By 12 hours, all muscle fibres were denervated. Reinnervation began at 3 days with the appearance of regenerating nerve terminals, a return of neuromuscular function in some muscles, and a progressive increase in the immunoreactivity of SNARE proteins. Full recovery occurred at 7 days .
Neurotoxicity in Snakebite—The Limits of Our Knowledge
Harris et al. They suggested that all pre-synaptically active PLA2s produce similar effects . Although the molecular basis of pre-synaptic toxicity induced by the PLA2s is still not completely understood  —  , more recent studies have added significantly to our current knowledge  — . They have shown that PLA2s from snake venom neurotoxins produce similar but complex effects on the pre-synaptic nerve terminal.
These include entry into nerve terminals after binding to specific receptors on the pre-synaptic membrane, morphological changes such as nerve terminal bulging, changes in mitochondrial morphology and permeability, increase in cytosolic calcium levels, changes in expression and interactions of SNARE proteins, increased vesicle fusion and neurotransmitter release, and impaired vesicle recycling. Montecucco and colleagues have shown that the effects produced by four different snake venom PLA2s beta-bungarotoxin, taipoxin, notexin, and textilotoxin were similar, suggesting a similar mechanism of action for pre-synaptic neurotoxins.
Hydrolysis of the phospholipids of the pre-synaptic membrane and membrane destabilization by the products of hydrolysis are likely to be key drivers in this process  —  ,  ,  , . The post-synaptically active neurotoxins alpha-neurotoxins bind to the post-synaptic muscle nAChRs. They are classified into three main groups—long-chain, short-chain, and non-conventional alpha-neurotoxins  — .
Some toxins e. In this type of toxicity, antivenom may facilitate dissociation of toxin from the ACh receptor and accelerate recovery  ,  , and a clinical response to AChEIs, similar to myasthenia, is more likely .
Most of the alpha-neurotoxins, however, bind almost irreversibly to the post-synaptic nAChRs, even though they produce a non-depolarising type of block  ,  , . Their action, therefore, is not readily reversible by antivenom or AChEIs. These include most of the long-chain 3FTXs such as alpha-bungarotoxin. Lee et al. This was characterized by slow onset, persistent and dose-dependent progression, lack of recovery for a long period, and lack of sustained reversibility to AChEIs.
Post-tetanic facilitation was prominent. Tetanic and TOF fade were not seen, and therefore this differed from the type of block seen with d-tubocurarine .
Neuropoisons: Their Pathophysiological Actions
The lack of tetanic and TOF fade is attributed to the failure of alpha-bungarotoxin to block the pre-synaptic neuronal nAChRs  — . The recent insights into NMJ transmission have enabled better and more comprehensive characterization of the more recently described toxins. 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  — .
However, in contrast to the nearly irreversible blockade produced by alpha-bungarotoxin, candoxin produces a readily reversible block of the post-synaptic nAChR. In addition, candoxin also inhibits the pre-synaptic, neuronal AChRs and produces tetanic and TOF fade on rapid repetitive stimulation  , . Although reversibility of blockade would be of crucial importance in the success of therapeutic interventions, what determines reversibility seems unclear.
Low receptor binding affinity and a short polypeptide chain length of the toxin molecules have been postulated as likely reasons, but it is more likely that substitution of amino acid residues in regions that interact with the AChR may be responsible  , . Some snake venom toxins interfere with NMJ transmission through various other mechanisms. Some pre-synaptic toxins, such as the dendrotoxins from venoms of the Eastern green mamba Dendroaspsis angusticeps and the black mamba D.
A different type of toxin from D. They have been named fasciculins due to their effect of producing generalized, long-lasting fasciculations  ,  — . Snake venoms do not contain a homogenous single toxin, but are complex cocktails of enzymes, polypeptides, non-enzymatic proteins, nucleotides, and other substances, many of which may have different neurotoxic properties  ,  ,  ,  ,  ,  ,  Table 2.
