Definition: Systemic effects caused by conduction changes in the nervous system and in muscle membranes, excluding the cardiac innervation and cardiac muscles.
Signs and symptoms:
- Sensory disturbances,
- muscle fasciculations and spasms,
- peripheral paralysis (ptosis, ophthalmoplegia, dysphagia, dysarthria, paralysis of the respiratory musculature and the extremities),
- catecholamine effects.
Pharmacological investigations of neurotoxins are widely based on experiments on animals or isolated preparations, such as ileum of guinea pigs or giant axons of squids. The results are only partly translatable to humans. One example is the ability to antagonise postsynaptically active neurotoxins with acetylcholinesterase inhibitors (neostigmine). In other cases, however, there are major discrepancies between laboratory experiments and clinical findings (Harris 1989).
The most important groups of animals whose venoms or poisons contain neurotoxic components are the venomous snakes, scorpions, spiders and poisonous animals. The majority of neurotoxins investigated to date have been polypeptides and proteins whose activity is based on interaction with ion channels or receptors of neurotransmitters.
Several toxins display central nervous effects when injected intrathecally in animal experiments. However, if neurotoxins are injected via the routes that occur under natural circumstances – s.c., i.m. or i.v. – they are generally not able to cross the blood-brain barrier. The primary point of action of neurotoxins from animal venoms/poisons is the peripheral nervous system and to a lesser extent the excitable muscle membranes.
Depending on their point of action on the conduction system, neurotoxic venom/poison components can be divided into those with presynaptic and postsynaptic activity.
Venom/poison components with presynaptic activity
Interactions with ion channels of nerve fibres
Sodium channels: Neurotoxins from scorpions and poisonous animals affect the permeability of voltage-gated sodium channels. Specific binding to various regions of the channels can cause activation (opening), stabilisation (delay or inhibition of the inactivation process) or blockade. The complex course of envenoming following bites by buthid scorpions can be broadly explained by effects of the venom on the autonomic nervous system and the release of catecholamines (Freire-Maia and Campos 1989).
Scorpion toxins have been isolated from the venom of representatives of the Buthidae family. They are heat-stable, alkaline polypeptides with 60–70 (long-chained toxins) or fewer than 40 amino acids (short-chained toxins). α-Scorpion toxins from the venom of Old World scorpions (Leiurus quinquestriatus, Androctonus australis, Buthus tamulus (=Hottentotta tamulus) and Buthus eupeus), tityustoxin γ from the New World scorpion Tityus serrulatus and to a lesser extent also β-scorpion toxins from several New World species (Centruroides sculpturatus and C. suffusus suffusus) have a stabilising effect on sodium channels, while the latter two have a predominantly activating effect.
Neurotoxic polypeptides from the venom of the South American Wandering spider (Phoneutria nigriventer) appear to exert their effect via activation of sodium channels.
Neurotoxins from poisonous animals do not display a proteinaceous nature. Brevetoxins and ciguatoxin, which determine the course of neurotoxic shellfish poisoning and ciguatera, respectively, have an activating effect on sodium channels. In contrast, tetrodotoxin (from Puffers and their relatives) and saxitoxin (paralytic shellfish poisoning and poisoning due to crabs) block sodium channels.
Potassium channels: Two scorpion toxins, noxiustoxin from Centruroides noxius and charybdotoxin from Leiurus quinquestriatus, are known to block potassium channels.
Dendrotoxins also have a blocking effects on potassium channels, which subsequently leads to increased acetylcholine release from nerve endings. These are alkaline polypeptides (57–60 amino acid residues) from the venom of various Mambas (Dendroaspis angusticeps, D. polylepis polylepis and D. viridis). They also block potassium channels of the autonomic nervous system.
Effects on nerve endings
Potentiation of transmitter release:
α-Latrotoxin, a high-molecular-weight protein without enzymatic activity, is a dominant component of the venom of the Black widow spider (Latrodectus mactans tredecimguttatus and possibly other Latrodectus sp.). The mechanism of action, which, after a delay of several minutes, leads to a massive release of neurotransmitters, is not yet fully elucidated. The toxin appears to bind to a specific receptor on the presynaptic membrane, where subsequently – and probably with the involvement of the toxin – an ion channel is formed that is permeable to various cations (Na+, K+ and Ca2+).
Inhibition of transmitter release:
Inhibition of transmitter release can take place via the blockade of calcium channels or direct action on membranes.
Blockade of calcium channels has been demonstrated for the ω-conotoxins (peptides with 25–27 amino acids) of several Cone shells (Conus geographus and Conus magus) as well as for maitotoxin (ciguatera). The protein holocyclotoxin, which plays a role in neurotoxic envenoming caused by ticks (e.g. Ixodes holocyclus), probably also belongs to the category of calcium channel blockers.
Inhibition of transmitter release via direct action on membranes has been described for snake β-neurotoxins. These β-neurotoxins include phospholipases A2, such as have been found in Australian elapids, kraits and several crotalids and viperids. They consist of either a single polypetide chain (114–122 amino acid residues, e.g. notexin), or they form complexes with another peptide (e.g. crotoxin), or they are composed of 3–4 homologous, non-covalently bound polypeptides (e.g. taipoxin, textilotoxin). The formation of complexes appears to lead to potentiation of the toxicity.
