Molecular Neurobiology

, Volume 54, Issue 9, pp 7042–7062 | Cite as

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 KimEmail author


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.


Phencyclidine Schizophrenia Nrf2 transcription factor Clozapine Prefrontal cortex Glutathione peroxidase-1 knockout mice Glutathione peroxidase-1 overexpressing transgenic mice 



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;

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12035_2016_239_MOESM1_ESM.pdf (487 kb)
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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • The-Vinh Tran
    • 1
  • Eun-Joo Shin
    • 1
  • Ji Hoon Jeong
    • 2
  • Ji Won Lee
    • 1
  • Youngho Lee
    • 1
  • Choon-Gon Jang
    • 3
  • Seung-Yeol Nah
    • 4
  • Xin Gen Lei
    • 5
  • Kazuya Toriumi
    • 6
  • Kiyofumi Yamada
    • 7
  • Toshitaka Nabeshima
    • 8
  • Hyoung-Chun Kim
    • 1
    Email author
  1. 1.Neuropsychopharmacology and Toxicology Program, College of PharmacyKangwon National UniversityChunchonRepublic of Korea
  2. 2.Department of Pharmacology, College of MedicineChung-Ang UniversitySeoulRepublic of Korea
  3. 3.Department of Pharmacology, School of PharmacySungkyunkwan UniversitySuwonRepublic of Korea
  4. 4.Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine and Bio/Molecular Informatics CenterKonkuk UniversitySeoulRepublic of Korea
  5. 5.Department of Animal ScienceCornell UniversityIthacaUSA
  6. 6.Project for Schizophrenia Research, Department of Psychiatry and Behavioral SciencesTokyo Metropolitan Institute of Medical ScienceTokyoJapan
  7. 7.Department of Neuropsychopharmacology and Hospital PharmacyNagoya University Graduate School of MedicineNagoyaJapan
  8. 8.Advanced Diagnostic System Research LaboratoryFujita Health University Graduate School of Health SciencesToyoakeJapan

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