title: Targeting of NMDA receptors in new treatments for schizophrenia.
abstract: BACKGROUND
  Abnormalities in glutamatergic neurotransmission mediated by N-methyl-d-aspartate (NMDA) are implicated in the pathophysiology of schizophrenia, although the precise mechanisms are unknown.
  
  
  METHODS
  The author examines the role of the NMDA receptor in schizophrenia, focusing on results from preclinical and clinical studies that support the NMDA receptor hypothesis of schizophrenia. The author first reviewed papers detailing alterations in the levels of endogenous substances such as glutamine, glutamate, d-serine, l-serine, kynurenic acid and glutathione (GSH), all of which can affect NMDA receptor function. Next, the author reviewed clinical findings for glycine, d-serine, d-cycloserine, d-amino acid oxidase inhibitors (e.g., sodium benzoate) and glycine transporter-1 inhibitors (e.g., sarcosine, bitopertin), as potential therapeutic drugs. In addition, the author outlined how oxidative stress associated with decreased levels of the endogenous antioxidant GSH may play a role in the pathophysiology of schizophrenia. Finally, the author reviewed N-acetylcysteine (NAC), a precursor of GSH and an activator of the cystine-glutamate antiporter, as a potential therapeutic drug.
  
  
  CONCLUSIONS
  Given the NMDA receptor hypothesis of schizophrenia, the glycine modulatory site on NMDA receptors is the most attractive therapeutic target for this disease. In addition, both the kynurenine pathway and cystine-glutamate antiporter represent credible potential therapeutic targets for schizophrenia.
authors: Chiba University Center for Forensic Mental Health, Division of Clinical Neuroscience , 1-8-1 Inohana, Chiba 260-8670 , Japan +81 43 226 2517 ; +81 43 226 2561 ; hashimoto@faculty.chiba-u.jp.
authors: Kenji
authors: K
authors: Hashimoto
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D014150:Antipsychotic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015195:Drug Design; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D058990:Molecular Targeted Therapy; D018384:Oxidative Stress; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012559:Schizophrenia / Q000188:drug therapy* / Q000503:physiopathology
chemical_list: D000975:Antioxidants; D014150:Antipsychotic Agents; D016194:Receptors, N-Methyl-D-Aspartate; D005978:Glutathione; D000111:Acetylcysteine
keywords: N-acetylcysteine; NMDA receptor; cystine-glutamate antiporter; d-serine; glutamate; glutathione; glycine; glycine transporter; kynurenic acid; sulforaphane