The present study was designed to evaluate the specific role of protein kinase C (PKC) δ in methamphetamine (MA)-induced dopaminergic toxicity. A multiple-dose administration regimen of MA significantly increases PKCδ expression, while rottlerin, a PKCδ inhibitor, significantly attenuates MA-induced hyperthermia and behavioral deficits. These behavioral effects were not significantly observed in PKCδ antisense oligonucleotide (ASO)-treated- or PKCδ knockout (-/-)-mice. There were no MA-induced significant decreases of dopamine (DA) content or tyrosine hydroxylase (TH) expression in the striatum in rottlerin-treated-, ASO-treated- or PKCδ (-/-)-mice. The administration of MA also results in a significant decrease of TH phosphorylation at ser 40, but not ser 31, while the inhibition of PKCδ consistently and significantly attenuates MA-induced reduction in the phosphorylation of TH at ser 40. Therefore, these results suggest that the MA-induced enhancement of PKCδ expression is a critical factor in the impairment of TH phosphorylation at ser 40 and that pharmacological or genetic inhibition of PKCδ may be protective against MA-induced dopaminergic neurotoxicity in vivo.
|Number of pages||12|
|State||Published - Aug 2011|
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, and by a Grant (#E00025) of the Korea-Japan Joint Research Program, National Research Foundation of Korea, 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 (MEXT): Academic Frontier Project. Xuan-Khanh Thi Nguyen and Jae-Hyung Bach were supported by BK 21 Program.
- Dopaminergic toxicity
- PKCδ gene
- Phospho-TH at ser-40
ASJC Scopus subject areas
- Cellular and Molecular Neuroscience
- Cell Biology