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Inhibitors of Mitochondrial Respiration, Iron (II), and Hydroxyl Radical Evoke Release and Extracellular Hydrolysis of Glutathione in Rat Striatum and Substantia Nigra
Author(s) -
Han Jilin,
Cheng FuChou,
Yang Zhaoliang,
Dryhurst Glenn
Publication year - 1999
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1999.731683.x
Subject(s) - microdialysis , extracellular , glutathione , substantia nigra , striatum , chemistry , neurotoxicity , neurotoxin , mptp , biochemistry , medicine , endocrinology , pharmacology , dopaminergic , biology , dopamine , toxicity , enzyme , organic chemistry
: In this investigation, microdialysis has been used to study the effects of 1‐methyl‐4‐phenylpyridinium (MPP + ), an inhibitor of mitochondrial complex I and α‐ketoglutarate dehydrogenase and the active metabolite of the dopaminergic neurotoxin 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (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 + (2.5 m M ) into the rat striatum or SN, extracellular concentrations of GSH and CySH remain at basal levels (both ~2 μ M ). 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 + . During perfusion of Fe 2+ (OH·) into the rat striatum and SN, extracellular levels of GSH also remain at basal levels. When perfusions of Fe 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 + are discontinued. This observation and the fact that MPTP/MPP + 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 γ‐GT/dipeptidase‐mediated hydrolysis of GSH to glutamate, glycine, and CySH may be important factors involved with the degeneration of dopamine neurons. It is interesting that a very early event in the pathogenesis of Parkinson's disease is a massive loss of GSH in the SN pars compacta that is not accompanied by corresponding increases of GSSG levels. Based on the results of this and prior investigations, a new hypothesis is proposed that might contribute to an understanding of the mechanisms that underlie the degeneration of dopamine neurons evoked by MPTP/MPP + , other agents that impair neuronal energy metabolism, and Parkinson's disease.