction in twitch height caused by N. kaouthia venom. The addition of KCAV, at the t90 time point, did not reverse the attenuation of indirectly stimulated twitches caused by either venom. In addition, none of the antivenoms, when added prior to venom, prevented attenuation of directly stimulated twitches. Differences in the capability of antivenoms, especially NPAV and CAV, to reverse neurotoxicity and myotoxicity indicate that there is a need to isolate and characterize neurotoxins and myotoxins from Malaysian N. kaouthia and N. sumatrana venoms to improve neutralization capability of the antivenoms.

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Isolation and pharmacological characterization of α-Elapitoxin-Na1a, a novel short-chain postsynaptic neurotoxin from the venom of the Chinese Cobra (Naja atra)

Cited by 6 publications

References 25 publications

An Examination of the Neutralization of In Vitro Toxicity of Chinese Cobra (Naja atra) Venom by Different Antivenoms

An Examination of the Neutralization of In Vitro Toxicity of Chinese Cobra (Naja atra) Venom by Different Antivenoms

Scope of practice and educational needs of infection prevention and control professionals in Australian residential aged care facilities

In Vitro neurotoxicity and myotoxicity of Malaysian Naja sumatrana and Naja kaouthia venoms: Neutralization by monovalent and Neuro Polyvalent Antivenoms from Thailand

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