snake venom neurotoxicity

There is a clear variation in the propensity of similar species of snakes to produce different patterns of neuromuscular weakness in different geographical locations. There are three main types of snake venom that affect the body differently which are neurotoxic, hemotoxic, and cytotoxic venom. More research into these fascinating molecules and their diverse actions would not only help us improve management of neurotoxic envenoming, but may also enable their use as potential treatments for infections, cancer, and various neurological disorders. Snake venom neurotoxic 3FTx are typically alpha-neurotoxic and this is the ancestral condition, this activity being widespread not only in elapid venoms but also in the venoms … Respiratory failure developed in some patients who had myokymia involving the shoulders or chest, perhaps due to underlying diaphragmatic involvement [60]. Most snakes do not carry venom, but the ones that do are called venomous. Each venom type targets a specific part or system of the body. Antivenoms used in developing countries are known to produce adverse reactions in 30–80% of patients [159], [182], and reactions can be seen in up to 25% even in developed countries [182]. In addition, several muscarinic toxins have been identified from Dendroaspis spp. Improvement in neurotoxicity has been reported when anti-venom … Although reversibility of blockade would be of crucial importance in the success of therapeutic interventions, what determines reversibility seems unclear. They have been named fasciculins due to their effect of producing generalized, long-lasting fasciculations [136], [142]–[144]. However, it is restricted by cold storage, snakebite diagnosis, and high price. Composition of snake venom 4. Neurotoxins in snake venom can be presynaptic or postsynaptic, both types can be found in a single species venom or only one can be present, these two different toxins work on two different nerve functions effecting the way nerve synapses function. Neuromuscular block at the post-synaptic level is classified into non-depolarising and depolarising types. Schematic representation of the neuromuscular junction showing different sites of action of snake neurotoxins, other toxins, and pharmacological substances, and sites of involvement in disease states (examples indicated where relevant). Prasarnpun et al. Snake venom can pack a serious punch. [142], [204]. Clinical recovery is slow as it is dependent on regeneration of the nerve terminal and formation of a new neuromuscular junction [109], [110]. Neurotoxins affect the Nervous system and are severely toxic. Voltage-gated calcium channel: Snake toxins: calciseptine (Dendroaspis spp. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Competing interests: The authors have declared that no competing interests exist. For example, it is becoming clear that many of the post-synaptic toxins produce nearly irreversible binding, and long-lasting effects. The Doctors: Hemotoxic and Neurotoxic Venom and Effects of … Neurotoxic venom. There are several reports of delayed neurological manifestations after snake envenomation. They have demonstrated a potential immunological basis for the syndrome, with cross-reactivity shown between glycosidic epitopes of venom proteins and neuronal GM2 ganglioside, without evidence of direct neurotoxicity of the venom [80]. They demonstrated that the main neuromuscular blocking effect was due to cobrotoxin, which produced a curare-like non-depolarising, competitive post-synaptic block, which was antagonised by neostigmine. Although the clinical manifestations of acute neuromuscular weakness with respiratory involvement are well recognised, it is surprising how many questions remain unanswered regarding neurotoxicity. A different type of toxin from D. angusticeps acts as an AChE inhibitor, thus increasing the availability of ACh at the NMJ. Such differences are perhaps unavoidable as confirming the identity of the envenoming snake is often difficult. These include alteration of receptor dynamics, desensitization, and channel blockade [102]. Snakes venoms are complex and contain numerous compounds with varied sites of action. In the first detailed clinical and neurophysiological study of long-term neurological deficits, Bell et al. They have shown that PLA2s from snake venom neurotoxins produce similar but complex effects on the pre-synaptic nerve terminal. Low-molecular weight components (<1500 Da) are usually considered the least physiologically active and includes peptides, lipids, nucleosides, carbohydrates, amines, and metal ions.Larger venom components (mol. ), taipoxin (O. scutellatus); Other toxins: botulinum toxin, tetanus