Dopamine D2 agonists, bromocriptine and quinpirole, increase MPP+ -induced toxicity in PC12 cells.
Dopaminergic cell loss in the mesencephalic substantia nigra is the hallmark of Parkinson's disease and may be associated with abnormal oxidative metabolic activity. However, the delicate balance underlying dopamine decline and oxidative stress is still a matter of debate. The aim of this study was to analyze the possible modulation of D2 agonists and antagonists on MPP+ (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridinium ion) -induced cellular death in differentiated and undifferentiated PC12 cells. Using colorimetric assays, western blots and reverse transcriptase-PCR, we demonstrated that two D2 agonists, bromocriptine and quinpirole, consistently increased MPP+ -induced cytotoxicity in both differentiated and undifferentiated PC12 cells, whereas D2 antagonists do not modulate cell death. However, this increase in cellular death was reversed when bromocriptine or quinpirole were used in presence of D2 antagonists. On the other hand, 1-{2-[bis-(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)piperazine (GBR 12909), a potent inhibitor of the dopamine transporter, partially reversed MPP+ -induced cellular death and completely abolished the increase of cellular death induced by bromocriptine. Dopamine agonists and antagonists also modulate the expression of the dopamine transporter in PC12 cells; in particular, bromocriptine may alter MPP+ uptake by increasing DAT expression We also show that, in our cellular paradigm, D2 receptor mRNA levels are more abundant that D3 mRNA levels and MPP+ and /or bromocriptine could not modulate D2 gene expression while D3 gene expression clearly decrease after MPP+ and /or bromocriptine treatment.
Chiasson
Keith
K
Department of Biochemistry and Groupe de Recherche en Neurosciences, Université du Québec á Trois-Riviéres, Trois-Riviéres, Québec, Canada.
Daoust
Benoît
B
Levesque
Daniel
D
Martinoli
Maria-Grazia
MG
D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D001971:Bromocriptine / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D018491:Dopamine Agonists / Q000494:pharmacology*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D015870:Gene Expression / Q000187:drug effects; D009498:Neurotoxins / Q000633:toxicity*; D016716:PC12 Cells / Q000187:drug effects* / Q000378:metabolism; D019257:Quinpirole / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism; D050637:Receptors, Dopamine D3 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods
D018491:Dopamine Agonists; D050483:Dopamine Plasma Membrane Transport Proteins; D009498:Neurotoxins; D012333:RNA, Messenger; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D019257:Quinpirole; D001971:Bromocriptine; D015655:1-Methyl-4-phenylpyridinium