Rotenone-induced PC12 cell toxicity is caused by oxidative stress resulting from altered dopamine metabolism

Yan Sai, Qiang Wu, Weidong Le, Feng Ye, Yunpeng Li, Zhaojun Dong

Research output: Contribution to journalArticle

50 Scopus citations

Abstract

Rotenone is a widely used pesticide. Administration of rotenone can induce biochemical and histological alterations similar to those of Parkinson's disease in rats, leading to the selective loss of dopaminergic neurons in the substantia nigra pars compacta. However, it remains unclear why rotenone seems to affect preferentially dopaminergic cells. To address this question, we studied the effects of rotenone on dopamine distribution and metabolism to determine the role of endogenous dopamine in rotenone-induced PC12 cells toxicity. Results showed that cell viability was decreased and intracellular dopamine concentration was increased with rotenone administration in a dose-dependent manner. Rotenone exposure led to changes of proteins and enzymes associated with dopamine synthesis and transportation in PC12 cells. Tyrosine hydroxylase (TH) and vesicular monoamine transporter 2 (VMAT2) were markedly down-regulated, and dopamine transporter (DAT) was up-regulated in the cells. The activity of monoamine oxidase (MAO) was also increased. In addition, rotenone increased ROS formation, which was clearly inhibited by the pretreatment of GSH. Similar inhibitions of ROS formation were also observed in PC12 cells pretreated with the classical dopamine transporter inhibitor of GBR-12909 and the MAO inhibitor l-deprenyl. Moreover, opposite effects were observed in PC12 cells pretreated with the specific VMAT2 inhibitor reserpine. These results suggest that rotenone administration may interfere with dopamine distribution and metabolism, leading to dopamine accumulated in the cytoplasm of PC12 cells, which may contribute to the ROS formation and cell death. Therefore, the endogenous dopamine resulted from the altered dopamine metabolism and redistribution may play an important role in rotenone toxicity in dopamine neurons.

Original languageEnglish (US)
Pages (from-to)1461-1468
Number of pages8
JournalToxicology in Vitro
Volume22
Issue number6
DOIs
StatePublished - Sep 2008

Keywords

  • Endogenous dopamine
  • Oxidative stress
  • Parkinson's disease
  • Rotenone

ASJC Scopus subject areas

  • Toxicology

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