Preferential resistance of dopaminergic neurons to glutathione depletion in a reconstituted nigrostriatal system

Depletion of glutathione in the substantia nigra is one of the earliest cha nges observed in Parkinson's disease (PD), and could initiate dopaminergic neuronal degeneration. Nevertheless, we have previously demonstrated that m esencephalic dopaminergic neurons in primary monolayer cultures are more re sistant to the toxicity of glutathione depletion than nondopaminergic neuro ns. To extend this finding to a system that more closely resembles the in v ivo situation, we characterized the effects of glutathione depletion on rea ggregate cultures derived from ventral mesencephalic and their striatal tar get neurons, as well as supporting elements including glia. Dopaminergic ne urons were found to be more resistant to the toxicity of buthionine-(S,R)-s ulfoximine, an inhibitor of glutathione synthesis, than other nigrostriatal neurons, while striatal target cells exhibited an intermediate susceptibil ity when examined after 48 h. Glutathione depletion, however, decreased the intracellular content of catecholamines after 48 h and eventually led to t he loss of dopaminergic neurons after 7 days. Our data indicate that the in trinsic resistance of dopaminergic neurons to the toxicity of glutathione d epletion occurs in a variety of experimental paradigms, and suggest that gl obal glutathione depletion alone is unlikely to account for the selective l oss of dopaminergic neurons in PD. Rather, it is more likely that either th e selective loss of glutathione from dopaminergic neurons, or the combinati on of glutathione loss with other insults contributes to the preferential d eath of dopaminergic neurons in PD. (C) 2000 Elsevier Science B.V. All righ ts reserved.