<scp>d</scp>‐Amino acid oxidase and serine racemase in human brain: normal distribution and altered expression in schizophrenia

Louise, Verrall; Walker, Mary A.; Rawlings, Nancy B.; Benzel, Isabel; Kew, James N.C.; Harrison, Paul J.; Burnet, Philip W.J.

doi:10.1111/j.1460-9568.2007.05769.x

Cited by 162 publications

(201 citation statements)

References 85 publications

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“…We speculate that the differences in efficacy between these mechanisms may stem from dissimilarities in CNS localization of GlyT1 and DAAO. GlyT1 is heavily expressed in forebrain regions rich in NMDA receptors (Smith et al, 1992), whereas DAAO is expressed primarily in the hindbrain and cerebellum (Verrall et al, 2007). Thus, the high density of GlyT1 in the cortex and the close proximity of GlyT1 to the synapse (Cubelos et al, 2005) may produce a greater increase in NMDA receptor transmission resulting from GlyT1 inhibition, relative to DAAO inhibition.…”

Section: Discussionmentioning

confidence: 98%

The Behavioral and Neurochemical Effects of a Novel d-Amino Acid Oxidase Inhibitor Compound 8 [4H-Thieno [3,2-b]pyrrole-5-carboxylic Acid] and d-Serine

Smith¹,

Uslaner²,

Yao³

et al. 2008

J Pharmacol Exp Ther

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Multiple studies indicate that N-methyl-D-aspartate (NMDA) receptor hypofunction underlies some of the deficits associated with schizophrenia. One approach for improving NMDA receptor function is to enhance occupancy of the glycine modulatory site on the NMDA receptor by increasing the availability of the endogenous coagonists D-serine. Here, we characterized a novel D-amino acid oxidase (DAAO) inhibitor, compound 8 [4H-thieno [3,2-b]pyrrole-5-carboxylic acid] and compared it with D-serine. Compound 8 is a moderately potent inhibitor of human (IC 50 , 145 nM) and rat (IC 50 , 114 nM) DAAO in vitro. In rats, compound 8 (200 mg/kg) decreased kidney DAAO activity by ϳ96% and brain DAAO activity by ϳ80%. This marked decrease in DAAO activity resulted in a significant (p Ͻ 0.001) elevation in both plasma (220% of control) and cerebrospinal fluid (CSF; 175% of control) D-serine concentration. However, compound 8 failed to significantly influence amphetamine-induced psychomotor activity, nucleus accumbens dopamine release, or an MK-801 (dizocilpine maleate)-induced deficit in novel object recognition in rats. In contrast, high doses of D-serine attenuated both amphetamine-induced psychomotor activity and dopamine release and also improved performance in novel object recognition. Behaviorally efficacious doses of D-serine (1280 mg/kg) increased CSF levels of D-serine 40-fold above that achieved by the maximal dose of compound 8. These findings demonstrate that pharmacological inhibition of DAAO significantly increases D-serine concentration in the periphery and central nervous system. However, acute inhibition of DAAO appears not to be sufficient to increase D-serine to concentrations required to produce antipsychotic and cognitive enhancing effects similar to those observed after administration of high doses of exogenous D-serine.

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Section: Discussionmentioning

confidence: 98%

The Behavioral and Neurochemical Effects of a Novel d-Amino Acid Oxidase Inhibitor Compound 8 [4H-Thieno [3,2-b]pyrrole-5-carboxylic Acid] and d-Serine

Smith¹,

Uslaner²,

Yao³

et al. 2008

J Pharmacol Exp Ther

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“…Second, in a 6-week double-blind, placebo-*Address correspondence to this author at the Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, 1-8-1 Inohana, Chiba 260-8670, Japan; Tel: +81-43-226-2147; Fax: +81-43-226-2150; Email: hashimoto@faculty.chiba-u.jp controlled study, Tsai et al [27] reported that D-alanine (100 mg/kg/day) significantly improved schizophrenic symptoms when used as adjunctive to conventional antipsychotic drugs. Third, mRNA expression and activity of D-amino acid oxidase (DAAO), which can metabolize D-alanine, is increased in the postmortem brain of schizophrenic patients [28,29]. Fourth, the G72 gene on the chromosome 13q was significantly associated with schizophrenia [30].…”

Section: Introductionmentioning

confidence: 99%

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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“…6,53-55 Accordingly, increased mRNA expression and activity of the enzyme responsible for the degradation of this D-amino acid, D-amino acid oxidase, have been observed in the postmortem brain of SCZ subjects. 8,56 Recent evidence suggests that the atypical amino acid D-Asp, enriched in the embryo brain, promotes NMDAR-dependent transmission. 38 Consistent with the hypothesis of NMDAR dysfunction in SCZ, [1][2][3][4] we have previously found reduced levels of D-Asp in the postmortem PFC of SCZ patients.…”

Section: Discussionmentioning

confidence: 99%

A Role for D-aspartate Oxidase in Schizophrenia and in Schizophrenia-related Symptoms Induced by Phencyclidine in Mice.

Squillace

Errico

D’Argenio

et al. 2015

European Psychiatry

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Increasing evidence points to a role for dysfunctional glutamate N-methyl-D-aspartate receptor (NMDAR) neurotransmission in schizophrenia. D-aspartate is an atypical amino acid that activates NMDARs through binding to the glutamate site on GluN2 subunits. D-aspartate is present in high amounts in the embryonic brain of mammals and rapidly decreases after birth, due to the activity of the enzyme D-aspartate oxidase (DDO). The agonistic activity exerted by D-aspartate on NMDARs and its neurodevelopmental occurrence make this D-amino acid a potential mediator for some of the NMDAR-related alterations observed in schizophrenia. Consistently, substantial reductions of D-aspartate and NMDA were recently observed in the postmortem prefrontal cortex of schizophrenic patients. Here we show that DDO mRNA expression is increased in prefrontal samples of schizophrenic patients, thus suggesting a plausible molecular event responsible for the D-aspartate imbalance previously described. To investigate whether altered D-aspartate levels can modulate schizophrenia-relevant circuits and behaviors, we also measured the psychotomimetic effects produced by the NMDAR antagonist, phencyclidine, in Ddo knockout mice (Ddo −/ − ), an animal model characterized by tonically increased D-aspartate levels since perinatal life. We show that Ddo − / − mice display a significant reduction in motor hyperactivity and prepulse inhibition deficit induced by phencyclidine, compared with controls. Furthermore, we reveal that increased levels of D-aspartate in Ddo − / − animals can significantly inhibit functional circuits activated by phencyclidine, and affect the development of cortico-hippocampal connectivity networks potentially involved in schizophrenia. Collectively, the present results suggest that altered D-aspartate levels can influence neurodevelopmental brain processes relevant to schizophrenia.

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d‐Amino acid oxidase and serine racemase in human brain: normal distribution and altered expression in schizophrenia

Cited by 162 publications

References 85 publications

The Behavioral and Neurochemical Effects of a Novel d-Amino Acid Oxidase Inhibitor Compound 8 [4H-Thieno [3,2-b]pyrrole-5-carboxylic Acid] and d-Serine

The Behavioral and Neurochemical Effects of a Novel d-Amino Acid Oxidase Inhibitor Compound 8 [4H-Thieno [3,2-b]pyrrole-5-carboxylic Acid] and d-Serine

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

A Role for D-aspartate Oxidase in Schizophrenia and in Schizophrenia-related Symptoms Induced by Phencyclidine in Mice.

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