GLUTATHIONE DEPLETION POTENTIATES MPTP AND MPP(+) TOXICITY IN NIGRAL DOPAMINERGIC NEURONES

GLUTATHIONE levels are decreased in the substantia nigra of patients w ith Parkinson's disease. We studied whether glutathione depletion cont ributes to dopaminergic cell death using a specific inhibitor of gluta thione biosynthesis, L-buthionine sulfoximine (BSO). We found no. sign ificant reduction of tyrosine hydroxylase-positive cells in the substa ntia nigra pars compacta (SNpc) when BSO was administered systemically to preweanling mice or locally to the SNpc of adult rats. However, th e combination of BSO with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropy ridine) in preweanling mice and the combination of nigral injections o f BSO with intrastriatal injections of MPP+ (1-methyl-4-phenylpyridini um), the active metabolite of MPTP in adult rats, potentiated the toxi c effects of MPTP and MPP+ on nigral neurones. Our data show that glut athione depletion can result in cell death if the nigrostriatal system is metabolically compromised.