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

doi:10.1016/j.neuint.2011.03.022

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

Neuroscience

Research output: Contribution to journal › Article › peer-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 language	English
Pages (from-to)	39-50
Number of pages	12
Journal	Neurochemistry International
Volume	59
Issue number	1
DOIs	https://doi.org/10.1016/j.neuint.2011.03.022
State	Published - 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.

Funding

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.

Funders	Funder number
National Institute on Drug Abuse	ZIADA000551
Ministry of Education, Culture, Sports, Science and Technology
Ministry of Health, Labour and Welfare
National Research Foundation of Korea
Ministry of Science and Technology, Croatia	00025

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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10.1016/j.neuint.2011.03.022

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title = "PKCδ inhibition enhances tyrosine hydroxylase phosphorylation in mice after methamphetamine treatment",

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.",

keywords = "Dopaminergic toxicity, Hyperthermia, Methamphetamine, PKCδ gene, Phospho-TH at ser-40, Striatum",

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

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.",

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language = "English",

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AU - Shin, Eun Joo

AU - Duong, Chu Xuan

AU - Nguyen, Xuan Khanh Thi

AU - Bing, Guoying

AU - Bach, Jae Hyung

AU - Park, Dae Hun

AU - Nakayama, Keiichi

AU - Ali, Syed F.

AU - Kanthasamy, Anumantha G.

AU - Cadet, Jean L.

AU - Nabeshima, Toshitaka

AU - Kim, Hyoung Chun

N1 - 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.

PY - 2011/8

Y1 - 2011/8

N2 - 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.

AB - 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.

KW - Dopaminergic toxicity

KW - Hyperthermia

KW - Methamphetamine

KW - PKCδ gene

KW - Phospho-TH at ser-40

KW - Striatum

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JO - Neurochemistry International

JF - Neurochemistry International

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PKCδ inhibition enhances tyrosine hydroxylase phosphorylation in mice after methamphetamine treatment

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

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