TY - JOUR
T1 - Effects of D-amino acid oxidase inhibitor on the extracellular D-alanine levels and the efficacy of D-alanine on dizocilpine-induced prepulse inhibition deficits in mice
AU - Horio, Mao
AU - Fujita, Yuko
AU - Ishima, Tamaki
AU - Iyo, Masaomi
AU - Ferraris, Dana
AU - Tsukamoto, Takashi
AU - Hashimoto, Kenji
PY - 2009
Y1 - 2009
N2 - D-Alanine, one of D-amino acids present in the mammalian brain, is a selective and potent agonist at the N-methyl-D-aspartate (NMDA) receptors. Like D-serine, D-alanine is reported to be effective in the treatment of schizophrenia. However, orally given D-alanine is metabolized substantially by D-amino acid oxidase (DAAO), diminishing its oral bioavailability. In this study, we studied the effects of oral D-alanine administration with or without the novel DAAO inhibitor, 5-chloro-benzo[d]isoxazol-3-ol (CBIO), on the extracellular D-alanine levels in the brain and on the prepulse inhibition (PPI) deficits after administration of the NMDA receptor antagonist dizocilpine. Co-administration of CBIO (30 mg/kg) with D-alanine (100 mg/kg), but not D-alanine (100 mg/kg) alone, significantly attenuated dizocilpine (0.1 mg/kg)-induced PPI deficits in mice. The in vivo microdialysis study of the conscious and free moving mice revealed that co-administration of CBIO (30 mg/kg) significantly increased extracellular levels of D-alanine in the frontal cortex after oral administration of D-alanine (100 mg/kg). These findings suggest that co-administration of CBIO can increase the bioavailability of D-alanine after oral administration of D-alanine, and that co-administration of CBIO can enhance the efficacy of D-alanine on dizocilpine-induced PPI deficits. Therefore, combination of D-alanine and a DAAO inhibitor such as CBIO offers new therapeutic potential for treatment of schizophrenia.
AB - D-Alanine, one of D-amino acids present in the mammalian brain, is a selective and potent agonist at the N-methyl-D-aspartate (NMDA) receptors. Like D-serine, D-alanine is reported to be effective in the treatment of schizophrenia. However, orally given D-alanine is metabolized substantially by D-amino acid oxidase (DAAO), diminishing its oral bioavailability. In this study, we studied the effects of oral D-alanine administration with or without the novel DAAO inhibitor, 5-chloro-benzo[d]isoxazol-3-ol (CBIO), on the extracellular D-alanine levels in the brain and on the prepulse inhibition (PPI) deficits after administration of the NMDA receptor antagonist dizocilpine. Co-administration of CBIO (30 mg/kg) with D-alanine (100 mg/kg), but not D-alanine (100 mg/kg) alone, significantly attenuated dizocilpine (0.1 mg/kg)-induced PPI deficits in mice. The in vivo microdialysis study of the conscious and free moving mice revealed that co-administration of CBIO (30 mg/kg) significantly increased extracellular levels of D-alanine in the frontal cortex after oral administration of D-alanine (100 mg/kg). These findings suggest that co-administration of CBIO can increase the bioavailability of D-alanine after oral administration of D-alanine, and that co-administration of CBIO can enhance the efficacy of D-alanine on dizocilpine-induced PPI deficits. Therefore, combination of D-alanine and a DAAO inhibitor such as CBIO offers new therapeutic potential for treatment of schizophrenia.
KW - Bioavailability
KW - D-alanine
KW - D-amino acid oxidase
KW - NMDA receptors
KW - Prepulse inhibition
KW - Schizophrenia
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U2 - 10.2174/1874241600902010016
DO - 10.2174/1874241600902010016
M3 - Article
AN - SCOPUS:70349770053
SN - 1874-2416
VL - 2
SP - 16
EP - 21
JO - Open Clinical Chemistry Journal
JF - Open Clinical Chemistry Journal
ER -