Vol. 54, Issue 6, 1046-1054, December 1998

Protective Effects of the Antiparkinsonian Drugs Talipexole and Pramipexole against 1-Methyl-4-phenylpyridinium-Induced Apoptotic Death in Human Neuroblastoma SH-SY5Y Cells

Yoshihisa Kitamura, Tadashi Kosaka, Jun-Ichi Kakimura, Yasuji Matsuoka, Yasuko Kohno, Yasuyuki Nomura, and Takashi Taniguchi

Department of Neurobiology (Y.Ki., T.K., J.K., Y.M., T.T.), Kyoto Pharmaceutical University, Kyoto 607-8412, Japan, Product Management Department (Y.Ko.), Marketing Division, Nippon Boehringer Ingelheim, Hyogo 666-0193, Japan, and Department of Pharmacology (Y.N.), Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan

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.