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

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

doi:10.1016/j.bbr.2012.04.001

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

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

Neuroscience

Research output: Contribution to journal › Article › peer-review

61 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	98-113
Number of pages	16
Journal	Behavioural Brain Research
Volume	232
Issue number	1
DOIs	https://doi.org/10.1016/j.bbr.2012.04.001
State	Published - Jun 15 2012

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 . 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.

Keywords

Dopamine
Methamphetamine
Oxidative stress
PKC isozymes
PKCδ gene deletion
Rottlerin

ASJC Scopus subject areas

Behavioral Neuroscience

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10.1016/j.bbr.2012.04.001

Cite this

Shin, E. J., Duong, C. X., Nguyen, X. K. T., Li, Z., Bing, G., Bach, J. H., Park, D. H., Nakayama, K., Ali, S. F., Kanthasamy, A. G., Cadet, J. L., Nabeshima, T., & Kim, H. C. (2012). Role of oxidative stress in methamphetamine-induced dopaminergic toxicity mediated by protein kinase Cδ. Behavioural Brain Research, 232(1), 98-113. https://doi.org/10.1016/j.bbr.2012.04.001

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title = "Role of oxidative stress in methamphetamine-induced dopaminergic toxicity mediated by protein kinase Cδ",

abstract = "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. G{\"o}6976 (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.",

keywords = "Dopamine, Methamphetamine, Oxidative stress, PKC isozymes, PKCδ gene deletion, Rottlerin",

author = "Shin, {Eun Joo} and Duong, {Chu Xuan} and Nguyen, {Xuan Khanh Thi} and Zhengyi Li 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 Lud} 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 . 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.",

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AU - Shin, Eun Joo

AU - Duong, Chu Xuan

AU - Nguyen, Xuan Khanh Thi

AU - Li, Zhengyi

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 Lud

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 . 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.

PY - 2012/6/15

Y1 - 2012/6/15

N2 - 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.

AB - 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.

KW - Dopamine

KW - Methamphetamine

KW - Oxidative stress

KW - PKC isozymes

KW - PKCδ gene deletion

KW - Rottlerin

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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