Protein Kinase Cδ Gene Depletion Protects Against Methamphetamine-Induced Impairments in Recognition Memory and ERK1/2 Signaling via Upregulation of Glutathione Peroxidase-1 Gene

The Vinh Tran, Eun Joo Shin, Lan Thuy Ty Nguyen, Youngho Lee, Dae Joong Kim, Ji Hoon Jeong, Choon Gon Jang, Seung Yeol Nah, Kazuya Toriumi, Toshitaka Nabeshima, Kiyofumi Yamada, Hyoung Chun Kim

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Accumulating evidence has suggested that repeated treatment with methamphetamine (MA) resulted in cognitive impairments. Importantly, we show that selective upregulation of protein kinase Cδ (PKCδ) in the prefrontal cortex (PFC) of wild-type mice persisted for 28 days post withdrawal of MA. On day 28, the MA-induced increase in phospho-PKCδ expression and decrease in phospho-ERK1/2 expression were significantly attenuated by both the Src inhibitor PP2 and the dopamine D1 receptor antagonist SCH 23390. However, neither protein kinase A inhibitor H89 nor calmodulin-dependent protein kinase II inhibitor KN93 attenuated MA-induced alterations in phospho-PKCδ expression and phospho-ERK1/2 expression. Since PKCδ knockout (KO) significantly increased the expression of glutathione peroxidase (GPx)-1, we also utilized GPx-1 KO and GPx-1-overexpressing transgenic (GPx-1 TG) mice. Repeated MA treatment induced cognitive impairment, as assessed by the novel object recognition test. Moreover, the extent of cognitive impairment correlated with the extent of increased phospho-PKCδ expression and decreased GPx1 expression. In the absence of MA, exposure to novel objects increased phospho-ERK1/2 and GPx-1 expression in the PFC; however, these expression levels were decreased in the presence of MA. PKCδ KO and GPx-1 TG mice each exhibited significantly attenuated MA-induced decreases in phospho-ERK1/2 and GPx-1 expression. Consistently, PKCδ inhibition induces GPx/GSH-dependent antioxidant systems. More importantly, the antipsychotic drug clozapine significantly protected against cognitive impairment and was associated with alterations in phospho-ERK1/2 and phospho-PKCδ expression. However, GPx-1 KO potentiated MA-induced cognitive deficits and alterations in phospho-ERK1/2 and phospho-PKCδ expression. These results suggest that MA induces cognitive impairment by inhibiting ERK1/2 signaling, activating PKCδ, and inactivating GPx-1 by upregulating Src kinase or the D1 receptor. They also suggest that clozapine requires activation of ERK1/2 signaling via positive modulation between the phospho-PKCδ and GPx-1 genes to restore cognitive function.

Original languageEnglish
Pages (from-to)4136-4159
Number of pages24
JournalMolecular Neurobiology
Volume55
Issue number5
DOIs
Publication statusPublished - 01-05-2018

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Methamphetamine
Protein Kinase C
Up-Regulation
Genes
Clozapine
Protein Kinase Inhibitors
Prefrontal Cortex
Recognition (Psychology)
glutathione peroxidase GPX1
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Dopamine D1 Receptors
Dopamine Antagonists
src-Family Kinases
Glutathione Peroxidase
Cyclic AMP-Dependent Protein Kinases
Cognition
Transgenic Mice
Antipsychotic Agents
Antioxidants
Cognitive Dysfunction

All Science Journal Classification (ASJC) codes

  • Neuroscience (miscellaneous)
  • Neurology
  • Cellular and Molecular Neuroscience

