Pathological Implications of Oxidative Stress in Patients and Animal Models with Schizophrenia: The Role of Epidermal Growth Factor Receptor Signaling

  • Tadasato Nagano
  • Makoto Mizuno
  • Keisuke Morita
  • Hiroyuki Nawa
Part of the Current Topics in Behavioral Neurosciences book series (CTBN, volume 29)


Proinflammatory cytokines perturb brain development and neurotransmission and are implicated in various psychiatric diseases, such as schizophrenia and depression. These cytokines often induce the production of reactive oxygen species (ROS) and regulate not only cell survival and proliferation but also inflammatory process and neurotransmission. Under physiological conditions, ROS are moderately produced in mitochondria but are rapidly scavenged by reducing agents in cells. However, brain injury, ischemia, infection, or seizure-like neural activities induce inflammatory cytokines and trigger the production of excessive amounts of ROS, leading to abnormal brain functions and psychiatric symptoms. Protein phosphatases, which are involved in the basal silencing of cytokine receptor activation, are the major targets of ROS. Consistent with this, several ROS scavengers, such as polyphenols and unsaturated fatty acids, attenuate both cytokine signaling and psychiatric abnormalities. In this review, we list the inducers, producers, targets, and scavengers of ROS in the brain and discuss the interaction between ROS and cytokine signaling implicated in schizophrenia and its animal models. In particular, we present an animal model of schizophrenia established by perinatal exposure to epidermal growth factor and illustrate the pathological role of ROS and antipsychotic actions of ROS scavengers, such as emodin and edaravone.


Psychosis Epidermal growth factor Reactive oxygen species Radical scavenger Edaravone Emodin Trolox 



We are grateful to Tomoyuki Sugano and Akira Yarimizu for their technical assistances. The authors’ original work was partly supported by Grants-in-Aid for Scientific Research on Innovative Areas and for Challenging Exploratory Research (No. 24116010, No. 21659273) and a grant for Promotion of Niigata University Research Projects. Human recombinant EGF was kindly provided by Higeta Shoyu Co. Ltd. Except this gift, all the authors have no conflicts of interest to declare.


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Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Tadasato Nagano
    • 1
  • Makoto Mizuno
    • 2
  • Keisuke Morita
    • 3
  • Hiroyuki Nawa
    • 3
  1. 1.Faculty of Human Life StudiesUniversity of Niigata PrefectureHigashi-ku, NiigataJapan
  2. 2.Aichi Human Service CenterInstitute for Developmental ResearchKasugai, AichiJapan
  3. 3.Department of Molecular Biology, Brain Research InstituteNiigata UniversityNiigataJapan

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