title: Protective Potential of the Glutathione Peroxidase-1 Gene in Abnormal Behaviors Induced by Phencyclidine in Mice.
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.
authors: Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, 24341, Republic of Korea.
authors: The-Vinh
authors: TV
authors: Tran
authors: Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, 24341, Republic of Korea.
authors: Eun-Joo
authors: EJ
authors: Shin
authors: Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea.
authors: Ji Hoon
authors: JH
authors: Jeong
authors: Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, 24341, Republic of Korea.
authors: Ji Won
authors: JW
authors: Lee
authors: Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, 24341, Republic of Korea.
authors: Youngho
authors: Y
authors: Lee
authors: Department of Pharmacology, School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
authors: Choon-Gon
authors: CG
authors: Jang
authors: Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine and Bio/Molecular Informatics Center, Konkuk University, Seoul, Republic of Korea.
authors: Seung-Yeol
authors: SY
authors: Nah
authors: Department of Animal Science, Cornell University, Ithaca, NY, USA.
authors: Xin Gen
authors: XG
authors: Lei
authors: Project for Schizophrenia Research, Department of Psychiatry and Behavioral Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors: Kazuya
authors: K
authors: Toriumi
authors: Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors: Kiyofumi
authors: K
authors: Yamada
authors: Advanced Diagnostic System Research Laboratory, Fujita Health University Graduate School of Health Sciences, Toyoake, Japan.
authors: Toshitaka
authors: T
authors: Nabeshima
authors: Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, 24341, Republic of Korea. kimhc@kangwon.ac.kr.
authors: Hyoung-Chun
authors: HC
authors: Kim
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001522:Behavior, Animal; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D003024:Clozapine / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D005721:Glutamate-Cysteine Ligase / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000235:genetics*; D005980:Glutathione Reductase / Q000378:metabolism; D006220:Haloperidol / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism*; D010084:Oxidation-Reduction; D010622:Phencyclidine; D017397:Prefrontal Cortex / Q000201:enzymology / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012919:Social Behavior; D013482:Superoxide Dismutase / Q000378:metabolism; D013997:Time Factors; D051996:Transcription Factor RelA / Q000378:metabolism; D000094765:Glutathione Peroxidase GPX1
chemical_list: D000975:Antioxidants; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D051996:Transcription Factor RelA; D004247:DNA; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D005980:Glutathione Reductase; C560749:GCLM protein, mouse; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D010622:Phencyclidine; D003024:Clozapine; D006220:Haloperidol; D000094765:Glutathione Peroxidase GPX1; C000722068:Gpx1 protein, mouse
keywords: Clozapine; Glutathione peroxidase-1 knockout mice; Glutathione peroxidase-1 overexpressing transgenic mice; Nrf2 transcription factor; Phencyclidine; Prefrontal cortex; Schizophrenia