Cite this

Tran, The Vinh ; Shin, Eun Joo ; Nguyen, Lan Thuy Ty ; Lee, Youngho ; Kim, Dae Joong ; Jeong, Ji Hoon ; Jang, Choon Gon ; Nah, Seung Yeol ; Toriumi, Kazuya ; Nabeshima, Toshitaka ; Yamada, Kiyofumi ; Kim, Hyoung Chun. / Protein Kinase Cδ Gene Depletion Protects Against Methamphetamine-Induced Impairments in Recognition Memory and ERK1/2 Signaling via Upregulation of Glutathione Peroxidase-1 Gene. In: Molecular Neurobiology. 2018 ; Vol. 55, No. 5. pp. 4136-4159.
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abstract = "Accumulating evidence has suggested that repeated treatment with methamphetamine (MA) resulted in cognitive impairments. Importantly, we show that selective upregulation of protein kinase Cδ (PKCδ) in the prefrontal cortex (PFC) of wild-type mice persisted for 28 days post withdrawal of MA. On day 28, the MA-induced increase in phospho-PKCδ expression and decrease in phospho-ERK1/2 expression were significantly attenuated by both the Src inhibitor PP2 and the dopamine D1 receptor antagonist SCH 23390. However, neither protein kinase A inhibitor H89 nor calmodulin-dependent protein kinase II inhibitor KN93 attenuated MA-induced alterations in phospho-PKCδ expression and phospho-ERK1/2 expression. Since PKCδ knockout (KO) significantly increased the expression of glutathione peroxidase (GPx)-1, we also utilized GPx-1 KO and GPx-1-overexpressing transgenic (GPx-1 TG) mice. Repeated MA treatment induced cognitive impairment, as assessed by the novel object recognition test. Moreover, the extent of cognitive impairment correlated with the extent of increased phospho-PKCδ expression and decreased GPx1 expression. In the absence of MA, exposure to novel objects increased phospho-ERK1/2 and GPx-1 expression in the PFC; however, these expression levels were decreased in the presence of MA. PKCδ KO and GPx-1 TG mice each exhibited significantly attenuated MA-induced decreases in phospho-ERK1/2 and GPx-1 expression. Consistently, PKCδ inhibition induces GPx/GSH-dependent antioxidant systems. More importantly, the antipsychotic drug clozapine significantly protected against cognitive impairment and was associated with alterations in phospho-ERK1/2 and phospho-PKCδ expression. However, GPx-1 KO potentiated MA-induced cognitive deficits and alterations in phospho-ERK1/2 and phospho-PKCδ expression. These results suggest that MA induces cognitive impairment by inhibiting ERK1/2 signaling, activating PKCδ, and inactivating GPx-1 by upregulating Src kinase or the D1 receptor. They also suggest that clozapine requires activation of ERK1/2 signaling via positive modulation between the phospho-PKCδ and GPx-1 genes to restore cognitive function.",
author = "Tran, {The Vinh} and Shin, {Eun Joo} and Nguyen, {Lan Thuy Ty} and Youngho Lee and Kim, {Dae Joong} and Jeong, {Ji Hoon} and Jang, {Choon Gon} and Nah, {Seung Yeol} and Kazuya Toriumi and Toshitaka Nabeshima and Kiyofumi Yamada and Kim, {Hyoung Chun}",
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Protein Kinase Cδ Gene Depletion Protects Against Methamphetamine-Induced Impairments in Recognition Memory and ERK1/2 Signaling via Upregulation of Glutathione Peroxidase-1 Gene. / Tran, The Vinh; Shin, Eun Joo; Nguyen, Lan Thuy Ty; Lee, Youngho; Kim, Dae Joong; Jeong, Ji Hoon; Jang, Choon Gon; Nah, Seung Yeol; Toriumi, Kazuya; Nabeshima, Toshitaka; Yamada, Kiyofumi; Kim, Hyoung Chun.

In: Molecular Neurobiology, Vol. 55, No. 5, 01.05.2018, p. 4136-4159.

Research output: Contribution to journalArticle

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T1 - Protein Kinase Cδ Gene Depletion Protects Against Methamphetamine-Induced Impairments in Recognition Memory and ERK1/2 Signaling via Upregulation of Glutathione Peroxidase-1 Gene