The studies of Chang and others of the Chinese or formerly Formosan cobra Naja atra venom ,  ,  highlighted the complexity of multiple actions of different neurotoxins in the same venom. 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. It had no effect on nerve conduction.
Neuropoisons their pathophysiological actions
However, the venom also contained cardiotoxin, which interfered with axonal conduction and produced muscle depolarisation  , . Characterization of new toxins continues to add to the rich diversity of snake venom, and many types of venom are now known to contain both pre- and post-synaptically active toxins. For example, a post-synaptic toxin DNTx-I—Daboia Neurotoxin 1 has been isolated from the venom of Russell's viper Daboia russelii  , in addition to the well-known pre-synaptic PLA2 toxin  , .
Venom of kraits Bungarus spp. In addition to the alpha-bungarotoxin post-synaptic block and beta-bungarotoxin pre-synaptic block already described, it also contains kappa-bungarotoxin which binds to the neuronal nAChR at the post-synaptic level in central cholinergic synapses in autonomic ganglia  ,  , . Experimental data on physiological, pathological, and ultrastructural changes due to snake neurotoxins are derived from studies in animal models, in vitro nerve-muscle preparations, or preparations of nAChRs. However, such laboratory data may not accurately reflect the effects of snake venom in humans.
It is known that the effects of envenoming can vary depending on the bitten species, and this may be due to the snake's prey preferences. For example, candoxin from the Malayan or blue krait B. Irditoxin from the venom of the brown tree snake Boiga irregularis shows taxa-specific lethal toxicity to birds and lizards, but not toward mice. In vitro studies showed that it produced potent post-synaptic toxicity similar to alpha-bungarotoxin at avian NMJs, but not in mammalian NMJs .
Waglerin from Wagler's pit viper Tropidolaemus wagleri binds more tightly to mouse nAChRs than to those from rats or humans . Similarly, interspecies differences in sensitivity of nerve-muscle preparations to pre-synaptic snake toxins have been well documented . It is known that the two different types of receptors have different opening times and speeds of ion conductance  , . 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.
In this context, it is interesting to note that waglerins from Wagler's pit viper Tropidolaemus wagleri and azemiopsin from Fea's viper Azemiops feae have shown specificity toward the ontogenetic state of the nAChR, with higher binding affinity to the adult or mature form than the foetal form  — .
Sri Lankan patient with severe neurotoxicity and respiratory paralysis being ventilated following a cobra Naja naja bite. Photograph courtesy of Prof. Kularatne, University of Peradeniya, Sri Lanka. The purpose of the photograph has been explained to the patient, and consent obtained for potential publication. Sri Lankan patient with bilateral ptosis and facial weakness following a Krait Bunagrus caeruleus bite.
Sri Lankan farmer with Russell's viper Daboia russelii envenoming: tissue necrosis at bite site, haematuria, and bilateral ptosis. Photographs courtesy of Prof. The purpose of the photographs has been explained to the patient, and consent obtained for potential publication. Reported prevalence rates of neuromuscular weakness vary between series, and with different snake species and different study settings.
As seen from above, each toxin can have a multitude of effects, venom of one snake species is a mix of multiple toxins, and venom composition varies between species of same genus. In addition, intraspecies variations in venom compositions are well known. It is therefore not surprising that wide variation is seen in the neurotoxic effects.
Possible methodological differences and lack of uniformity in description contribute to the large variation between studies, and make interpretation of data from different studies difficult. Variations in case fatality are likely to be influenced by many factors including intensity of staff observation, development of respiratory failure, and availability of ventilation.
Intensive care units are more likely to admit more severe patients with respiratory involvement  ,  ,  ,  , and therefore may have higher mortality rates than less-biased samples.
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 . The envenoming snake species is highly likely to influence the clinical presentation and outcome, but many studies have considered together bites from different snake species  ,  ,  ,  ,  ,  — . Such differences are perhaps unavoidable as confirming the identity of the envenoming snake is often difficult.
Only a few studies have reported snake identification by detection of venom antigens  ,  ,  ,  ,  ,  , .
Related Neuropoisons: Their Pathophysiological Actions
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