Snake Venoms and the Neuromuscular Junction

Robert L. Lewis, M.D.; Ludwig Gutmann, M.D.


Semin Neurol. 2004;24(2) 

In This Article

Presynaptic Inhibition

Presynaptic neurotoxins are commonly called β-neurotoxins and have been isolated from venoms of snakes of families Elapidae, Viperidae, Crotalidae, and Hydrophiidae.[14] β-Bungarotoxin was the first presynaptically active toxin to be isolated from Bungarus multi-cinctus (Banded Krait) of the Elapidae family.[6] Presynaptic neurotoxins are rich sources of phospholipases,[9] which hydrolyze phosphoglycerides. They are classified according to the precise site of hydrolysis,[6] and phospholipases isolated from snake venoms belong to the A2 class of phospholipases.[15] The majority of the presynaptic neurotoxins inhibit transmitter release; however, a few toxins have been identified that enhance neurotransmitter release. Dendrotoxin from the Eastern green mamba (Dendroaspis Angusticeps) has been shown to block presynaptic K+ channels in vitro, which results in enhanced transmitter release.[16,17]

Presynaptic neurotoxins produce neuromuscular blockade, by inhibiting the release of acetylcholine from the presynaptic membrane,[11] and do not significantly alter the sensitivity of the postsynaptic membrane.[9] Neurotoxins targeted toward the presynaptic membrane produce a characteristic triphasic effect on acetylcholine release. First there is a decrease, followed by a transient increase, and then complete block of acetylcholine release.[18,19] The initial two phases are reported to be independent of phospholipase A2 activity; however, the late block of acetylcholine release is reported to be a direct result of phospholipase A2 activity.[20] The transient increase of acetylcholine release is hypothesized to be a result of slowing of repolarization following an action potential, which allows a greater influx of calcium and thus an increased release of acetylcholine into the synapse.[9] Connolly and colleagues found that taipoxin, from snakes of the Elapidae family, irreversibly interferes with the formation of synaptic vesicles by arresting vesicle membrane recycling at the presynaptic membrane.[11] They found that a neuromuscular block results when the preexisting stores of acetylcholine vesicles are depleted by nerve activity. In vitro, the rate of neuromuscular block exhibited by β-neurotoxins has been found to depend on the temperature and on the frequency of nerve stimulation and dramatically decreases as the temperature and/or frequency of stimulation is lowered.[9]

β-bungarotoxin and Notechis scutatus toxin are basic proteins of 119 amino-acid residues arranged in a single chain and cross-linked by seven disulphide bridges.[21] All the other β-neurotoxins are complexes of multiple subunits.[9] The precise sequence of events that results in neuromuscular blockade varies with species and toxin. In general, there is a lag period of between 5 and 20 minutes before any effect on transmission is noted; this lag has been reported to represent the time during which the toxins are becoming bound to the presynaptic membrane. This is supported by the observation that removal of excess toxin in vitro by washing during this period has little measurable effect on either the rate or degree of neuromuscular block.[9]

Human victims injected with venoms containing large quantities of β-neurotoxins suffer from profound neuromuscular weakness and do not respond well to antivenoms. Medications such as anticholinesterases and diaminopyidines have little effect on neuromuscular blockade.[21] Harris and colleagues showed that within 1 hour of inoculation of notexin and taipoxin, many presynaptic nerve terminals exhibited signs of irreversible physical damage and were devoid of synaptic vesicles.[21] Large numbers of terminals were totally destroyed by 24 hours, leaving up to 70% of muscle fibers denervated. This demonstrates why envenomation with β-neurotoxins results in severe and prolonged paralysis that is very difficult to manage. Paralysis has been reported to last several weeks and frequently requires prolonged assisted ventilation for survival due to weakness of respiratory muscles.[7] Recovery is dependent upon regeneration of the terminal axon.[22]