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

研究成果: Article

20 引用 (Scopus)

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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.

元の言語English
ページ(範囲)7042-7062
ページ数21
ジャーナルMolecular Neurobiology
54
発行部数9
DOI
出版物ステータスPublished - 01-11-2017

All Science Journal Classification (ASJC) codes

  • Neurology
  • Cellular and Molecular Neuroscience

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    Tran, T. V., Shin, E. J., Jeong, J. H., Lee, J. W., Lee, Y., Jang, C. G., Nah, S. Y., Lei, X. G., Toriumi, K., Yamada, K., Nabeshima, T., & 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