Mechanisms of L-cysteine neurotoxicity

We review here the possible mechanisms of neuronal degeneration caused by L -cysteine, an odd excitotoxin. L-Cysteine lacks the omega carboxyl group re quired for excitotoxic actions via excitatory amino acid receptors, yet it evokes N-methyl-D-aspartate (NMDA) -like excitotoxic neuronal death and pot entiates the Ca2+ influx evoked by NMDA. Both actions are prevented by NMDA antagonists. One target for cysteine effects is thus the NMDA receptor. Th e following mechanisms are discussed now: (1) possible increase in extracel lular glutamate via release or inhibition of uptake/degradation, (2) genera tion of cysteine alpha -carbamate, a toxic analog of hTMDA, (3) generation of toxic oxidized cysteine derivatives, (4) chelation of Zn2+ which blocks the NMDA receptor-ionophore, (5) direct interaction with the NMDA receptor redox site(s), (6) generation of free radicals, and (7) formation of S-nitr osocysteine. In addition to these, we describe another new alternative for cytotoxicity: (8) generation of the neurotoxic catecholamine derivative, 5- S-cysteinyl-3,4-dihydroxyphenylacetate (cysdopac).