Neurotoxic action

In order to understand the exact mechanism of the neurotoxic action, it is important to know the secondary structure of the neurotoxins as well. It is now known that postsynaptic neurotoxins attach to the a-subunits of acetylcholine receptor (AChR). 

The amino acid residues in neurotoxins which are important for neurotoxic action are still not entirely clarified. Some neurotoxins contain one free SH group, while others do not. From this fact, it would be logical to assume the sulfhydryl group is not essential. This was actually proven to be the case. 

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. 

Harvey, J.A., and MeMaster, S.E. Fenfluramine Evidence for a neurotoxic action on a long-term depletion of serotonin. Psychopharmacological Communications 1 217-228, 1975. 

COMMENT You have presented some evidence that dopamine may be involved in the neurotoxic action of methamphetamine in terms of dopaminergic neurons, and you presented evidence suggesting that it may be involved in not only the dopamine system but also the serotonin system. 

Harvey, J. McMaster, S. and Yunger, L. p-Chloroamphetamine Selective neurotoxic action in brain. Science 187 841-843, 1975. 

Sundstrom, E., and Jonsson, G. Pharmacological interference with the neurotoxic action of l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) on central catecholamine neurons in the mouse. Eur J Pharmacol 110 293-299, 1985. 

Intermediate-duration inhalation exposures to aerosols of a few organophosphate ester hydraulic fluids (Durad MP280 and "triaryl phosphate ester") produced lethal neurotoxic effects in chickens and rabbits (MacEwen and Vemot 1983 Siegel 1965). Rats and hamsters appear to be less susceptible to the neurotoxic action of organophosphate esters tests of several organophosphate fluids produced no deaths in rats exposed to substantial aerosol concentrations. 

Abou-Donia MB, Lapadula DM, Campbell G, et al. 1985. The joint neurotoxic action of inhaled methyl butyl ketone vapor and dermally applied O-ethyl O-4-nitrophenyl phenylphosphonothioate in hens Potentiating effect. Toxicol Appl Pharmacol 79 69-82. 

Some OP compounds induce delayed neurotoxic effects ("delayed neuropathy") after acute poisoning. This delayed neurotoxic action is independent of cholinesterase inhibition but related to phosphorylation of a specific esterasic enzyme in the nervous tissue, called "neurotoxic esterase" or "neuropathy target esterase" (NTE) (Johnson, 1982). NTE is present in the nervous tissue, liver lymphocytes, platelets, and other tissues, but its physiological function is unknown. There is a rather large inter-individual variation of lymphocyte and platelet NTE activity (Table 2). 

Taylor, K.S., G.D. Waller, and L.A. Crowder. 1987. Impairment of a classical conditioned response of the honey bee (Apis mellifera L.) by sublethal doses of synthetic pyrethroid insecticides. Apidologie 18 243-252. Theophilidis, G., M. Benaki, and E. Papadopoulu-Mourkidou. 1997. Neurotoxic action of six pyrethroid insecticides on the isolated sciatic nerve of a frog (Rana ridibunda). Comp. Biochem. Physiol. 118C 97-103. Tippe, A. 1987. Evidence for different mechanisms of action of the three pyrethroids, deltamethrin, cypermethrin, and fenvalerate, on the excitation threshold of myelinated nerve. Pestic. Biochem. Physiol. 28 67-74. 

The development of efficient means for prevention of neurotoxic action of OPC (TOCP, mipaphox, dichlorvos, DFP, etc.) of the delayed type (DNE) remains to be relevant. 

There have been many studies over the last 40 years that provide substantial evidence that voltage-gated sodium channels in the CNS are major sites of action for the pyrethroids in mammals [1, 20-25]. This literature has been recently critically reviewed by Soderlund [10] from the viewpoint of the neurotoxic action of pyrethroids in mammals and we will rely heavily on this review in our summary below. 

Most insecticides, especially the organophosphate group, cause neurotoxicity as their major mode of action. Assessment of the neurotoxicity includes neurochemical endpoints such as cholinesterase (including acetylcholinesterase, which is the major neurotransmitter in vertebrates such as fish, and other enzymes such as butyrylcholinesterase) inhibition and behavioral endpoints such as swimming speed [79]. Studies done in rats show the neurotoxic action of insecticides such as dimethoate, methyl parathion, dichlorvos, ethyl parathion or propoxur after a prolonged exposure [80,81]. 