neurotoxin. There is considerable variation between individual patients in the clinical manifestations following envenoming by any particular species. Snakebites from neurotoxic snakes work by disrupting nerve functions i.e., disrupting chemical signals sent between neurons. There is also some experimental evidence for delayed neuropathic effects. (1977) showed that alpha-bungarotoxin (a-BuTX) produced a pure post-synaptic, non-depolarising, but almost irreversible neuromuscular blockade [106]. A key limitation in this study was that patients given antivenom were compared with a group of patients treated during an earlier period for whom antivenom was not available (historical control). Minor neurotoxic snakes include – Summary of studies on interventions in neurotoxic envenoming. They are preferentially affected in some diseases such as myasthenia and chronic progressive ophthalmoplegia, and selectively spared in Duchenne muscular dystrophy and amyotrophic lateral sclerosis [161], [163], [164]. ), Sri Lankan farmer with Russell's viper (Daboia russelii) envenoming: tissue necrosis at bite site, haematuria, and bilateral ptosis. Neurotoxicity is a well-known feature of envenoming due to elapids (family Elapidae) such as kraits (Bungarus spp.) Lalloo DG, Trevett AJ, Korinhona A, Nwokolo N, Laurenson IF, et al. In addition, there are several reports of fascinating regional variations in venom composition and potency from the same species (intraspecies variation) within the same country, e.g., Russell's viper (Daboia russelii) in India [147], [169], the Mojave rattlesnake (Crotalus scutulatus) in the United States [170], the asp viper (Vipera aspis) in France [76], [81], and tiger snakes (Notechis scutatus) in Australia [171]. Envenomations by neurotoxic species are one of the most challenging and time-critical situations in snakebite medicine. The substances include a wide range of natural and human-made chemical compounds, from snake venom and pesticides to ethyl alcohol, heroin, and cocaine. [58]–[67]. Envenoming is a significant public health problem in tropical and subtropical regions. Mechanical ventilation, intensive care, antivenom treatment, other ancillary care, and prolonged hospital stays all contribute to a significant cost of provision of care. Given the lack of clarity over mechanisms of neurotoxicity, the lack of consensus on the value of antivenom or AChEI therapy in snake envenoming is not surprising. The venom consists of neurotoxins with a median lethal dose 1.7-1.93 mg/kg subcutaneously, with a venom yield of 200-500 mg, average of 420 mg. One bite contains enough venom to kill twenty grown man, or an elephant. Although symptoms are mild in most cases, severe systemic anaphylaxis may develop, and further understanding of their harm-benefit balance is important. Coral snake venom does cause euphoria and drowsiness, along with cranial nerve deficits. ), candoxin (B. candidus), azemiopsin (A. feae), waglerin (T. wagleri ); Other toxins: alpha-conotoxin (marine snail, Conus spp. Data from the Million Deaths Study in India estimates that snakebite deaths are more than 30-fold higher than recorded in official hospital returns [5]. "The target of snake venom neurotoxins is a strongly negatively charged nerve receptor," Dr Fry said. Ptosis is reported in between 70–93% of patients in most series, and extraocular muscle weakness in 68–82% [9]–[11], [42], [73], [75], [156]. Increased exposure to snakes due to traditional agricultural practices, lack of good health care services, poor access to available services, influence of health-seeking behaviour on accessing the available health care services, and lack of effective antivenom all contribute to this [2], [8]. Altogether, 624 titles and abstracts were screened, and 287 full articles were retrieved and read by a single author (UKR) for data acquisition. It is unclear whether geographical variation in venom composition plays a significant role in … Rinkhals have a Cytotoxic as well as a Neurotoxic venom. Alterations in smell and taste have been reported in envenoming by several snake species [67], [193], [194], and whether these are central effects or due to peripheral cranial nerve involvement is not clear. Another report is of a patient who had acute neurotoxicity and respiratory arrest after a krait bite and developed quadriparesis 3 weeks later with elevated CSF protein and evidence of a sensorimotor axonal-type polyneuropathy [22]. Both adult (αβεδ-) and foetal (δβγδ-) isoforms of nAChR are expressed in adult extraocular muscles, unlike in other skeletal muscles [163], [165], [166]. (Photograph courtesy of Prof. S. A. M. Kularatne, University of Peradeniya, Sri Lanka. Comparing findings