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Re: Cysteine neuroprotection

Posted by lars1 on January 14, 2005, at 8:20:38

In reply to Methamphetamine vs N-acetyl-l-cysteine, posted by JayDee on January 9, 2005, at 22:32:37

Reports cited earlier in this thread suggest that N-acetyl-l-cysteine may be protective against amphetamine neurotoxicity. Other reports (see below) indicate that L-cysteine is itself neurotoxic. Are N-acetyl-l-cysteine and L-cysteine completely different substances with respect to their neurological effects? Or is this another case where the dose makes the poison?

Lars

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Science. 1990 May 4;248(4955):596-9.

L-cysteine, a bicarbonate-sensitive endogenous excitotoxin.

Olney JW, Zorumski C, Price MT, Labruyere J.
Washington University School of Medicine, Department of Psychiatry, St. Louis, MO 63110.

After systemic administration to immature rodents, L-cysteine destroys neurons in the cerebral cortex, hippocampus, thalamus, and striatum, but the underlying mechanism has never been clarified. This neurotoxicity of L-cysteine, in vitro or in vivo, has now been shown to be mediated primarily through the N-methyl-D-aspartate subtype of glutamate receptor (with quisqualate receptor participation at higher concentrations). In addition, the excitotoxic potency of L-cysteine was substantially increased in the presence of physiological concentrations of bicarbonate ion. L-Cysteine is naturally present in the human brain and in the environment, and is much more powerful than beta-N-methylamino-L-alanine, a bicarbonate-dependent excitotoxin, which has been implicated in an adult neurodegenerative disorder endemic to Guam. Thus, the potential involvement of this common sulfur-containing amino acid in neurodegenerative processes affecting the central nervous system warrants consideration.

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Neurochem Res. 1996 Mar;21(3):293-8.

Contributing mechanisms for cysteine excitotoxicity in cultured cerebellar granule cells.

Mathisen GA, Fonnum F, Paulsen RE.
Norwegian Defence Research Establishment, Division for Environmental Toxicology, Kjeller, Norway.

Several possible mechanisms for cysteine toxicity on rat cerebellar granule cells were studied and compared with the excitotoxic effect of glutamate. It was shown that the excitotoxic potency of both cysteine and glutamate increased in the presence of elevated concentrations of bicarbonate or increased pH. Pharmacological studies showed that the cysteine toxicity was specifically coupled to the NMDA receptor, whereas the glutamate toxicity was mediated to a smaller extent also by non-NMDA receptors. Treatment of cerebellar granule cells with cysteine led to an increased extracellular level of glutamate. In addition, cysteine sensitized NMDA receptors by reducing disulfide bonds in the receptor to sulfhydryl groups. A mechanism for cysteine excitotoxicity may therefore be formation of cysteine-sensitized NMDA receptors that are stimulated either by cysteine and/or by endogenous glutamate. This mechanism may also be important for the effects observed during regulated physiological release of cysteine.


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poster:lars1 thread:439943
URL: http://www.dr-bob.org/babble/20050113/msgs/442057.html