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.
|Number of pages||16|
|Journal||Behavioural Brain Research|
|State||Published - Jun 15 2012|
Bibliographical noteFunding Information:
This study was supported by a grant ( #2011K000271 ) from the Brain Research Center from 21st Century Frontier Research Program funded by the Ministry of Science and Technology, Republic of Korea . This work was, in part, supported by grants from Ministry of Health Labour and Welfare (MHLW): Research on Risk of Chemical Substances , and Ministry of Education, Culture, Sports, Science and Technology (MEST): Academic Frontier Project . Xuan-Khanh Thi Nguyen and Jae-Hyung Bach were supported by BK 21 program. Equipment at the Institute of Pharmaceutical Science (Kangwon National University) was used for this study.
- Oxidative stress
- PKC isozymes
- PKCδ gene deletion
ASJC Scopus subject areas
- Behavioral Neuroscience