At least a dozen such phospholipases have been described to date. After an incubation period of 5–60 min, there is initially suppression of transmitter release via their action on synapse membranes. Subsequently there is a phase of enhanced release; however, this changes back into a phase of gradually decreasing transmitter release. The mechanism that leads to these effects has not been elucidated. It is controversial whether the hydrolytic activity of the phospholipases plays a role in this process. However, sooner or later the hydrolytic activity causes destruction of the motor nerve endings (Harris 1989). This may explain the lack of efficacy of antivenoms, as has been observed in some cases of krait envenoming (Warrell et al. 1983).
Interestingly, some of the β-neurotoxins, such as crotoxin, taipoxin or notexin, also display myotoxic activity. Conversely, the myotoxic phospholipase VI:5 from Enhydrina schistosa (Hydrophiidae) also possesses weak presynaptic neurotoxic activity (Mebs and Ownby 1990).This suggests that is not necessarily useful to make a strict division between neurotoxic and myotoxic phospholipases.
Venom/poison components with postsynaptic activity
Blockade of nicotinic acetylcholine receptors
Most if not all elapids and Hydrophiidae possess α-neurotoxins (so-called curaremimetic toxins) in their venoms. In several elapids, such as various Australian elapids or the kraits (Bungarus sp.), they are present in combination with presynaptically active neurotoxins (see above).
With a few exceptions, the α-neurotoxins can be divided into 2 groups, i.e. short-chained (60–62 amino acids) and long-chained toxins (70–74 amino acids). Both types of toxins are structurally homologous. Their spatial organization consists of 3 loops joined at a single point. The long-chained toxins are contained in the venoms of many elapids and Hydrophiidae. They bind specifically to the α-subunit of nicotinic acetylcholine receptors, prevent interaction between acetylcholine and these receptors and thus block conduction between the nerves and muscles.
Short-chained toxins appear to bind less effectively to human receptors than the long-chained toxins; in some cases there appears to be no binding at all. Thus the venom of the medically most important sea snake, Enhydrina schistosa, leads to fatal neuromuscular paralysis in a number of mammals. In humans, however, marked neuromuscular paralysis is absent or, if present, completely overshadowed by the massive myotoxic effects. The reason for this is that Enhydrina, unlike most sea snakes, only possesses short-chained α-neurotoxins, which in this case cannot bind to the specific binding site on human acetylcholine receptors. A further example of the discrepancy between the effects of venom on humans and animals was found with the venoms of Southeast Asian cobras (Naja kaouthia and N. sputatrix). In mice these venoms are strongly neurotoxic, whereas in humans there were barely any signs of paralysis (Reid 1964).
Like the α-neurotoxins, some phospholipases from the venom of Laticauda semifasciata (Hydrophiidae) and Daboia russelli (Viperinae), as well as the α-conotoxins from Cone shells (Conus geographus and C. magus), lead to the blockade of acetylcholine receptors on motor end plates. In contrast, the glycosides surugatoxin and neosurugatoxin, isolated from the marine snail Babylonia japonica, appear to bind with high specificity to nicotinic receptors of ganglia.
Inhibition of acetylcholinesterase
Angusticeps-type toxins have been isolated from the venom of mambas (Dendroaspis sp.). They consist of 60 or 61 amino acid residues. Their pharmacological effects are largely unknown, although an acetylcholinesterase-inhibiting effect could be determined with 2 such toxins (Dendroaspis angusticeps and D. polylepis polylepis). Due to decreased degradation, the activity of acetylcholine is intensified, thus leading to muscle fasciculations.
Effects on sodium channels of muscle membranes
The above-mentioned brevetoxins, saxitoxin and tetrodotoxin also act on the sodium channels of skeletal muscle membranes. As with nerve fibres, brevetoxins lead to the activation of sodium channels on muscle membranes and subsequently depolarisation; tetrodotoxin and saxitoxin, in contrast, lead to blockade of the channels and thus to an absence of membrane excitability. The μ-conotoxins, a series of peptides isolated from the venom of the Cone shell Conus geographus, also lead to the blockade of sodium channels on skeletal muscle membranes. However, they do not appear to have any effect at all on the ion channels of nerve fibres.
Crotamine and myotoxin a, two polypeptides from rattlesnake venoms (Crotalus durissus terrificus and Crotalus viridis viridis, respectively), appear to act exclusively on sodium channels of the skeletal musculature, by which they increase sodium permeability. However, their clinical significance seems to be associated more with their myotoxic effects than their neurotoxic effects.
Indefinite pathomechanisms
The polypeptide robustoxin (42 amino acids) from the venom of the Sydney funnel-web spider (Atrax robustus) leads to spontaneous transmitter release at the neuromuscular synapses of the autonomic nervous system in humans. Humans and primates are very sensitive to this venom, whereas sheep, horses, rabbits, toads and other animals are much less sensitive or barely react to it (Sutherland 1978).
Fasciculations of the extremities and the face, such as frequently occur in envenoming due to rattlesnakes (Crotalus sp.), are connected with presynaptically active venom components that have not been further characterised. They appear to have a reversible effect on the excitability of peripheral nerves. These are believed to be toxins that interact directly with Ca2+ or Ca2+-binding sites on axonal membranes (Brick and Gutmann 1982, Brick et al. 1987).
Literature: Harris 1989, Mebs 1988, 1992, Mebs and Hucho 1990, Mebs and Ownby 1990, Minton 1990a, Rosenberg 1988
Figure 5.5 Points of action of neurological venom/poison components