Protective effects of the antiparkinsonian drugs talipexole and pramipexole against 1-methyl-4-phenylpyridinium-induced apoptotic death in human neuroblastoma SH-SY5Y cells.
Treatment of human neuroblastoma SH-SY5Y cells with 1 mM 1-methyl-4-phenylpyridinium (MPP+) for 3 days induced production of reactive oxygen species (ROS), followed by caspase-3 activation, cleavage of poly(ADP-ribose) polymerase (PARP), and apoptotic cell death with DNA fragmentation and characteristic morphological changes (condensed chromatin and fragmented nuclei). Simultaneous treatment with 1 mM talipexole slightly inhibited the MPP+-induced ROS production and apoptotic cell death. In contrast, pretreatment with 1 mM talipexole for 4 days markedly protected the cells against MPP+-induced apoptosis. However, this protective effect might not be mediated by dopamine receptors. The talipexole pretreatment induced an increase in antiapoptotic Bcl-2 protein level but had no effect on levels of proapoptotic Bax, Bak, and Bad. It also inhibited MPP+-induced ROS production, p53 expression, and cleavages of caspase-3 and PARP. Similarly, pramipexole pretreatment increased Bcl-2 and inhibited MPP+-induced apoptosis. Although pretreatment with bromocriptine also had a protective effect against MPP+-induced apoptosis, it had no effect on the protein levels of Bcl-2 family members. On the other hand, N6,2'-O-dibutyryl cAMP or calphostin C induced a decreased Bcl-2 level and enhanced MPP+-induced cell death. These results suggest that talipexole has dual actions: (1) it directly scavenges ROS, affording slight protection against MPP+-induced apoptosis, and (2) it induces Bcl-2 expression, thereby affording more potent protection, if it is administrated before MPP+. Pramipexole has similar effects, whereas bromocriptine seems to exhibit the former but not the latter effect.
Kitamura
Y
Y
Department of Neurobiology, Kyoto Pharmaceutical University, Kyoto 607-8412, Japan.
Kosaka
T
T
Kakimura
J I
JI
Matsuoka
Y
Y
Kohno
Y
Y
Nomura
Y
Y
Taniguchi
T
T
D015655:1-Methyl-4-phenylpyridinium / Q000037:antagonists & inhibitors*; D000978:Antiparkinson Agents / Q000494:pharmacology*; D017209:Apoptosis; D001381:Azepines / Q000494:pharmacology*; D052160:Benzothiazoles; D001971:Bromocriptine / Q000494:pharmacology; D003994:Bucladesine / Q000494:pharmacology; D053148:Caspase 3; D020169:Caspases / Q000032:analysis; D018491:Dopamine Agonists / Q000494:pharmacology; D006801:Humans; D000077487:Pramipexole; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D017382:Reactive Oxygen Species; D013844:Thiazoles / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000032:analysis
D000978:Antiparkinson Agents; D001381:Azepines; D052160:Benzothiazoles; D018491:Dopamine Agonists; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53; D001971:Bromocriptine; D003994:Bucladesine; C024763:talipexole; D000077487:Pramipexole; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D015655:1-Methyl-4-phenylpyridinium