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

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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
Publication statusPublished - 15-06-2012
Externally publishedYes

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All Science Journal Classification (ASJC) codes

  • Behavioral Neuroscience

Cite this

Shin, E. J., Duong, C. X., Nguyen, X. K. T., Li, Z., Bing, G., Bach, J. H., Park, D. H., Nakayama, K., Ali, S. F., Kanthasamy, A. G., Cadet, J. L., Nabeshima, T., & Kim, H. C. (2012). Role of oxidative stress in methamphetamine-induced dopaminergic toxicity mediated by protein kinase Cδ. Behavioural Brain Research, 232(1), 98-113. https://doi.org/10.1016/j.bbr.2012.04.001