Co-Administration of a D-Amino Acid Oxidase Inhibitor Potentiates the Efficacy of D-Serine in Attenuating Prepulse Inhibition Deficits After Administration of Dizocilpine

Hashimoto, Kenji; Fujita, Yūkō; Horio, Mao; Kunitachi, Shinsui; Iyo, Masaomi; Ferraris, Dana; Tsukamoto, Takashi

doi:10.1016/j.biopsych.2009.01.002

Cited by 120 publications

(91 citation statements)

References 18 publications

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“…2). Treatment with CBIO (30 mg/kg) alone was no effect on dizocilpine-induced PPI deficits in mice, as reported previously [35].…”

Section: Discussionsupporting

confidence: 88%

“…The dose (0.1 mg/kg) of dizocilpine was selected because this dose caused PPI deficits in mice as reported previously [35,38]. D-Alanine (100, 300 or 1000 mg/kg, Wako Pure Chemical Industries, Ltd., Tokyo, Japan), dissolved in 0.5% carbomethoxycellulose (CMC: Wako Pure Chemical Co., Tokyo, Japan), was administered orally in a volume of 10 ml/kg.…”

Section: Drugs and Drug Administrationmentioning

confidence: 99%

“…D-Alanine (100, 300 or 1000 mg/kg, Wako Pure Chemical Industries, Ltd., Tokyo, Japan), dissolved in 0.5% carbomethoxycellulose (CMC: Wako Pure Chemical Co., Tokyo, Japan), was administered orally in a volume of 10 ml/kg. CBIO (30 mg/kg) [34,35] was suspended in 0.5% CMC, was administered orally in a volume of 10 ml/kg. The other chemicals used were purchased from commercial sources.…”

Section: Drugs and Drug Administrationmentioning

confidence: 99%

“…D-Alanine (100, 300 or 1000 mg/kg) with or without CBIO (30 mg/kg) [34,35], or vehicle (0.5% CMC) (10 ml/kg) were administered 60 min (including 10-min acclimation period) before the machine records, and dizocilpine (0.1 mg/kg) or saline (10 ml/kg) was administered s.c. 10 min (including 10-min acclimation period) before. The PPI test lasted 20 min in total.…”

Section: Measurement Of Acoustic Startle Reactivity and Prepulse Inhimentioning

confidence: 99%

“…Recently, we reported that oral administration of the novel and potent DAAO inhibitor, 5-chloro-benzo[d]isoxazol-3-ol (CBIO) (Fig. 1), in conjunction with D-serine could enhance the plasma and brain levels of D-serine in rats and mice compared to the oral administration of D-serine alone [34,35]. The IC 50 value of CBIO for DAAO was 188 nM [34].…”

Section: Introductionmentioning

confidence: 99%

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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

Horio¹,

Fujita²,

Ishima³

et al. 2009

TOCCHEMJ

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D-Alanine, one of D-amino acids present in the mammalian brain, is a selective and potent agonist at the Nmethyl-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.

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“…2). Treatment with CBIO (30 mg/kg) alone was no effect on dizocilpine-induced PPI deficits in mice, as reported previously [35].…”

Section: Discussionsupporting

confidence: 88%

Section: Drugs and Drug Administrationmentioning

confidence: 99%

Section: Drugs and Drug Administrationmentioning

confidence: 99%

Section: Measurement Of Acoustic Startle Reactivity and Prepulse Inhimentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Horio¹,

