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

초록

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 alpha, PKC beta I PKC beta II, or PKC zeta expression in the striatum, but did significantly increase PKC delta expression. Go6976 (a co-inhibitor of PKC alpha and -beta), hispidin (PKC beta inhibitor), and PKC zeta pseudosubstrate inhibitor (PKC zeta inhibitor) did not significantly alter MA-induced behavioral impairments. However, rottlerin (PKC delta inhibitor) significantly attenuated behavioral impairments in a dose-dependent manner. In addition, MA-induced behavioral impairments were not apparent in PKC delta 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 PKC delta (-/-) 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 delta (-/-) mice. Our results suggest that PKC delta gene expression is a key mediator of oxidative stress and dopaminergic damage induced by MA. Thus, inhibition of PKC delta may be a useful target for protection against MA-induced neurotoxicity. (C) 2012 Elsevier B.V. All rights reserved.

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