CYSTEINE SULFINATE AND CYSTEATE - MEDIATORS OF CYSTEINE TOXICITY IN THE NEONATAL RAT-BRAIN

Excitotoxic amino acids contain two acidic groups, but cysteine repres ents an exception to this rule. The hypothesis that cysteine toxicity is mediated by the oxidized and diacidic metabolites cysteine sulphina te and/or cysteate was tested in the present study. The issue was appr oached in three different ways. Firstly, the distribution of brain inj ury after subcutaneous administration of cysteine (1 mg/g) to 4-day-ol d rats was compared with that caused by cysteine sulphinate (3 mg/g). Secondly, the effects of excitatory amino acid receptor antagonists on cysteine and cysteine sulphinate toxicity were investigated. Thirdly, the cerebral concentrations of cysteine sulphinate were determined af ter cysteine administration and compared with those obtained after cys teine sulphinate injection. The cerebral cortex was the region most vu lnerable to cysteine toxicity, followed by the hippocampus (especially the medial subicular neurons), amygdala, caudoputamen, cerebellum and septum. Pronounced extravasation of red blood cells was observed in l esioned areas. One day after cysteine administration, the injury was i nfarction-like and sharply demarcated. Cysteine sulphinate-induced dam age resembled cysteine-induced lesions in some respects: the anterior cingulate and retrosplenial cortices, as well as medial subicular cell s, were quite vulnerable. However, the differences prevailed. Cysteine sulphinate, but not cysteine, killed neurons of the superficial part of the tectum, the medial habenula, the ventromedial hypothalamus and the arcuate nucleus. Further, while cysteine toxicity was prominent in deep cortical layers, cysteine sulphinate preferentially damaged supe rficial cortical neurons. Cysteine toxicity was abolished by pretreatm ent with MK-801, a selective NMDA antagonist, but not by ihydroxy-6-ni tro-7-sulphamoyl-benzo(F)quinoxaline, a selective AMPA receptor blocke r. In contrast, the considerably smaller lesion seen after cysteine su lphinate administration was only partially prevented by MK-801. Large (19-fold) increases in cortical cysteine sulphinate concentration were noted after injection of a toxic dose of cysteine. This corresponds t o 90 nmol cysteine sulphinate/g protein. The cysteate concentration wa s not increased above the detection limit. Injection of a toxic dose o f cysteine sulphinate elevated cysteine sulphinate concentration in th e frontomedial cortex (a region consistently injured by cysteine sulph inate) almost three orders of magnitude more than that observed after cysteine administration. Taken together, these results strongly sugges t that neither cysteine sulphinate nor cysteate alone mediate cysteine toxicity. Possible candidates for such a role include cysteine carbam ate and S-sulpho-cysteine. Another alternative is that the sulphydryl group of cysteine sensitizes the NMDA receptor complex and thereby enh ances the effect of glutamate and/or some other endogenous NMDAmimetic s.