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

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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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Acknowledgments

This study was supported by a grant (14182MFDS979) from the Korea Food and Drug Administration, Republic of Korea and in part by JSPS KAKENHI Grants (No. 26460240, 16K10195) from the Ministry of Education, Culture, Sports, Science and Technology of Japan and Grant in aid of SRF. The-Vinh Tran was supported by the BK21 PLUS program. The English in this document has been checked by at least two professional editors, both native speakers of English (E-Worldediting; www.eworldediting.com).

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Authors and Affiliations

  1. Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, 24341, Republic of Korea

    The-Vinh Tran, Eun-Joo Shin, Ji Won Lee, Youngho Lee & Hyoung-Chun Kim

  2. Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea

    Ji Hoon Jeong

  3. Department of Pharmacology, School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea

    Choon-Gon Jang

  4. Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine and Bio/Molecular Informatics Center, Konkuk University, Seoul, Republic of Korea

    Seung-Yeol Nah

  5. Department of Animal Science, Cornell University, Ithaca, NY, USA

    Xin Gen Lei

  6. Project for Schizophrenia Research, Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

    Kazuya Toriumi

  7. Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Kiyofumi Yamada

  8. Advanced Diagnostic System Research Laboratory, Fujita Health University Graduate School of Health Sciences, Toyoake, Japan

    Toshitaka Nabeshima

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  1. The-Vinh Tran
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The-Vinh Tran and Eun-Joo Shin contributed equally to this work.

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Tran, TV., Shin, EJ., Jeong, J.H. et al. Protective Potential of the Glutathione Peroxidase-1 Gene in Abnormal Behaviors Induced by Phencyclidine in Mice. Mol Neurobiol 54, 7042–7062 (2017). https://doi.org/10.1007/s12035-016-0239-y

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