Pramipexole protects against apoptotic cell death by non-dopaminergic mechanisms.
We have investigated the ability of pramipexole, a dopamine agonist used in the symptomatic treatment of Parkinson's disease (PD), to protect against cell death induced by 1-methyl-4-phenylpyridinium (MPP+) and rotenone in dopaminergic and non-dopaminergic cells. Pre-incubation with either the active (-)- or inactive (+)-enantiomer forms of pramipexole (10 microm) decreased cell death in response to MPP+ and rotenone in dopaminergic SHSY-5Y cells and in non-dopaminergic JK cells. The protective effect was not prevented by dopamine receptor blockade using sulpiride or clozapine. Protection occurred at concentrations at which pramipexole did not demonstrate antioxidant activity, as shown by the failure to maintain aconitase activity. However, pramipexole reduced caspase-3 activation, decreased the release of cytochrome c and prevented the fall in the mitochondrial membrane potential induced by MPP+ and rotenone. This suggests that pramipexole has anti-apoptotic actions. The results extend the evidence for the neuroprotective effects of pramipexole and indicate that this is not dependent on dopamine receptor occupation or antioxidant activity. Further evaluation is required to determine whether the neuroprotective action of pramipexole is translated to a disease-modifying effect in PD patients.
Gu
Mei
M
Royal Free and University College Medical School, University College London, London, UK.
Iravani
M M
MM
Irvani
M
M
Cooper
J Mark
JM
King
Diane
D
Jenner
Peter
P
Schapira
Anthony H V
AH
D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology; D000154:Aconitate Hydratase / Q000378:metabolism; D000975:Antioxidants / Q000494:pharmacology*; D052160:Benzothiazoles; D002232:Carbocyanines; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002452:Cell Count; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005434:Flow Cytometry / Q000379:methods; D006801:Humans; D019169:Jurkat Cells; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D009336:Necrosis; D009447:Neuroblastoma; D000077487:Pramipexole; D012402:Rotenone / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology*
D000975:Antioxidants; D052160:Benzothiazoles; D002232:Carbocyanines; D013844:Thiazoles; D012402:Rotenone; C007392:3,3'-dihexyl-2,2'-oxacarbocyanine; D000077487:Pramipexole; D045304:Cytochromes c; D007770:L-Lactate Dehydrogenase; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D000154:Aconitate Hydratase; D015655:1-Methyl-4-phenylpyridinium