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

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• 作者：Eun-Joo Shin^a ; ¹ ; Chu Xuan Duong^a ; ¹ ; ² ; Xuan-Khanh Thi Nguyen^a ; Zhengyi Li^a ; Guoying Bing^b ; Jae-Hyung Bach^a ; Dae Hun Park^a ; Keiichi Nakayama^c ; Syed F. Ali^d ; Anumantha G. Kanthasamy^e ; Jean Lud Cadet^f ; Toshitaka Nabeshima^g ; Hyoung-Chun Kim^a ; ^{kimhc@kangwon.ac.kr}
• 关键词：Methamphetamine ; PKC isozymes ; PKC未 gene deletion ; Rottlerin ; Dopamine ; Oxidative stress
• 刊名：Behavioural Brain Research
• 出版年：2012
• 期刊代码：3_01664328
• 类别：neu
• 出版时间：15 June, 2012
• 卷：232
• 期：1
• 页码：98-113
• 文件大小：2426 K

摘要

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 PKC伪, PKC尾I, PKC尾II, or PKC味 expression in the striatum, but did significantly increase PKC未 expression. G枚6976 (a co-inhibitor of PKC伪 and -尾), hispidin (PKC尾 inhibitor), and PKC味 pseudosubstrate inhibitor (PKC味 inhibitor) did not significantly alter MA-induced behavioral impairments. However, rottlerin (PKC未 inhibitor) significantly attenuated behavioral impairments in a dose-dependent manner. In addition, MA-induced behavioral impairments were not apparent in PKC未 knockout (鈭?鈭? mice. MA-induced oxidative stress (i.e., lipid peroxidation and protein oxidation) was significantly attenuated in rottlerin-treated mice and was not apparent in PKC未 (鈭?鈭? 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 PKC未 (鈭?鈭? mice. Our results suggest that PKC未 gene expression is a key mediator of oxidative stress and dopaminergic damage induced by MA. Thus, inhibition of PKC未 may be a useful target for protection against MA-induced neurotoxicity.