Pramipexole reduces reactive oxygen species production in vivo and in vitro and inhibits the mitochondrial permeability transition produced by the parkinsonian neurotoxin methylpyridinium ion.
Sporadic Parkinson's disease is associated with a defect in the activity of complex I of the mitochondrial electron transport chain. This electron transport chain defect is transmitted through mitochondrial DNA, and when expressed in host cells leads to increased oxygen free radical production, increased antioxidant enzyme activities, and increased susceptibility to programmed cell death. Pramipexole, a chemically novel dopamine agonist used for the treatment of Parkinson's disease symptoms, possesses antioxidant activity and is neuroprotective toward substantia nigral dopamine neurons in hypoxic-ischemic and methamphetamine models. We found that pramipexole reduced the levels of oxygen radicals produced by methylpyridinium ion (MPP+) both when incubated with SH-SY5Y cells and when perfused into rat striatum. Pramipexole also exhibited a concentration-dependent inhibition of opening of the mitochondrial transition pore induced by calcium and phosphate or MPP+. These results suggest that pramipexole may be neuroprotective in Parkinson's disease by attenuating intracellular processes such as oxygen radical generation and the mitochondrial transition pore opening, which are associated with programmed cell death.
Cassarino
D S
DS
The Neuroscience Graduate Program, University of Virginia Health Sciences Center, Charlottesville 22908, USA.
Fall
C P
CP
Smith
T S
TS
Bennett
J P
JP
D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology*; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D052160:Benzothiazoles; D001692:Biological Transport / Q000187:drug effects; D002118:Calcium / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology*; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D008099:Liver / Q000737:chemistry; D008297:Male; D017551:Microdialysis; D008928:Mitochondria / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D009447:Neuroblastoma; D018696:Neuroprotective Agents / Q000494:pharmacology; D009498:Neurotoxins / Q000494:pharmacology; D010302:Parkinson Disease, Secondary / Q000188:drug therapy / Q000378:metabolism; D010758:Phosphorus / Q000494:pharmacology; D018272:Porins / Q000378:metabolism; D000077487:Pramipexole; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000978:Antiparkinson Agents; D052160:Benzothiazoles; D015259:Dopamine Agents; D018696:Neuroprotective Agents; D009498:Neurotoxins; D018272:Porins; D017382:Reactive Oxygen Species; D013844:Thiazoles; D010758:Phosphorus; D000077487:Pramipexole; D015655:1-Methyl-4-phenylpyridinium; D002118:Calcium