Neurotoxic venoms

Neurotoxic venoms of cobras, mambas, and coral snakes Inhibit the enzyme acetylcholinesterase. - This hydrolase normally breaks down the neurotransmitter acetylcholine within nerve synapses. 

Lactrodectus mactans (lactrodectism is produced by a bite from the female spider). The female is larger than the male. It is noted for a black color that is shiny, with a rounded abdomen and a red hourglass mark on the ventral surface. The black widow spider produces neurotoxic venom. Alpha latrotoxin is the protein of the neurotoxin. 

Before we can understand how the neurotoxic venoms work, it is essential to understand how a nervous impulse is formed and transmitted. For this 1 will use a specific example, wiggling the big toe. If you want to move your big toe, you first think that you would like to do so (this might not be a conscious thought). This occurs in the frontal region of the brain. This message of desire is passed to the region of the brain which controls movement (the Motor Cortex in the Central Sulcus) where an impulse is generated. The impulse passes from the Motor Cortex, via the spinal cord, to peripheral nerves in the leg and eventually to the toe. The toe then moves. This whole process occurs within a second. 

I. Mechanism of toxicity. Snake venoms are complex mixtures of 50 or more components that function to immobilize, kill, and predigest prey. In human victims, these substances produce local digestive effects on tissues as well as hemotoxic, neurotoxic, and other systemic effects. The relative predominance of digestive, hemotoxic, or neurotoxic venom components depends on the species of the snake and geographic variables. 

Snake venom is modified saliva that is stored in a specialized structure and has been augmented with a series of toxic proteins. Despite the wide array of proteins that may contribute to the toxicity of snake venom (no fewer than twenty-five), the impacts of venom fall loosely into two categories venoms that impair the circulation of blood, and venoms that impair the electrical connections between locomotor nerves and muscles. The pit vipers of the Americas—the ratdesnakes, for example—generally employ venoms that target circulation, while the kraits of Asia and the mambas of Africa employ neurotoxic venom. 

Insecticides such as DDT elicit their lethal efiects on insects in much the same way as do naturally occurring neurotoxic venoms or poisons that is, the molecule attacks the nervous system. As discussed previously, the proteins embedded in the cell membrane of a neuron that transport sodium, potassium, and calcium are crucial to its overall function. Chemical agents such as snake venom and animal poisons, as well as insecticides, all either stimulate or block the activity of these proteins, interrupting cell-to-cell communication and ultimately causing death. 

Turning now to chemical attack, many predators immobilize their prey by injecting toxins, often neurotoxins, into them. Examples include venomous snakes, spiders, and scorpions. Some spider toxins (Quick and Usherwood 1990 Figure 1.3) are neurotoxic through antagonistic action upon glutamate receptors. The venom of some scorpions contains polypeptide neurotoxins that bind to the sodium channel. 

While most investigations show that sea snake neurotoxins are postsynaptic type, Gawade and Gaitonde (23) stated that Enhydrina schistosa major toxin has dual actions or postsynaptic as well as presynaptic toxicity. E, schistosa venom phospholipase A is both neurotoxic and myotoxic. Neurotoxic action of the enzyme is weak so that there is sufficient time for myonecrotic action to take place (24), Sea snake, L. semifasciata toxin also inhibits transmission in autonomic ganglia, but has no effect on transmission in choroid neurons. 

Lambeau, G., Barhanin, J., Schweitz, H., Qar, J. and Lazdunski, M. Identification and properties of very high affinity brain membrane-binding sites for a neurotoxic phosphohpase from the taipan venom. /. Biol. Chem. 264,11503-11510,1989. 

Since the rate constants of bimolecular diffusion-limited reactions in isotropic solution are proportional to T/ these data testify to the fact that the kt values are linearly dependent on the diffusion coefficient D in water, irrespective of whether the fluorophores are present on the surface of the macromolecule (human serum albumin, cobra neurotoxins, proteins A and B of the neurotoxic complex of venom) or are localized within the protein matrix (ribonuclease C2, azurin, L-asparaginase).1 36 1 The linear dependence of the functions l/Q and l/xF on x/t] indicates that the mobility of protein structures is correlated with the motions of solvent molecules, and this correlation results in similar mechanisms of quenching for both surface and interior sites of the macromolecule. 

The amount of acetylcholine present in the synapse and the amount of time that it remains there are critical. For example, the venom of the black widow spider is highly neurotoxic. It contains a protein known as a-latrotoxin that elicits the release of massive amounts of acetylcholine at the neuromuscular junction. Too much of a good thing can be a serious problem. 

