Molecular mechanisms of 6-hydroxydopamine-induced cytotoxicity in PC12 cells: Involvement of hydrogen peroxide-dependent and -independent action

Yoshiro Saito, Keiko Nishio, Yoko Ogawa, Tomoya Kinumi, Yasukazu Yoshida, Yoshinori Masuo, Etsuo Niki

Research output: Contribution to journalArticle

135 Citations (Scopus)

Abstract

The neurotoxin 6-hydroxydopamine (6-OHDA) has been widely used to generate an experimental model of Parkinson's disease. It has been reported that reactive oxygen species (ROS), such as the superoxide anion and hydrogen peroxide (H2O2), generated from 6-OHDA are involved in its cytotoxicity; however, the contribution and role of ROS in 6-OHDA-induced cell death have not been fully elucidated. In the present study using PC12 cells, we observed the generation of 50 μM H2O2 from a lethal concentration of 100 μM 6-OHDA within a few minutes, and compared the sole effect of H2O2 with 6-OHDA. Catalase, an H2O2-removing enzyme, completely abolished the cytotoxic effect of H2O2, while a significant but partial protective effect was observed against 6-OHDA. 6-OHDA induced peroxiredoxin oxidation, cytochrome c release, and caspase-3 activation. Catalase exhibited a strong inhibitory effect against the peroxiredoxin oxidation, and cytochrome c release induced by 6-OHDA; however, caspase-3 activation was not effectively inhibited by catalase. On the other hand, 6-OHDA-induced caspase-3 activation was inhibited in the presence of caspase-8, caspase-9, and calpain inhibitors. These results suggest that the H2O2 generated from 6-OHDA plays a pivotal role in 6-OHDA-induced peroxiredoxin oxidation, and cytochrome c release, while H2O2- and cytochrome c-independent caspase activation pathways are involved in 6-OHDA-induced neurotoxicity. These findings may contribute to explain the importance of generated H2O2 and secondary products as a second messenger of 6-OHDA-induced cell death signal linked to Parkinson's disease.

Original languageEnglish
Pages (from-to)675-685
Number of pages11
JournalFree Radical Biology and Medicine
Volume42
Issue number5
DOIs
Publication statusPublished - 2007 Mar 1
Externally publishedYes

Keywords

  • 6-Hydroxydopamine
  • Caspase
  • Catalase
  • Cytochrome c
  • Glutathione
  • Hydrogen peroxide
  • Peroxiredoxin
  • p-Quinone

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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