Dopamine turnover and glutathione oxidation: implications for Parkinson disease.
Parkinson disease is characterized by a major loss (approximately 80% or more) of dopaminergic nigrostriatal neurons and by an increased turnover of neurotransmitter by surviving neurons of the nigrostriatal tract. In theory, increased turnover of dopamine should be associated with an oxidative stress derived from increased production of hydrogen peroxide. The peroxide is formed during the oxidative deamination of dopamine by monoamine oxidase. In experiments with mice, increased presynaptic turnover of dopamine was evoked by injection of reserpine, which interferes with the storage of dopamine in synaptic vesicles. Loss of dopamine and formation of deaminated metabolites were accompanied by a significant rise (87.8%) in the level of oxidized glutathione in brain. This change was observed in the striatum, which is richly innervated by dopamine terminals, but not in the frontal cortex, which receives a much sparser innervation by catecholamine nerve terminals. The rise in oxidized glutathione was seen even though dopamine terminals constitute only 1% or less of the mass of the striatum. Clorgyline, an inhibitor of monoamine oxidase type A, blocked the formation of oxidized glutathione. These observations confirm that a selective increase in neurotransmitter turnover within nigrostriatal nerve terminals can evoke a change in cellular redox status. We suggest that an oxidative stress may play a role in the natural history of Parkinson disease.
Spina
M B
MB
Department of Neurology, Mount Sinai School of Medicine, City University of New York, NY 10029.
Cohen
G
G
D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D003010:Clorgyline / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D005978:Glutathione / Q000031:analogs & derivatives* / Q000378:metabolism*; D019803:Glutathione Disulfide; D008297:Male; D051379:Mice; D010300:Parkinson Disease / Q000378:metabolism*; D012110:Reserpine / Q000494:pharmacology
D012110:Reserpine; D005978:Glutathione; D003010:Clorgyline; D019803:Glutathione Disulfide; D004298:Dopamine