from different studies is difficult, as there is a lack of uniformity in description or grading of neuromuscular weakness, or in assessment of response to treatment. However, the evidence for benefit of AChEI is conflicting. Post-tetanic facilitation was prominent. Learn more about how to manage these difficult cases with the printable guidelines provided below: Click here to download Part I of the Management of Neurotoxic Snake Envenomations! In addition, such variations may well be related to the differences between pre-synaptic and post-synaptic types of toxin in snake venom, and also to the specificity of antivenom to the envenoming snake species. [40]–[46], coral snakes (Micrurus spp.) 4. They produce neuromuscular block that occurs in three phases: an immediate depression of ACh release, followed by a period of enhanced ACh release, and then complete inhibition of NMJ transmission [108], [112]–[116]. A. Y. Udara (drawing the diagram on neuromuscular transmission). Some toxins (e.g., alpha-cobratoxin) have been shown to produce a competitive, non-depolarising type of post-synaptic blockade similar to dTC [138], [139]. It contains neurotoxins (nerve-attacking chemicals) that can kill small mammals in minutes – including other snakes. Improved case definitions are the key to a better understanding of neurotoxicity from different snakes. There is an additional miscellaneous class of snake venom neurotoxins that includes weak neurotoxin, muscarinic toxin‐like proteins and vipoxin. Persistent axonal damage due to neurotoxins, and delayed immune-mediated reactions to toxins or antivenom are possible explanations. They showed that beta-bungarotoxin produces pre-synaptic toxicity characterized by depletion of synaptic vesicles, destruction of motor nerve terminals, and axonal degeneration followed by reinnervation [108]. Although the molecular basis of pre-synaptic toxicity induced by the PLA2s is still not completely understood [119]–[127], more recent studies have added significantly to our current knowledge [119]–[133]. At the post-synaptic level, ACh binds to muscle nAChRs (adult or mature type—α1β1εδ) on the post-synaptic membrane. A nationally representative survey in Bangladesh suggested that incidence of snakebite is much higher than previously estimated [4]. Either both types can be found in snake venom or only one may be present. For example, candoxin from the Malayan or blue krait (B. candidus), which feeds mainly on rodents and reptiles, preferentially binds to murine nAChRs rather than to those of chick origin [135]. Several cases of possible Guillain-Barré syndrome (GBS) have been reported. ... A second neurotoxin, which we designate Toxin F, blocked transmission at 1-3 micrograms/ml and also blocked ganglionic depolarizations induced by carbachol. Neurotoxicity is a key feature of some envenomings, and there are many unanswered questions regarding this manifestation. This article will focus only on the direct neurotoxic effects of envenoming. The venom targets the central nervous system, which leads to severe pain, blurry vision, vertigo, drowsiness, and paralysis. There are many challenges to the study of neurotoxicity after snakebite. Coral snake venom does cause euphoria and drowsiness, along with cranial nerve deficits. The possibility that distinct patterns of neuromuscular weakness exist in snake envenomation has not been studied. Some are reports of persistence of neurological deficits which first developed during the acute stage. Respiratory muscle weakness is reported in 27–87% [9]–[11], [25], [42], [45], [156]. The occupation of a single binding site by one molecule of a NMBA would therefore effectively “block” the receptor [98]–[100], [102]. Respiratory paralysis in neurotoxic envenoming. Your email address will not be published. However, there can be significant variations in the effects of the so-called “curare-mimetic” neurotoxins on the post-synaptic nAChR. Neurological manifestations can also result from non-neurotoxic effects of envenoming, such as cerebral haemorrhage and infarction due to coagulopathy, and myotoxicity. Snake venom phospholipase A₂s … Copyright: © 2013 Ranawaka et al. venom has been shown to act on voltage-gated sodium and potassium channels [183]–[189], and similar molecules may be responsible for the myokymia in envenoming by North American rattlesnakes (Crotalus spp.). Development of more effective and safer antivenoms including monospecific antivenoms and Fab fragments, and a better understanding of the cross-neutralisations possible with available antivenom, may help to optimize the use of antivenom in neurotoxicity [182], [223]–[226]. All types have the potential to be deadly and/or cause severe