Release and aggregation of cytochrome c and alpha-synuclein are inhibited by the antiparkinsonian drugs, talipexole and pramipexole.
Recently, it has been shown that release of cytochrome c from the mitochondria to the cytosol is required for activation of the caspase-3-dependent cascade in apoptosis, and also for alpha-synuclein aggregation. In the present study, we examined the effects of talipexole and pramipexole on the release of cytochrome c and alpha-synuclein, their aggregations, and activation of caspases. Treatment of human neuroblastoma SH-SY5Y cells with 1-methyl-4-phenylpyridinium (MPP(+), 1 mM) induced the first event, which was the release of cytochrome c from the organellar fraction to the cytosolic fraction, then came the DNA fragmentation, and caused the last event, which was the accumulation of alpha-synuclein protein in the cytosolic fraction. Talipexole and pramipexole at low concentration (0.1-1 mM) significantly inhibited the accumulation of cytochrome c or alpha-synuclein in the cytosolic fraction. These drugs at high concentration (3-10 mM) inhibited in vitro aggregation of cytochrome c by hydrogen peroxide or that of alpha-synuclein by cytochrome c and hydrogen peroxide. In addition, in vitro activation of caspase-3 induced by cytochrome c and/or dATP was also inhibited by drugs at high concentration (5-10 mM). These results suggest that talipexole and pramipexole may have protective effects against the neurodegeneration, which is induced by intracellular accumulation of cytochrome c and alpha-synuclein.
Kakimura
J
J
Department of Neurobiology, Kyoto Pharmaceutical University, Misasagi, Kyoto 607-8412, Yamashina, Japan.
Kitamura
Y
Y
Takata
K
K
Kohno
Y
Y
Nomura
Y
Y
Taniguchi
T
T
D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology; D000978:Antiparkinson Agents / Q000494:pharmacology*; D001381:Azepines / Q000494:pharmacology*; D052160:Benzothiazoles; D020169:Caspases / Q000378:metabolism; D002474:Cell-Free System / Q000187:drug effects / Q000201:enzymology; D003574:Cytochrome c Group / Q000187:drug effects* / Q000378:metabolism / Q000494:pharmacology; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D003838:Deoxyadenine Nucleotides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D009419:Nerve Tissue Proteins / Q000187:drug effects* / Q000378:metabolism; D015388:Organelles / Q000187:drug effects / Q000378:metabolism; D000077487:Pramipexole; D051843:Synucleins; D013844:Thiazoles / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D051844:alpha-Synuclein
D000978:Antiparkinson Agents; D001381:Azepines; D052160:Benzothiazoles; D003574:Cytochrome c Group; D003838:Deoxyadenine Nucleotides; D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; D051843:Synucleins; D013844:Thiazoles; D051844:alpha-Synuclein; C024763:talipexole; D000077487:Pramipexole; D020169:Caspases; D015655:1-Methyl-4-phenylpyridinium