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

Autor: Shin EJ; Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200-701, South Korea., Duong CX; Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200-701, South Korea., Nguyen XT; Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200-701, South Korea., Li Z; Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200-701, South Korea., Bing G; Department of Anatomy and Neurobiology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA., Bach JH; Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200-701, South Korea., Park DH; Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200-701, South Korea., Nakayama K; Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan., Ali SF; Division of Neurotoxicology, National Center of Toxicological Research, FDA, Jefferson, Arkansas 72079, USA., Kanthasamy AG; Parkinson's Disorder Research Laboratory, Iowa Center for Advanced Neurotoxicology, Department of Biomedical Sciences, Iowa State University, Ames, IA 50011, USA., Cadet JL; Molecular Neuropsychiatry Research Branch, DHHS/NIH/NIDA Intramural Research Program, Baltimore, MD 21224, USA., Nabeshima T; Department of Regional Pharmaceutical Care and Sciences and Department of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya 468-8503, Japan., Kim HC; Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200-701, South Korea.
Jazyk: angličtina
Zdroj: Behavioural brain research [Behav Brain Res] 2012 Jun 15; Vol. 232 (1), pp. 98-113. Date of Electronic Publication: 2012 Apr 09.
DOI: 10.1016/j.bbr.2012.04.001
Abstrakt: 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.
(Copyright © 2012 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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