damage. However, such laboratory data may not accurately reflect the effects of snake venom in humans. Crotamine in South American rattlesnake (Crotalus spp.) Accurate case definition is the key to meaningful interpretation of available data and comparison between studies. Some snake venom toxins interfere with NMJ transmission through various other mechanisms. The recent insights into NMJ transmission have enabled better and more comprehensive characterization of the more recently described toxins. In a randomized double-blind trial in Philippine cobra (Naja philippinensis) envenoming, antivenom was not found to be effective [30]. If adequate ACh is released, this end-plate potential is propagated by the opening of sodium channels along the perijunctional zone and muscle membrane and initiates calcium release and muscle contraction [98]–[100], [102]. Candoxin, a novel toxin isolated from the venom of the Malayan or blue krait (Bungarus candidus), is a non-conventional 3FTX with structural similarities to alpha-bungarotoxin [134]–[136]. It is likely that the effects of toxins on the two different types of receptor, and therefore the in vivo effects on humans, may be different to what may be observed in the laboratory. Delays in accessing ICU care, and lack of adequate facilities for optimal care in resource-limited areas where snakebite is common, also would contribute to higher mortality [20]. Malayan krait (Bungarus candidus) is a medically important snake species found in Southeast Asia. (1995) Snake bites by the Papuan taipan (, Watt G, Theakston RD, Hayes CG, Yambao ML, Sangalang R, et al. (2004, 2005) [109], [117] showed that beta-bungarotoxin produced calcium influx through voltage-gated calcium channels and increased release of ACh via SNARE-complex dependent mechanisms leading to depletion of synaptic vesicles. The venom composition in Russell's viper in Sri Lanka (Daboia russelii) and South India (D. russelii) was found to be different from that found in Pakistan (D. russelii), Thailand (D. siamensis), and Taiwan (D. siamensis) [167]. The mechanisms of many of these acute manifestations are not clear, and there has been no systematic study of these in a large series. For example, a post-synaptic toxin (DNTx-I—Daboia Neurotoxin 1) has been isolated from the venom of Russell's viper (Daboia russelii) [146], in addition to the well-known pre-synaptic PLA2 toxin [147], [148]. NMBAs are known to impair NMJ transmission by several additional effects on the nAChRs, without binding to the receptor binding sites. ); Other toxins: omega-conotoxin (marine snail, Conus spp. 9. Depolarising neuromuscular blocking agents (NMBAs) (such as suxamethonium) bind irreversibly to the post-synaptic muscle nAChRs, and produce a non-competitive block, which is not reversed by acetyl cholinesterase inhibitor drugs (AChEIs). Extraocular muscles are developmentally, histologically, ultrastructurally, immunologically, metabolically, and functionally different to other skeletal muscle groups [160]–[166]. Tracy J. Eicher, in Clinical Neurotoxicology, 2009 Snakes. Yet some species of snake survive bites that are deadly to others, even from their own species. 1) The elapines, short front fangs (Proteroglyphs) snakes, which include the cobra, mamba, and coral snakes, their venom is neurotoxic (nerve toxins) and paralyses the respiratory centre. These are further pointers to the diversity of the types of neurotoxicity produced by different snake species. The purpose of the photograph has been explained to the patient, and consent obtained for potential publication. Major neurotoxic snakes include – BLACK MAMBA, GREEN MAMBA, CAPE COBRA, FOREST COBRA, SNOUTED COBRA (formerly known as Egyptian Cobra), RINKHALS, SEA SNAKES. PLOS Neglected Tropical Diseases is the top Open Access tropical medicine journal, featuring an International Editorial Board and increased support for developing country authors. Envenoming is a significant public health problem in tropical and subtropical regions. They repetitively associate with and dissociate from the ACh binding sites, rather than producing prolonged binding, and therefore can be displaced by ACh [97]. Either both types can be found in snake venom or only one may be present. We also obtained articles on “neuromuscular junction” and “neuromuscular block.” Additional related articles were obtained from citation tracking of retrieved articles and tracking of “related citations” in PubMed. However, it is restricted by cold storage, snakebite diagnosis, and high price. It contains neurotoxins (nerve-attacking chemicals) that can kill small mammals in minutes – including other snakes.

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