Fujita²,

Ishima³

et al. 2009

TOCCHEMJ

Self Cite

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Add-on Treatment of Benzoate for Schizophrenia

et al. 2013

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In addition to dopaminergic hyperactivity, hypofunction of the N-methyl-D-aspartate receptor (NMDAR) has an important role in the pathophysiology of schizophrenia. Enhancing NMDAR-mediated neurotransmission is considered a novel treatment approach. To date, several trials on adjuvant NMDA-enhancing agents have revealed beneficial, but limited, efficacy for positive and negative symptoms and cognition. Another method to enhance NMDA function is to raise the levels of D-amino acids by blocking their metabolism. Sodium benzoate is a D-amino acid oxidase inhibitor.OBJECTIVE To examine the clinical and cognitive efficacy and safety of add-on treatment of sodium benzoate for schizophrenia. DESIGN, SETTING, AND PARTICIPANTSA randomized, double-blind, placebo-controlled trial in 2 major medical centers in Taiwan composed of 52 patients with chronic schizophrenia who had been stabilized with antipsychotic medications for 3 months or longer.INTERVENTIONS Six weeks of add-on treatment of 1 g/d of sodium benzoate or placebo. MAIN OUTCOMES AND MEASURESThe primary outcome measure was the Positive and Negative Syndrome Scale (PANSS) total score. Clinical efficacy and adverse effects were assessed biweekly. Cognitive functions were measured before and after the add-on treatment.RESULTS Benzoate produced a 21% improvement in PANSS total score and large effect sizes (range, 1.16-1.69) in the PANSS total and subscales, Scales for the Assessment of Negative Symptoms-20 items, Global Assessment of Function, Quality of Life Scale and Clinical Global Impression and improvement in the neurocognition subtests as recommended by the National Institute of Mental Health's Measurement and Treatment Research to Improve Cognition in Schizophrenia initiative, including the domains of processing speed and visual learning. Benzoate was well tolerated without significant adverse effects. CONCLUSIONS AND RELEVANCEBenzoate adjunctive therapy significantly improved a variety of symptom domains and neurocognition in patients with chronic schizophrenia. The preliminary results show promise for D-amino acid oxidase inhibition as a novel approach for new drug development for schizophrenia. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT 00960219

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D‐Serine metabolism in C6 glioma cells: Involvement of alanine‐serine‐cysteine transporter (ASCT2) and serine racemase (SRR) but not D‐amino acid oxidase (DAO)

Sikka

Martin

Cockayne

et al. 2010

J of Neuroscience Research

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D-serine is an endogenous N-methyl-D-aspartate (NMDA) receptor coagonist. It is synthesized from L-serine by serine racemase (SRR), but many aspects of its metabolism remain unclear, especially in the forebrain, which lacks active D-amino acid oxidase (DAO), the major D-serine degradative enzyme. Candidate mechanisms include SRR operating in α,β-eliminase mode (converting D-serine to pyruvate) and regulation by serine transport, in which the alanine-serine-cysteine transporter ASCT2 is implicated. Here we report studies in C6 glioma cells, which “simulate” the forebrain, in that the cells express SRR and ASCT2 but lack DAO activity. We measured D-serine, ASCT2, SRR, and DAO expression and DAO activity in two situations: after incubation of cells for 48 hr with serine isomers and after increased or decreased SRR expression by transfection and RNA interference, respectively. Incubation with serine enantiomers decreased [3H]D-serine uptake and ASCT2 mRNA and increased SRR immunoreactivity but did not alter DAO immunoreactivity, and DAO activity remained undetectable. SRR overexpression increased D-serine and pyruvate and decreased [3H]D-serine uptake and ASCT2 mRNA but did not affect DAO. SRR knockdown did not alter any of the parameters. Our data suggest that D-serine transport mediated by ASCT2 contributes prominently to D-serine homeostasis when DAO activity is absent. The factors regulating D-serine are important for understanding normal NMDA receptor function and because D-serine, along with DAO and SRR, is implicated in the pathogenesis and treatment of schizophrenia. © 2010 Wiley-Liss, Inc.

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Co-Administration of a D-Amino Acid Oxidase Inhibitor Potentiates the Efficacy of D-Serine in Attenuating Prepulse Inhibition Deficits After Administration of Dizocilpine

Cited by 120 publications

References 18 publications

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

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

Add-on Treatment of Benzoate for Schizophrenia

D‐Serine metabolism in C6 glioma cells: Involvement of alanine‐serine‐cysteine transporter (ASCT2) and serine racemase (SRR) but not D‐amino acid oxidase (DAO)

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