Role of oxidative stress in methamphetamine-induced dopaminergic toxicity mediated by protein kinase Cδ

Eun Joo Shin, Chu Xuan Duong, Xuan Khanh Thi Nguyen, Zhengyi Li, Guoying Bing, Jae Hyung Bach, Dae Hun Park, Keiichi Nakayama, Syed F. Ali, Anumantha G. Kanthasamy, Jean Lud Cadet, Toshitaka Nabeshima, Hyoung Chun Kim

Research output: Contribution to journalArticlepeer-review

65 Scopus citations

Abstract

This study examined the role of protein kinase C (PKC) isozymes in methamphetamine (MA)-induced dopaminergic toxicity. Multiple-dose administration of MA did not significantly alter PKCα, PKCβI, PKCβII, or PKCζ expression in the striatum, but did significantly increase PKCδ expression. Gö6976 (a co-inhibitor of PKCα and -β), hispidin (PKCβ inhibitor), and PKCζ pseudosubstrate inhibitor (PKCζ inhibitor) did not significantly alter MA-induced behavioral impairments. However, rottlerin (PKCδ inhibitor) significantly attenuated behavioral impairments in a dose-dependent manner. In addition, MA-induced behavioral impairments were not apparent in PKCδ knockout (-/-) mice. MA-induced oxidative stress (. i.e., lipid peroxidation and protein oxidation) was significantly attenuated in rottlerin-treated mice and was not apparent in PKCδ (-/-) mice. Consistent with this, MA-induced apoptosis (. i.e., terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive apoptotic cells) was significantly attenuated in rottlerin-treated mice. Furthermore, MA-induced increases in the dopamine (DA) turnover rate and decreases in tyrosine hydroxylase (TH) activity and the expression of TH, dopamine transporter (DAT), and vesicular monoamine transporter 2 (VMAT2) were not significantly observed in rottlerin-treated or PKCδ (-/-) mice. Our results suggest that . PKCδ gene expression is a key mediator of oxidative stress and dopaminergic damage induced by MA. Thus, inhibition of PKCδ may be a useful target for protection against MA-induced neurotoxicity.

Original languageEnglish
Pages (from-to)98-113
Number of pages16
JournalBehavioural Brain Research
Volume232
Issue number1
DOIs
StatePublished - Jun 15 2012

Bibliographical note

Funding Information:
This study was supported by a grant ( #2011K000271 ) from the Brain Research Center from 21st Century Frontier Research Program funded by the Ministry of Science and Technology, Republic of Korea . This work was, in part, supported by grants from Ministry of Health Labour and Welfare (MHLW): Research on Risk of Chemical Substances , and Ministry of Education, Culture, Sports, Science and Technology (MEST): Academic Frontier Project . Xuan-Khanh Thi Nguyen and Jae-Hyung Bach were supported by BK 21 program. Equipment at the Institute of Pharmaceutical Science (Kangwon National University) was used for this study.

Keywords

  • Dopamine
  • Methamphetamine
  • Oxidative stress
  • PKC isozymes
  • PKCδ gene deletion
  • Rottlerin

ASJC Scopus subject areas

  • Behavioral Neuroscience

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