Determination of free d-aspartic acid, d-serine and d-alanine in the brain of mutant mice lacking d-amino-acid oxidase activity

Morikawa, Akiko; Hamase, Kenji; Inoue, Tomomi; Konno, Ryuichi; Niwa, Akira; Zaitsu, Kiyoshi

doi:10.1016/s0378-4347(01)00131-1

Cited by 139 publications

(118 citation statements)

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“…Because of the hindbrain-shifted distribution of DAO activity, physiological D-serine level in the spinal cord is strictly maintained at ≈1/50th of that in the forebrain (30). In the mSOD1 mice, reduced DAO activity in the reactive astrocytes caused by repressions of its mRNA and protein expression contributes dominantly to the progressive D-serine increase and raises Dserine level by nearly three times at the end stage.…”

Section: Discussionmentioning

confidence: 99%

d -Amino acid oxidase controls motoneuron degeneration through d -serine

Sasabe

Miyoshi

Suzuki

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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180

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder involving an extensive loss of motoneurons. Aberrant excitability of motoneurons has been implicated in the pathogenesis of selective motoneuronal death in ALS. D-Serine, an endogenous coagonist of N-methyl-D-aspartate receptors, exacerbates motoneuronal death and is increased both in patients with sporadic/ familial ALS and in a G93A-SOD1 mouse model of ALS (mSOD1 mouse). More recently, a unique mutation in the D-amino acid oxidase (DAO) gene, encoding a D-serine degrading enzyme, was reported to be associated with classical familial ALS. However, whether DAO affects the motoneuronal phenotype and D-serine increase in ALS remains uncertain. Here, we show that genetic inactivation of DAO in mice reduces the number and size of lower motoneurons with axonal degeneration, and that suppressed DAO activity in reactive astrocytes in the reticulospinal tract, one of the major inputs to the lower motoneurons, predominantly contributes to the D-serine increase in the mSOD1 mouse. The DAO inactivity resulted from expressional down-regulation, which was reversed by inhibitors of a glutamate receptor and MEK, but not by those of inflammatory stimuli. Our findings provide evidence that DAO has a pivotal role in motoneuron degeneration through D-serine regulation and that inactivity of DAO is a common feature between the mSOD1 ALS mouse model and the mutant DAO-associated familial ALS. The therapeutic benefit of reducing D-serine or controlling DAO activity in ALS should be tested in future studies.excitotoxicity | motor neuron disease | neurodegeneration | enzyme histochemistry | 2D-HPLC A myotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by selective loss of motoneurons in the spinal cord and brain leading to fatal paralysis. Approximately 90% of all cases are sporadic, and the remaining cases are inherited. Of inherited cases, 20% are associated with mutations in superoxide dismutase 1 (SOD1), and 10% involves 43-kDa transactivation response DNA-binding protein (TDP-43) and fused in sarcoma/translocated in liposarcoma (FUS/TLS). Despite extensive studies of previously identified ALS-causing genes, the mechanism underlying the selective motoneuronal loss in ALS remains uncertain. Given that the mechanism is at least, in part, common between sporadic and familial ALS, identification of the common pathology is a clue to conquering ALS. Among numerous etiological hypotheses, motoneuronal vulnerability to excitotoxicity is one of the most intensely investigated targets for the treatment of ALS because it is observed in both sporadic and familial ALS with SOD1 mutations (1, 2). For motoneurons, glutamate is the main excitatory transmitter, and excessive motoneuron excitability by glutamate through ionotropic glutamate receptors has been demonstrated.The N-methyl-D-aspartate (NMDA) receptor (NMDAR) is a subtype of the ionotropic glutamate receptors and exhibits relatively higher permeability to the calcium ion (Ca ...

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Section: Discussionmentioning

confidence: 99%

d -Amino acid oxidase controls motoneuron degeneration through d -serine

Sasabe

Miyoshi

Suzuki

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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180

145

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“…In animals, D-alanine, like D-serine, is suggested to be metabolized substantially by DAAO in peripheral organs, diminishing its oral bioavailability [32,33]. These findings prompted us to identify small molecule DAAO inhibitors that can be co-administered with D-amino acids (e.g., Dserine and D-alanine) to minimize its metabolism by DAAO.…”

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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“…As described above, a large amount of D-Ser (ca. 300 nmol/g tissue) is observed in the frontal brain, 7,[17][18][19] and this D-amino acid is now recognized as an endogenous neuromodulator. [8][9][10] D-Asp is widely present in the endocrine tissues (higher than 100 nmol/g tissue) 18,20,21 and its physiological function in regulating hormonal synthesis and secretion has gradually been clarified.…”

Section: Two-dimensional Hplc Determination Of Small Amounts Of D-amimentioning

confidence: 99%

“…D-Ser is reported to be widely present in the central nervous system. 7,[17][18][19] Especially, large amounts of D-Ser were observed in the frontal brain areas, such as the cerebrum, hippocampus, striatum and olfactory lobe (100 -300 nmol/g tissue). On the other hand, the amounts in the cerebellum, medulla oblongata and spinal cord are extremely low.…”

Section: Tissue Distribution Of D-alanine In Rodentsmentioning

confidence: 99%

“…To obtain fundamental knowledge of its function, we have investigated the tissue distribution of D-Ala in the brain and periphery of rodents. 18,19,31,36,41 Figure 4(A) shows the distribution of D-Ala in the entire body of rats (22 tissues and serum). Among all the tested tissues, the highest amount of D-Ala was observed in the anterior pituitary gland, and the second highest amount was observed in the pancreas.…”

Section: Tissue Distribution Of D-alanine In Rodentsmentioning

confidence: 99%

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Analysis of Small Amounts of d-Amino Acids and the Study of Their Physiological Functions in Mammals

et al. 2009

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D-Amino acids, the enantiomers of L-amino acids, are candidates to be novel physiologically active substances and the biomarkers in mammals. However, the amounts of D-amino acids in the tissues and physiological fluids are extremely small in most cases, and sensitive and selective analytical methods are needed for their determination. In the present manuscript, we review the analytical technologies including our recent advances for the determinations of small amounts of D-amino acids in mammals and the applications to clarify their physiological meanings.

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Determination of free d-aspartic acid, d-serine and d-alanine in the brain of mutant mice lacking d-amino-acid oxidase activity

Cited by 139 publications

References 22 publications

d -Amino acid oxidase controls motoneuron degeneration through d -serine

d -Amino acid oxidase controls motoneuron degeneration through 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

Analysis of Small Amounts of d-Amino Acids and the Study of Their Physiological Functions in Mammals

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