Neurotoxicity cellular mechanisms

Lyles, J. and Cadet, J.L., Methylenedioxymethamphetamine (MDMA, Ecstasy) neurotoxicity cellular and molecular mechanisms, Brain Res. Brain Res. Rev. 42(2), 155-168, 2003. 

The cultures can either consist of one predominant neuronal cell type, a mixture of different neuronal populations, pure glial cells, or mixed neuronal-glial cultures. These characteristics make it possible to determine the specific sensitivity to chemical perturbation in different neuronal and glia cell types [31, 32], The presence of astrocytes is known to modify the neuronal response to toxicants and it has been identified as an important contributing factor to neurotoxicity [33]. Primary neuronal cultures are often used to investigate cellular mechanisms of toxicity observed after in vivo chemical exposure. 

Whitney, K, D Seidler, E, J and Slotkin, T. A. (1995). Developmental neurotoxicity of chlorpyrifos Cellular mechanisms. Toxicol. Appl. Pharmacol. 134, 53-62,... 

The mechanism of bromomethane-induced neurotoxicity is not known. It is generally agreed that effects are not the result of metabolic breakdown products such as methanol or bromide, since neither the characteristic effects nor the dose dependency correspond to those of the metabolites (Clarke et al. 1945 Honma et al. 1985). Rather, it is more likely that bromomethane acts by alkylating key cellular components such as enzymes (Lewis 1948 Rathus and Landy 1961). 

The precise mechanism by which NO causes glutamase neurotoxicity is unknown. Calcium must be required because of the requirement for NMDA- and glutamate-induced NO formation in brain tissue (Garthwaite etal., 1988). Although both NMDA-receptor agonists and sodium nitroprusside induce specific neurotoxicity as well as cyclic GMP formation in brain tissue (Dawson et al., 1991), it is unlikely that cyclic GMP is the ultimate cause of the neurotoxicity. Instead, NO is most likely involved in producing target cell death. One possible mechanistic pathway is that locally synthesized NO and superoxide anion react with each other to yield peroxynitrite anion (Beckman et al., 1990), which can destroy cell membranes either directly via interaction with cellular thiols (Radi et al., 1991) or indirectly via decomposition to hydroxyl and other free radicals (Beckman et al., 1990). 

Cellular and molecular mechanisms of neurotoxicity are also influenced by the fact that neurons are postmitotic and do not divide. Thus, the capacity for replacement of damaged cells does not exist in the nervous system, whereas most other organ systems have a well-established capacity for regeneration. Many neurotoxins can cause encephalopathy and an important concept in neurotoxicology is the delayed manifestation of symptoms sometimes up to years after the exposure started. Several agents show a lag time between exposure and neurotoxicity. Examples are the organophosphate chemical warfare agents [245], bismuth intoxications [246] and methylmercury... 

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