Release of dopamine by perfusion with 1-methyl-4-phenylpyridinium ion (MPP(+)) into the striatum is associated with hydroxyl free radical generation.
In Parkinson's disease (PD), the dopamine (DA) neuronal cell death in the nigrostriatal system has been proposed to be mediated by reactive oxygen radicals such as hydroxyl radicals (.OH). This.OH production may cause lipid peroxidation of cell membranes leading to neuronal cell death. This paper report that the DA-selective neurotoxin, 1-methyl-4-phenylpyridinium ion (MPP(+)), (1 nmol/microl per min for 1 h) infusion into the striatum of rats induces elevation of extracellular DA and.OH formation. These elevations seem to induce lipid peroxidation of striatum membranes, as detected by increases in non-enzymatic formation of 2,3-dihydroxybenzoic acid (DHBA) levels. To test the involvement of DA release in the.OH generation and lipid peroxidation, the rats were pretreated with reserpine (5 mg/kg, i.v., 24 h before MPP(+) or without MPP(+)) to deplete presynaptic DA. Reserpine treatment alone did not change the levels of DA or 2,3-DHBA, while the combined treatment with both MPP(+) and reserpine clearly decreased 2,3-DHBA, as well as DA levels, compared to those in the group treated with MPP(+) alone. After injection into reserpinized rats, DA at various doses (2, 5 and 10 microM) small increased 2,3-DHBA levels dose-dependently, as compared to the MPP(+) alone-treated group. These results clearly indicate that MPP(+) perfusion into the striatum increases extracellular DA levels and this increase may concomitantly induce the formation of reactive free oxygen radicals, such as.OH free radicals. These events may contribute, at least in part, to the nigrostriatal neurons cell death after MPP(+).
Obata
T
T
Department of Pharmacology, Oita Medical University, 1-1, Hasama-machi, Oita 879-5593, Japan. tobata@oita-med.ac.jp
Yamanaka
Y
Y
Kinemuchi
H
H
Oreland
L
L
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D006540:Herbicides / Q000633:toxicity*; D062385:Hydroxybenzoates / Q000378:metabolism; D017665:Hydroxyl Radical / Q000378:metabolism*; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology; D008297:Male; D017072:Neostriatum / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D009434:Neural Pathways / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D012110:Reserpine / Q000494:pharmacology; D020156:Salicylic Acid / Q000494:pharmacology; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology
D018759:Adrenergic Uptake Inhibitors; D000935:Antifungal Agents; D006540:Herbicides; D062385:Hydroxybenzoates; D017665:Hydroxyl Radical; C009135:2,3-dihydroxybenzoic acid; D012110:Reserpine; D020156:Salicylic Acid; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine