Inhibitors of Mitochondrial Respiration, Iron (II), and Hydroxyl Radical Evoke Release and Extracellular Hydrolysis of Glutathione in Rat Striatum and Substantia Nigra: Potential Implications to Parkinson's Disease.

In this investigation, microdialysis has been used to study the effects of 1-methyl-4-phenylpyridinium (MPP[sup +]), an inhibitor of mitochondrial complex I and α-ketoglutarate dehydrogenase and the active metabolite of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP), on extracellular concentrations of glutathione (GSH) and cysteine (CySH) in the rat striatum and substantia nigra (SN). During perfusion of a neurotoxic concentration of MPP[sup +] (2.5 mM) into the rat striatum or SN, extracellular concentrations of GSH and CySH remain at basal levels (both ∼2 µM). However, when the perfusion is discontinued, a massive but transient release of GSH occurs, peaking at 5,000% of basal levels in the striatum and 2,000% of basal levels in the SN. The release of GSH is followed by a slightly delayed and smaller elevation of extracellular concentrations of CySH that can be blocked by the γ-glutamyl transpeptidase (γ-GT) inhibitor acivicin. Low-molecular-weight iron and extracellular hydroxyl radical (OH...) have been implicated as participants in the mechanism underlying the dopaminergic neurotoxicity of MPTP/MPP[sup +]. During perfusion of Fe[sup 2+] (OH...) into the rat striatum and SN, extracellular levels of GSH also remain at basal levels. When perfusions of Fe[sup 2+] are discontinued, a massive transient release of GSH occurs followed by a delayed, small, but progressive elevation of extracellular CySH level that again can be blocked by acivicin. Previous investigators have noted that extracellular concentrations of the excitatory/excitotoxic amino acid glutamate increase dramatically when perfusions of neurotoxic concentrations of MPP[sup +] are discontinued. This observation and the fact that MPTP/MPP[sup +] causes the loss of nigrostriatal GSH without corresponding increases of glutathione disulfide (GSSG) and the results of the present investigation suggest that the release and &gamma... [ABSTRACT FROM AUTHOR]