AU - Tran, The Vinh

AU - Shin, Eun Joo

AU - Nguyen, Lan Thuy Ty

AU - Lee, Youngho

AU - Kim, Dae Joong

AU - Jeong, Ji Hoon

AU - Jang, Choon Gon

AU - Nah, Seung Yeol

AU - Toriumi, Kazuya

AU - Nabeshima, Toshitaka

AU - Yamada, Kiyofumi

AU - Kim, Hyoung Chun

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N2 - Accumulating evidence has suggested that repeated treatment with methamphetamine (MA) resulted in cognitive impairments. Importantly, we show that selective upregulation of protein kinase Cδ (PKCδ) in the prefrontal cortex (PFC) of wild-type mice persisted for 28 days post withdrawal of MA. On day 28, the MA-induced increase in phospho-PKCδ expression and decrease in phospho-ERK1/2 expression were significantly attenuated by both the Src inhibitor PP2 and the dopamine D1 receptor antagonist SCH 23390. However, neither protein kinase A inhibitor H89 nor calmodulin-dependent protein kinase II inhibitor KN93 attenuated MA-induced alterations in phospho-PKCδ expression and phospho-ERK1/2 expression. Since PKCδ knockout (KO) significantly increased the expression of glutathione peroxidase (GPx)-1, we also utilized GPx-1 KO and GPx-1-overexpressing transgenic (GPx-1 TG) mice. Repeated MA treatment induced cognitive impairment, as assessed by the novel object recognition test. Moreover, the extent of cognitive impairment correlated with the extent of increased phospho-PKCδ expression and decreased GPx1 expression. In the absence of MA, exposure to novel objects increased phospho-ERK1/2 and GPx-1 expression in the PFC; however, these expression levels were decreased in the presence of MA. PKCδ KO and GPx-1 TG mice each exhibited significantly attenuated MA-induced decreases in phospho-ERK1/2 and GPx-1 expression. Consistently, PKCδ inhibition induces GPx/GSH-dependent antioxidant systems. More importantly, the antipsychotic drug clozapine significantly protected against cognitive impairment and was associated with alterations in phospho-ERK1/2 and phospho-PKCδ expression. However, GPx-1 KO potentiated MA-induced cognitive deficits and alterations in phospho-ERK1/2 and phospho-PKCδ expression. These results suggest that MA induces cognitive impairment by inhibiting ERK1/2 signaling, activating PKCδ, and inactivating GPx-1 by upregulating Src kinase or the D1 receptor. They also suggest that clozapine requires activation of ERK1/2 signaling via positive modulation between the phospho-PKCδ and GPx-1 genes to restore cognitive function.

AB - Accumulating evidence has suggested that repeated treatment with methamphetamine (MA) resulted in cognitive impairments. Importantly, we show that selective upregulation of protein kinase Cδ (PKCδ) in the prefrontal cortex (PFC) of wild-type mice persisted for 28 days post withdrawal of MA. On day 28, the MA-induced increase in phospho-PKCδ expression and decrease in phospho-ERK1/2 expression were significantly attenuated by both the Src inhibitor PP2 and the dopamine D1 receptor antagonist SCH 23390. However, neither protein kinase A inhibitor H89 nor calmodulin-dependent protein kinase II inhibitor KN93 attenuated MA-induced alterations in phospho-PKCδ expression and phospho-ERK1/2 expression. Since PKCδ knockout (KO) significantly increased the expression of glutathione peroxidase (GPx)-1, we also utilized GPx-1 KO and GPx-1-overexpressing transgenic (GPx-1 TG) mice. Repeated MA treatment induced cognitive impairment, as assessed by the novel object recognition test. Moreover, the extent of cognitive impairment correlated with the extent of increased phospho-PKCδ expression and decreased GPx1 expression. In the absence of MA, exposure to novel objects increased phospho-ERK1/2 and GPx-1 expression in the PFC; however, these expression levels were decreased in the presence of MA. PKCδ KO and GPx-1 TG mice each exhibited significantly attenuated MA-induced decreases in phospho-ERK1/2 and GPx-1 expression. Consistently, PKCδ inhibition induces GPx/GSH-dependent antioxidant systems. More importantly, the antipsychotic drug clozapine significantly protected against cognitive impairment and was associated with alterations in phospho-ERK1/2 and phospho-PKCδ expression. However, GPx-1 KO potentiated MA-induced cognitive deficits and alterations in phospho-ERK1/2 and phospho-PKCδ expression. These results suggest that MA induces cognitive impairment by inhibiting ERK1/2 signaling, activating PKCδ, and inactivating GPx-1 by upregulating Src kinase or the D1 receptor. They also suggest that clozapine requires activation of ERK1/2 signaling via positive modulation between the phospho-PKCδ and GPx-1 genes to restore cognitive function.

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