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- Title
Oral administration of D-alanine in monkeys robustly increases plasma and cerebrospinal fluid levels but experimental D-amino acid oxidase inhibitors had minimal effect.
- Authors
Rojas, Camilo; Alt, Jesse; Ator, Nancy A.; Wilmoth, Heather; Rais, Rana; Hin, Niyada; DeVivo, Michael; Popiolek, Michael; Tsukamoto, Takashi; Slusher, Barbara S.
- Abstract
Hypofunction of the N-methyl-d-aspartate (NMDA) receptor is thought to exacerbate psychosis in patients diagnosed with schizophrenia. Consistent with this hypothesis, D-alanine, a co-agonist at the glycine site of the NMDA receptor, was shown to improve positive and cognitive symptoms when used as add-on therapy for schizophrenia treatment. However, D-alanine had to be administered at high doses (~7 g) to observe clinical effects. One possible reason for the high dose is that D-alanine could be undergoing oxidation by D-amino acid oxidase (DAAO) before it reaches the brain. If this is the case, the dose could be reduced by co-administration of D-alanine with a DAAO inhibitor (DAAOi). Early studies with rodents showed that co-administration of D-alanine with 5-chloro-benzo[d]isoxazol-3-ol (CBIO), a prototype DAAOi, significantly enhanced the levels of extracellular D-alanine in the frontal cortex compared with D-alanine alone. Further, the use of CBIO reduced the dose of D-alanine needed to attenuate prepulse inhibition deficits induced by dizocilpine. The objective of the work reported herein was to confirm the hypothesis that DAAO inhibition can enhance D-alanine exposure in a species closer to humans: non-human primates. We report that while oral D-alanine administration to baboons (10 mg/kg) enhanced D-alanine plasma and CSF levels over 20-fold versus endogenous levels, addition of experimental DAAOi to the regimen exhibited a 2.2-fold enhancement in plasma and no measurable effect on CSF levels. The results provide caution regarding the utility of DAAO inhibition to increase D-amino acid levels as treatment for patients with schizophrenia.
- Subjects
ALANINE; CEREBROSPINAL fluid; METHYL aspartate receptors; AMINO acid oxidase; CHLOROBENZOATES; ALTERNATIVE treatment for schizophrenia; THERAPEUTICS; ANIMAL experimentation; CELL receptors; DOSE-effect relationship in pharmacology; ENZYME inhibitors; HETEROCYCLIC compounds; IMMUNITY; ORAL drug administration; OXIDOREDUCTASES; PRIMATES; RESEARCH funding; CHEMICAL inhibitors; PHARMACODYNAMICS
- Publication
Journal of Psychopharmacology, 2016, Vol 30, Issue 9, p887
- ISSN
0269-8811
- Publication type
journal article
- DOI
10.1177/0269881116652586