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Paralytic Neurotoxins Overview

Snake venom neurotoxins are a diverse group of toxins which clinically cause paralytic effects mediated at the neuromuscular junction (in most cases). 100 years ago, snakebite paralysis usually condemned the victim to death due to respiratory failure. In the current era of ICU care, intubation, ventilators etc, such an outcome should be rare, but in many regions such “high tech” facilities are unavailable, thus many snakebite victims still die annually of neurotoxic paralysis.

Presynaptic neurotoxins generally are modified phospholipase A2 toxins which specifically target the terminal axon of the neuromuscular junction, causing first release of neurotransmitter, then extensive damage to the axonal structure, completely disrupting transmitter synaptic vesicle production and thus cessation of transmitter release. Clinically this causes a progressive flaccid paralysis, with onset of first signs usually 1+ hours post bite, with progressive paralysis thereafter. Full respiratory paralysis, including the diaphragm, may take 3-24 hours, but once paralysed, recovery rate is determined by axonal repair and is not influenced by antivenom therapy. It is therefore critically important in this type of envenoming to recognise the early signs of paralysis and institute effective antivenom therapy before more extensive paralysis becomes irreversibly established. Complete paralysis may take days, weeks or, rarely, months to resolve. During this period the victim is dependent on external ventilatory support and at risk of a number of potentially severe complications. Presynaptic neurotoxins are found in selected Elapid and Viperid venoms.

Postsynaptic neurotoxins are polypeptides of varying size, usually below 12 kD and also target the neuromuscular junction. They act extracellularly, binding to the acetylcholine receptor on the muscle end-plate, blocking neurotransmitter binding, thus causing paralysis. The cell is not specifically damaged, therefore this type of flaccid paralysis is often reversible with antivenom therapy, even if very extensive. The mode of action also may allow more rapid onset and progression of paralysis, though major paralysis is uncommon in under one hour post-bite. Postsynaptic neurotoxins are present in many Elapid and a few Viperid venoms.

Dendrotoxins and Fasciculins are synergistic neurotoxins found in some African mamba venoms. They both target the neuromuscular junction, causing paralysis and muscle spasms or fasciculation. The dendrotoxins target certain potassium channels in the terminal axon membrane, ultimately resulting in over-release of neurotransmitter molecules, which swamp and overstimulate the adjacent muscle end-plate receptors. The fasciculins inhibit or interfere with the anticholinesterases in the junctional space, significantly reducing the normal removal of synaptic acetylcholine. This enhances the effect of the dendrotoxins, resulting in gross overstimulation of the muscle, causing spasm or fasciculation, effectively paralysing the victim. Both toxins may exert their effect rapidly, thus the clinical effects may manifest in less than an hour post-bite.

There are other types of snake neurotoxins, some targeting different areas, but they are either uncommon or have limited or no significant clinical effects, particularly compared with the foregoing toxins.

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