Dopamine D2-type agonists protect mesencephalic neurons from glutamate neurotoxicity: mechanisms of neuroprotective treatment against oxidative stress.
Oxidative stress, a process in which neurotoxic oxygen free radicals cause dopaminergic neuronal degeneration, has been implicated in the degenerative process in Parkinson's disease. Glutamate-induced neurotoxicity is a model of oxidative stress. We demonstrated that preincubation with D2-type dopamine agonists bromocriptine and quinpirole provides neuroprotection against glutamate-induced neurotoxicity in cultured rat mesencephalic neurons. Simultaneous administration of D2 agonists, however, did not provide neuroprotection. The protective effects were dependent on the duration of preincubation and were blocked by a D2 antagonist and a protein synthesis inhibitor. Furthermore, preincubation with D2 agonists provided neuroprotection against toxicity induced by calcium overload and exposure to superoxide anions. Confocal microscopic analysis, using 2,7-dichlorofluorescin diacetate, revealed that bromocriptine preincubation suppressed the action of radicals on neurons. These findings indicate that dopamine D2 agonists provide protection mediated not only by the inhibition of dopamine turnover but also via D2-type dopamine receptor stimulation and the subsequent synthesis of proteins that scavenge free radicals.
Sawada
H
H
Department of Neurology, Graduate School of Medicine, Kyoto University, Japan.
Ibi
M
M
Kihara
T
T
Urushitani
M
M
Akaike
A
A
Kimura
J
J
Shimohama
S
S
D000818:Animals; D001971:Bromocriptine / Q000494:pharmacology*; D000001:Calcimycin / Q000494:pharmacology; D002478:Cells, Cultured / Q000187:drug effects; D018491:Dopamine Agonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D016166:Free Radical Scavengers / Q000494:pharmacology; D018698:Glutamic Acid; D006861:Hydrogen Peroxide / Q000494:pharmacology; D019271:Hypoxanthine / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D008636:Mesencephalon / Q000187:drug effects*; D018613:Microscopy, Confocal; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D019257:Quinpirole / Q000494:pharmacology*; D051381:Rats; D014969:Xanthine Oxidase / Q000494:pharmacology
D018491:Dopamine Agonists; D016166:Free Radical Scavengers; D007476:Ionophores; D018696:Neuroprotective Agents; D016877:Oxidants; D019257:Quinpirole; D019271:Hypoxanthine; D000001:Calcimycin; D001971:Bromocriptine; D018698:Glutamic Acid; D006861:Hydrogen Peroxide; D014969:Xanthine Oxidase