EFFECTS OF L-CYSTEINE ON THE OXIDATION CHEMISTRY OF DOPAMINE - NEW REACTION PATHWAYS OF POTENTIAL RELEVANCE TO IDIOPATHIC PARKINSONS-DISEASE

Oxidation of the catecholamine;gic neurotransmitter dopamine (1) at ph ysiological pH normally results in formation of black, insoluble melan in polymer. In this study, it is demonstrated that L-cysteine (CySH) c an divert the melanin pathway by scavenging the proximate o-quinone ox idation product of 1 to give 5-S-cysteinyldopamine (8). This cysteinyl conjugate is further oxidized in the presence of free CySH to give ih ydro-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid (11) and its 6-S -cysteinyl (12), 8-S-cysteinyl (14), and 6,8-di-S-cysteinyl (16) conju gates in addition to many other unidentified compounds. 5-S-Cysteinyld opamine (8) and dihydrobenzothiazines 11, 12, 14, and 16 are all more easily oxidized than 1. With increasing molar excesses of CySH, the fo rmation of melanin is decreased and, ultimately, completely blocked. P reliminary experiments have revealed that when injected into the brain s of laboratory mice, dihydrobenzothiazine 11 and its cysteinyl conjug ates 12 and 14 are lethal and evoke profound behavioral responses incl uding hyperactivity and tremor. On the basis of these results and othe r recent observations, a new hypothesis has been advanced which might help explain the selective degeneration of nigrostriatal dopaminergic neurons which occurs in idiopathic Parkinson's Disease (PD). This hypo thesis proposes that in response to some form of chronic brain insult, the activity of gamma-glutamyltranspeptidase is upregulated leading t o an increased rate of translocation of glutathione (GSH) into the cyt oplasm of dopaminergic cell bodies in the substantia nigra (SN) pars c ompacta. The results of this in vitro study predict that such an eleva ted translocation of GSH into heavily pigmented dopaminergic neurons w ould cause a diversion of the neuromelanin pathway with consequent dep igmentation of these cells and formation of 8, all of which occur in t he Parkinsonian SN. The further very facile oxidation of 8 which must occur under intraneuronal conditions where 1 is autoxidized, i.e., in neuromelanin-pigmented cells, would lead to dihydrobenzothiazine 11 an d its cysteinyl conjugates which could be the endotoxins responsible f or the selective degeneration of dopaminergic SN neurons in PD. The ea se of autoxidation of 8 is suggested to account for the low levels of this conjugate found in the degenerating and Parkinsonian SN. The latt er reaction and the intraneuronal autoxidation/redox cycling of 11 and its cysteinyl conjugates would be expected to result in greatly incre ased rates of intraneuronal formation of O-2. which could (a) catalyze the oxidation of 1 by molecular oxygen, hence accounting for the sign ificantly elevated 8/1 ratio observed in the Parkinsonian SN, and (b) lead to increased production of H2O2 and HO., resulting in the extensi ve peroxidative damage which occurs in the SN in PD.