Though some very elegant methods are now available to study the biochemistry of the brain and nervous system, none has yet discovered any generalized marker chemicals which will serve as reliable indicators or early warnings of neurotoxic actions or potential actions. There are, however, some useful methods. Before looking at these, however, one should understand the basic problems involved. 

Shankland DL. 1982. Neurotoxic action of chlorinated hydrocarbon insecticides. Neurobehav Toxicol Teratol 4(6) 805-811. 

Alternative iboga alkaloids Potential neurotoxic effects of ibogaine have raised concern over its clinical use. It is possible that the antiaddictive and neurotoxic actions of ibogaine are discrete, allowing for potential separation of clinical and toxic effects (Molinari et al. 1996). Some other iboga alkaloids may have these properties, such as 18-MC. 

Biochemical changes in animal central nervous sterns have been reported by Skillen et who noted a decrease in brain 5-hydroxytiypt-amine (serotonin) in rats exposed to ozone at 6 ppm for 4 h, and by Trams et who observed decreases in catecholamines and catechol-O-methyl-transferase in dogs chronically exposed to ozone at 1,2, or 3 ppm. Electro-encephalographic (eeg) measurements in the same dogs were recently presented by Johnson et who noted alterations in eeg patterns at 9 months of ozone exposure, but not after 18 months of exposure. Previously, Xintaras et o/. had observed alterations in the visual evoked electric response in rats acutely exposed to 0.5-1.0 ppm. As pointed out by Johnson et it is not clear whether these findings indicate a direct neurotoxic action of ozone or are secondary to damage in other organs. 

Lindane is the active y-isomer of hexachlorocyclohexane. It also exerts a neurotoxic action on insects (as well as humans). Irritation of skin or mucous membranes may occur after topical use. Lindane is active also against intrader-mal mites (Sarcoptes scabiei, causative agent of scabies), besides lice and fleas. It is more readily degraded than DDT. 

The neurotoxic actions of T17 on membrane excitability were examined in squid giant axon initially and in more detail using crayfish giant axon and intracellular microelectrode techniques(14). Detailed studies utilizing T34 are not available due to technical problems associated with its extreme hydrophobicity and resulting diffi-... 

Johnson MK Delayed neurotoxic action of some organophosphorus compounds. Br Med Bull 25 231-235, 1969... 

In an early study in rats, subcutaneous injections of triphenyl phosphite caused two distinct stages of neurotoxic action. The early, rapidly developing stage was characterized by fine or coarse tremor, usually involving the large muscle groups. The tremor disappeared in surviving animals within a few hours. The... 

Although a great deal of the work currendy being done in chiral separations is related to pharmaceuticals, the agricultural and the food and beverage industries are affected as well. For instance, several chiral pesticides are used commercially. It is possible that the enantiomers may differ in their persistence in the environment and their effectiveness against specific pests. For example, the neurotoxic action of the pesticide, ethyl-4-nitrophenyl phenylphosphono thionate (EPN), resides almost entirely in the S enantiomer while the desired insecticidal activity resides entirely in the R enantiomer (5). This raises the question of whether the pesticide may be safer and more effective if applied as an enantiomerically pure formulation. In the food and beverage industry,... 

Coyle J. T. (1983). Neurotoxic action of kainic acid. J. Neurochem. 41 1-11. 

Bonnet, R., Pavlovic, S., Lehmann, J., Rommelspacher, H. The strong inhibition of TPI by the natural /1-carbolines may explain their neurotoxic actions. Neuroscience 2004,127 443 153. 

Peng, Y.G., Taylor, T.B., Finch, R.E., Switzer, R.C., and Ramsdell, J.S. 1994. Neuroexcitatory and neurotoxic actions of the amnesic shellfish poison, domoic acid. NeuroReport 5, 981-985. 

Le, H.H., Carlson, E.M., Chua, J.P., Belcher, S.M. Bisphenol A is released from polycarbonate drinking bottles and mimics the neurotoxic actions of estrogen in developing cerebellar neurons. Toxicol. Lett. 176, 149-156 (2008)... 

Eosinophil-derived neurotoxin (EDN) is another protein that is found in the granule matrix of eosinophils and it exhibits significant sequence homology with ECP (Barker et al., 1989). As implied by its name, EDN has a powerfiil neurotoxic action that can dam e myelinated neurones in experimental animals (Durack et al., 1981). However, unlike ECP or MBP there is no significant... 

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