Since predators of snakes (and humans) have to deal with snake venoms as defenses, they are included here, even though they serve in predation. Snake venoms are primarily enzymes (proteins), especially of the phospholipase A2 type, which breaks down cell membrane phospholipids hydrolytically. Other snake venoms such as cobrotoxin contain peptides with 60-70 amino acid residues. Pharmacologically, they have neurotoxic, cytotoxic, anticoagulant, and other effects. The neurotoxins, in turn, can have pre- or postsynaptic effects. Snake venoms with both neurotoxic and hemolytic effects on the heart are known as cardiotoxins. Cytotoxins attach to the cells of blood vessels and cause hemorrhage. Snake venom factors may stimulate or inhibit blood clotting. Finally, platelet-active factors can contribute to hemorrhage. 

The clinical features depend upon the type of snake bite. There are three main patterns neurotoxic, as with elapidae such as cobras and kraits vasculotoxic with alteration in blood coagulation as with vipers and myotoxic as with sea snakes although they are all often complicated by local tissue damage. The severity of poisoning will depend on the amount and potency of venom injected and the patient s general health. 

McCormick, K.D. and Meinwald, J. (1993). Neurotoxic acylpolyamines from spider venoms. Journal of Chemical Ecology 19 2411-2451. 

De, P., Dasgupta, S.C., Gomes, A. (2002). A lethal neurotoxic protein from Indian king cobra (Ophiophagus hannah) venom. Indian J. Exp. Biol., 40(12), 1359-1364. 

Bacteria, protozoa, and venomous animals synthesize numerous toxins that are used to kill their prey or to defend themselves. Sea anemones, jellyfish, cone snails, insects, spiders, scorpions, and snakes all make potent and highly specific neurotoxins. Plants form a host of alkaloids and other specialized products, some of which are specifically neurotoxic and able to deter predators. More than 500 species of marine cone snails of the genus Conus synthesize a vast array of polypeptide toxins (conotoxins), 487-489 some with unusual posttranslational modifications.490 491 The slow-moving snails are voracious predators that use their toxins, which they inject with a disposible harpoonlike tooth,492 to paralyze fish, molluscs, or worms.493... 

Snake venoms have been studied extensively their effects are due, in general, to toxins that are peptides with 60 to 70 amino acids. These toxins are cardiotoxic or neurotoxic, and their effects are usually accentuated by the phospholipases, peptidases, proteases, and other enzymes present in venoms. These enzymes may affect the bloodclotting mechanisms and damage blood vessels. Snake bites are responsible for less than 10 deaths per year in the United States but many thousand worldwide. 

Harris JB, Grubb BD, Maltin CA, Dixon R (2000) The neurotoxicity of the venom phospholipases A(2), notexin and taipoxin. Exp Neurol 161 517-26 Haug G, Wilde C, Leemhuis J, Meyer DK, Aktories K et al. (2003) Cellular uptake of Clostridium botulinum C2 toxin membrane translocation of a fusion toxin requires unfolding of its dihydrofolate reductase domain. Biochemistry 42 15284-91 Hauschild A (1993) Epidemiology of human foodborne botulism. In Hauschild A, Dodds KL (eds) Clostridium botulinum ecology and control in foods. Marcel Dekker, Inc. New York, pp 69-104... 

Schiavo G, Papini E, Genna G, Montecucco C (1990) An intact interchain disulfide bond is required for the neurotoxicity of tetanus toxin. Infect Immun 58 4136 11 Scott AB, Magoon EH, McNeer KW, Stager DR (1989) Botulinum treatment of strabismus in children. Trans Am Ophthalmol Soc 87 174-180 discussion 180 1 Scott D (1997) Phospholipase A2 structure and catalytic properties. In Kini R (ed) Venom phospholipase A2 enzymes structure, function and mechanism. John Wiley Sons, Chichester, p 97-128. 

Initial pain at the site of the bite may be followed with a metallic sensation in the mouth. Victims may become weak, and experience nausea, diarrhea, diaphoresis, and chills. Edema may begin around the bite area or may be delayed. Observation of the site for edema is a clue as to whether or not a dry bite has occurred that is, that no venom was injected into the site. Envenomation is most serious if venom is injected directly into joints, muscles, or veins. Hemorrhagic blisters and tissue destruction are possible. Neurotoxicity from rattlesnakes (but generally not from cottonmouths or copperheads) may be manifested as fasciculations, which are fine continuous contractions. In some cases, systemic neurotoxicity may involve respiratory failure. In the most serious cases, massive envenomation may lead to serious bleeding, hypotension, shock, multiple organ failure, and a high incidence of mortality. 

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