PKCδ inhibition enhances tyrosine hydroxylase phosphorylation in mice after methamphetamine treatment

Eun Joo Shin, Chu Xuan Duong, Xuan Khanh Thi Nguyen, Guoying Bing, Jae Hyung Bach, Dae Hun Park, Keiichi Nakayama, Syed F. Ali, Anumantha G. Kanthasamy, Jean L. Cadet, Toshitaka Nabeshima, Hyoung Chun Kim

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)39-50
Number of pages12
JournalNeurochemistry International
Volume59
Issue number1
DOIs
StatePublished - Aug 2011

Bibliographical note

Funding 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.

Keywords

  • Dopaminergic toxicity
  • Hyperthermia
  • Methamphetamine
  • PKCδ gene
  • Phospho-TH at ser-40
  • Striatum

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Cell Biology

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