title: Role of oxidative stress in methamphetamine-induced dopaminergic toxicity mediated by protein kinase Cδ.
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.
authors.affiliation: Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200-701, South Korea.
authors.forename: Eun-Joo
authors.initials: EJ
authors.lastname: Shin
authors.affiliation: Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200-701, South Korea.
authors.forename: Chu Xuan
authors.initials: CX
authors.lastname: Duong
authors.affiliation: Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200-701, South Korea.
authors.forename: Xuan-Khanh Thi
authors.initials: XT
authors.lastname: Nguyen
authors.affiliation: Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200-701, South Korea.
authors.forename: Zhengyi
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Anatomy and Neurobiology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Guoying
authors.initials: G
authors.lastname: Bing
authors.affiliation: Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200-701, South Korea.
authors.forename: Jae-Hyung
authors.initials: JH
authors.lastname: Bach
authors.affiliation: Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200-701, South Korea.
authors.forename: Dae Hun
authors.initials: DH
authors.lastname: Park
authors.affiliation: Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Nakayama
authors.affiliation: Division of Neurotoxicology, National Center of Toxicological Research, FDA, Jefferson, Arkansas 72079, USA.
authors.forename: Syed F
authors.initials: SF
authors.lastname: Ali
authors.affiliation: Parkinson's Disorder Research Laboratory, Iowa Center for Advanced Neurotoxicology, Department of Biomedical Sciences, Iowa State University, Ames, IA 50011, USA.
authors.forename: Anumantha G
authors.initials: AG
authors.lastname: Kanthasamy
authors.affiliation: Molecular Neuropsychiatry Research Branch, DHHS/NIH/NIDA Intramural Research Program, Baltimore, MD 21224, USA.
authors.forename: Jean Lud
authors.initials: JL
authors.lastname: Cadet
authors.affiliation: Department of Regional Pharmaceutical Care and Sciences and Department of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya 468-8503, Japan.
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Nabeshima
authors.affiliation: Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200-701, South Korea.
authors.forename: Hyoung-Chun
authors.initials: HC
authors.lastname: Kim
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western; D000697:Central Nervous System Stimulants / Q000633:toxicity*; D004298:Dopamine / Q000502:physiology*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D057967:Infusions, Intraventricular; D007527:Isoenzymes / Q000096:biosynthesis; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008694:Methamphetamine / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D018384:Oxidative Stress / Q000502:physiology*; D004856:Postural Balance / Q000187:drug effects; D050050:Protein Carbonylation / Q000502:physiology; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D000697:Central Nervous System Stimulants; D007527:Isoenzymes; D047428:Protein Kinase Inhibitors; D008694:Methamphetamine; D008315:Malondialdehyde; D014446:Tyrosine 3-Monooxygenase; D051745:Protein Kinase C-delta; D004298:Dopamine