Neurotoxic effects/action

In addition to its relatively high affinity at postsynaptic 5-HT receptors, MDMA exhibited high affinity for 5-HT uptake sites and has been shown to increase the release of [ H]5-HT and block [ H]5-HT uptake in vitro. These data suggest that some of the actions of MDMA may be mediated at presynaptic binding sites. With respect to [ H]5-HT release, MDMA has been reported to increase the release of [ H]5-HT from brain synaptosomes (Nichols et al. 1982) and hippocampal slices (Johnson et al. 1986). With respect to uptake blockade, MDMA has been reported to competitively inhibit H-5-HT uptake in vitro (Shulgin 1986). Furthermore, the neurotoxic effects of in vivo administration of MDMA on serotonin terminals can be blocked by concomitant administration of the 5-HT uptake blocker citalo-pram (Battaglia et al. 1988b Schmidt and Taylor 1987). Additional evidence in support of the hypothesis that MDMA produces some of its... 

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. 

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). 

The significance of mirex residues in various tissues is unresolved, as is the exact mode of action of mirex and its metabolites. Minchew et al. (1980) and others indicated that mirex is a neurotoxic agent, with a mode of action similar to that of other chlorinated hydrocarbon insecticides, such as DDT. In studies with crayfish and radiolabeled mirex, mirex toxicosis was associated with neurotoxic effects that included hyperactivity, uncoordinated movements, loss of equilibrium, and... 

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. 

Danysz W, Parsons CG, Mobius HJ, et al (2000) Neuroprotective and symptomatological action of memantine relevant for Alzheimer s disease—an unified glutamatergic hypothesis on the mechanism of action. Neurotox Res 2 85-97 Davis SM, Lees KR, Albers GW, et al (2000) Selfotel in acute ischemic stroke possible neurotoxic effects of an NMDA antagonist. Stroke 31 347-354 DeKeyser J (1991) Excitotoxic mechanisms may be involved in the pathophysiology of tardive dyskinesia. Clin Neuropharmacol 14 562-565 Del Dotto P, Pavese N, Gambaccini G, et al (2001) Intravenous amantadine improves levodopa-induced dyskinesias an acute double-blind placebo-controlled study. Mov Disord 16 515-520... 

At the physiological level it is well established that vital dyes such as nile blue, neutral red and methylene blue retard larval development under normal lighting conditions (12L/12D with source unspecified) (25 27). Female but not male pupal weights are also reduced. Unfortunately experiments were conducted without dark controls so that it is difficult to evaluate the role of photosensitization in these effects. As house flies and fire ants succumb to photosensitization, they lose motor control and become more excitable (28). This suggested a neurotoxic effect and investigation of fire ant acetylcholinesterase vitro revealed that this enzyme was sensitive to photo-oxidation. vivo results, however, revealed no effect on the enzyme which suggests another mode of action. Epoxldatlon of cholesterol and membrane lysis may be alternative primary sites. If this were the case ecdysone metabolism of insects would probably also be effected. 

The synergistic action of aluminum ions with fluoride may be the underlying mechanism of the observed neurotoxic effects of fluoride. Chronic exposure of humans to A1FX begins in the fetus. Elevated fluoride content was found in embryonic brain tissues obtained from required abortions in areas where fluorosis was prevalent [78, 124]. These studies showed poor differentiation of brain nerve cells and delayed brain development. High fluoride exposure appears to weaken mental function among children, as well as adults [125, 126]. 

In vitro systems have been developed to try and understand the mechanism of action of mancozeb, similar to other dithiocarbamates. The genotoxic, cytotoxic, and neurotoxic effects of mancozeb have been studied using a variety of primary cultures as well as cell-lines. 

In vitro systems have been developed to try and understand the mechanism of action of maneb. In particular, the mechanism of toxicity of maneb on the central nervous system using synaptosomal and mitochondrial preparations from brain tissue has been utilized. These studies have shown that maneb has adverse effects on the dopaminergic system, via mechanisms that relate to mitochondrial inhibition and altered neurotransmitter uptake. The genotoxic, cytotoxic, and neurotoxic effects of maneb have been studied using a variety of primary cultures as well as cell lines, including human lymphocytes. As noted above, maneb has little mutagenic potential. 

Johnson, M.K., Organophosphorus esters causing delayed neurotoxic effects. Mechanism of action and structure / activity studies, Arch. Toxicol. 34,259-288,1975. 

Many of the substituted (hydroxy, dihydroxy) tryptamines are neurotoxic. These molecules have not been tested in human subjects for obvious reasons. In the study of brain biochemistry, neurotoxins are discovered and then molecules are developed to block the actions of the toxins. Drugs which block these neurotoxic effects might be useful in the treatment of mental illness. In many cases drugs which have been effective in the treatment of mental illness have been found to block the neurotoxic effects of various molecules. This allows scientists to gain a better understanding of disease mechanisms and future development of more effective drugs for the mentally ill. 

Johnson, M. K. (1975). Organophosphorus csiers causing delayed neurotoxic effects Mechanism of action and structure-activity studies. Toxicol. 34, 2.59-288. 

Carbamazepine is metabolized in the liver to carbamtizepine-10, 11-epoxide, an active metabolite that partly contributes to both its anticonvulsant action and neurotoxicity. In contrast to phenytoin. there is u linear increa.se in serum concentration with dosage. Mild neurotoxic effects are common (nau.sea. dizziness, drowsiness, blurred vision and ataxia] and often detemiine the limit of dosage. Agranulocytosis is a rarer idiosyncratic reaction to carbamazepine. 

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