Glutamate toxicity mechanisms

The precise mechanism of dimethylhydrazine toxicity is uncertain. In addition to the contact irritant effects, the acute effects of dimethylhydrazine exposure may involve the central nervous system as exemplified by tremors and convulsions (Shaffer and Wands 1973) and behavioral changes at sublethal doses (Streman et al. 1969). Back and Thomas (1963) noted that the deaths probably involve respiratory arrest and cardiovascular collapse. The central nervous system as a target is consistent with the delayed latency in response reported for dimethylhydrazine (Back and Thomas 1963). There is some evidence that 1,1-dimethylhydrazine may act as an inhibitor of glutamic acid decarboxylase, thereby adversely affecting the aminobutyric acid shunt, and could explain the latency of central-nervous-system effects (Back and Thomas 1963). Furthermore, vitamin B6 analogues that act as coenzymes in the aminobutyric acid shunt have been shown to be effective antagonists to 1,1-dimethylhydrazine toxicity (reviewed in Back and Thomas 1963). 

Cannabidiol and THC reduced neurotoxicty induced by glutamate in cortical neurons (Hampson et al. 1998). This result was effective for toxicity induced at both NMDA and AMPA/kainate receptors, and was independent of cannabinoid receptor activity. The mechanism of neuroprotection appears to be by their potent antioxidant activity. They were even more protective against glutamate neurotoxicity than either ascorbate or o-tocopherol. 

Much of the data related to the mechanism of hexachlorobutadiene toxicity indicate that the intermediates produced by modification of the S-1,1,2,3,4-pentachlorodienyl cysteine derivative are responsible for the observed effects on the proximal tubules of the nephrons. The cysteine derivative is formed from the hexachlorobutadiene conjugate in the liver, intestines, and/or kidney through the action of yglutamyl transferase which removes the glutamate from the glutathione tripeptide followed by the action of a peptidase that removes the glycine from the carboxy terminus. 

Rouach N, Nicoll RA (2003) Endocannabinoids contribute to short-term but notlong-term mGluR-induced depression in the hippocampus. Eur J Nemosci 18 1017-1020 Roy J, Minotti S, Dong LC, et al (1998) Glutamate potentiates the toxicity of mutant Cu/Zn-superoxide dismutase in motor neurons by postsynaptic calcium-dependent mechanisms. J Neurosci 18 9673-9684... 

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