Protective Potential of the Glutathione Peroxidase-1 Gene in Abnormal Behaviors Induced by Phencyclidine in Mice

The Vinh Tran, Eun Joo Shin, Ji Hoon Jeong, Ji Won Lee, Youngho Lee, Choon Gon Jang, Seung Yeol Nah, Xin Gen Lei, Kazuya Toriumi, Kiyofumi Yamada, Toshitaka Nabeshima, Hyoung Chun Kim

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Abstract

Escalating evidence suggests that the impairment of glutathione (GSH)-dependent systems is one of the etiologic factors of schizophrenia. GSH is an important substrate of glutathione peroxidase (GPx). Among GPx isozymes, selenium-dependent GPx (GPx-1) is recognized as a major type, and therefore, this study investigates the role of the GPx-1 gene in abnormal behaviors induced by repeated phencyclidine (PCP) treatment using GPx-1 knockout (KO) and overexpressing transgenic (GPx-1 TG) mice. PCP-induced abnormal behaviors were more pronounced in GPx-1 KO mice than abnormal behaviors in wild-type (WT) mice, and the abnormal behaviors were less pronounced in GPx-1 TG mice than abnormal behaviors in non-TG mice. PCP treatment significantly reduced GSH levels and enhanced oxidative burdens in the prefrontal cortex of the test animals. In addition, PCP treatment significantly upregulated the nuclear translocations of nuclear factor erythroid-2-related factor 2 (Nrf2) and nuclear factor kappa-B (NF-κB) p65, as well as their DNA binding activities and γ-glutamylcysteine (GCL) mRNA expression in WT and non-TG mice. However, GPx-1 KO abolished this upregulation system. In contrast, genetic overexpression of GPx-1 further upregulated Nrf2-dependent GSH synthetic system, but downregulated NF-κB p65 activity in the presence of PCP. Clozapine, an antipsychotic, significantly upregulated GPx-1 and Nrf2-dependent GSH synthetic systems in the presence of PCP, but failed to affect NF-κB p65 activity. Our results suggest that interactive modulations between the GPx-1 gene and Nrf2-dependent GSH induction are critical for attenuating PCP-induced abnormal behaviors in mice.

Original languageEnglish
Pages (from-to)7042-7062
Number of pages21
JournalMolecular Neurobiology
Volume54
Issue number9
DOIs
Publication statusPublished - 01-11-2017

Fingerprint

Phencyclidine
Genes
NF-kappa B
Glutathione Peroxidase
glutathione peroxidase GPX1
Clozapine
Selenium
Prefrontal Cortex
Knockout Mice
Antipsychotic Agents
Isoenzymes
Glutathione
Schizophrenia
Up-Regulation
Down-Regulation

All Science Journal Classification (ASJC) codes

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

Cite this

Tran, T. V., Shin, E. J., Jeong, J. H., Lee, J. W., Lee, Y., Jang, C. G., ... Kim, H. C. (2017). Protective Potential of the Glutathione Peroxidase-1 Gene in Abnormal Behaviors Induced by Phencyclidine in Mice. Molecular Neurobiology, 54(9), 7042-7062. https://doi.org/10.1007/s12035-016-0239-y
Tran, The Vinh ; Shin, Eun Joo ; Jeong, Ji Hoon ; Lee, Ji Won ; Lee, Youngho ; Jang, Choon Gon ; Nah, Seung Yeol ; Lei, Xin Gen ; Toriumi, Kazuya ; Yamada, Kiyofumi ; Nabeshima, Toshitaka ; Kim, Hyoung Chun. / Protective Potential of the Glutathione Peroxidase-1 Gene in Abnormal Behaviors Induced by Phencyclidine in Mice. In: Molecular Neurobiology. 2017 ; Vol. 54, No. 9. pp. 7042-7062.
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abstract = "Escalating evidence suggests that the impairment of glutathione (GSH)-dependent systems is one of the etiologic factors of schizophrenia. GSH is an important substrate of glutathione peroxidase (GPx). Among GPx isozymes, selenium-dependent GPx (GPx-1) is recognized as a major type, and therefore, this study investigates the role of the GPx-1 gene in abnormal behaviors induced by repeated phencyclidine (PCP) treatment using GPx-1 knockout (KO) and overexpressing transgenic (GPx-1 TG) mice. PCP-induced abnormal behaviors were more pronounced in GPx-1 KO mice than abnormal behaviors in wild-type (WT) mice, and the abnormal behaviors were less pronounced in GPx-1 TG mice than abnormal behaviors in non-TG mice. PCP treatment significantly reduced GSH levels and enhanced oxidative burdens in the prefrontal cortex of the test animals. In addition, PCP treatment significantly upregulated the nuclear translocations of nuclear factor erythroid-2-related factor 2 (Nrf2) and nuclear factor kappa-B (NF-κB) p65, as well as their DNA binding activities and γ-glutamylcysteine (GCL) mRNA expression in WT and non-TG mice. However, GPx-1 KO abolished this upregulation system. In contrast, genetic overexpression of GPx-1 further upregulated Nrf2-dependent GSH synthetic system, but downregulated NF-κB p65 activity in the presence of PCP. Clozapine, an antipsychotic, significantly upregulated GPx-1 and Nrf2-dependent GSH synthetic systems in the presence of PCP, but failed to affect NF-κB p65 activity. Our results suggest that interactive modulations between the GPx-1 gene and Nrf2-dependent GSH induction are critical for attenuating PCP-induced abnormal behaviors in mice.",
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Tran, TV, Shin, EJ, Jeong, JH, Lee, JW, Lee, Y, Jang, CG, Nah, SY, Lei, XG, Toriumi, K, Yamada, K, Nabeshima, T & Kim, HC 2017, 'Protective Potential of the Glutathione Peroxidase-1 Gene in Abnormal Behaviors Induced by Phencyclidine in Mice', Molecular Neurobiology, vol. 54, no. 9, pp. 7042-7062. https://doi.org/10.1007/s12035-016-0239-y

Protective Potential of the Glutathione Peroxidase-1 Gene in Abnormal Behaviors Induced by Phencyclidine in Mice. / Tran, The Vinh; Shin, Eun Joo; Jeong, Ji Hoon; Lee, Ji Won; Lee, Youngho; Jang, Choon Gon; Nah, Seung Yeol; Lei, Xin Gen; Toriumi, Kazuya; Yamada, Kiyofumi; Nabeshima, Toshitaka; Kim, Hyoung Chun.

In: Molecular Neurobiology, Vol. 54, No. 9, 01.11.2017, p. 7042-7062.

Research output: Contribution to journalArticle

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AU - Tran, The Vinh

AU - Shin, Eun Joo

AU - Jeong, Ji Hoon

AU - Lee, Ji Won

AU - Lee, Youngho

AU - Jang, Choon Gon

AU - Nah, Seung Yeol

AU - Lei, Xin Gen

AU - Toriumi, Kazuya

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AU - Kim, Hyoung Chun

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