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

  1. Yoshihisa Kitamura1,
  2. Tadashi Kosaka1,
  3. Jun-Ichi Kakimura1,
  4. Yasuji Matsuoka1,
  5. Yasuko Kohno2,
  6. Yasuyuki Nomura3 and
  7. Takashi Taniguchi1
  1. 1Department of Neurobiology (Y.Ki., T.K., J.K., Y.M., T.T.), Kyoto Pharmaceutical University, Kyoto 607-8412, Japan, 2Product Management Department (Y.Ko.), Marketing Division, Nippon Boehringer Ingelheim, Hyogo 666-0193, Japan, and 3Department of Pharmacology (Y.N.), Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan

    Abstract

    Treatment of human neuroblastoma SH-SY5Y cells with 1 mm1-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.

    Footnotes

    • Send reprint requests to: Takashi Taniguchi, Ph.D., Department of Neurobiology, Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto 607-8412, Japan. E-mail:taniguti{at}mb.kyoto-phu.ac.jp

    • This work was supported in part by Grants-in-Aid from the Ministry of Education, Science, Sports and Culture in Japan (Y. Ki, Y.M., Y.N., T.T.).

    • Abbreviations:
      MPTP
      1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
      diBu-cAMP
      N6,2′-O-dibutyryl cAMP
      C-DCDHF-DA
      6-carboxy-2′,7′-dichlorodihydrofluorescein diacetate di(acetoxymethyl) ester
      MPP+
      1-methyl-4-phenylpyridinium
      MTT
      3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide
      PARP
      poly(ADP-ribose) polymerase
      PKA
      protein kinase A
      PKC
      protein kinase C
      PMA
      phorbol-12-myristate-13-acetate
      ROS
      reactive oxygen species
      ANOVA
      analysis of variance
      • Received April 28, 1998.
      • Accepted August 28, 1998.
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    1. Molecular Pharmacology December 1, 1998 vol. 54 no. 6 1046-1054
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