Oral administration of D-alanine in monkeys robustly increases plasma and cerebrospinal fluid levels but experimental D-amino acid oxidase inhibitors had minimal effect.
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.
Johns Hopkins Drug Discovery Program, Johns Hopkins School of Medicine, Baltimore, MD, USA Department of Comparative Medicine and Molecular Pathobiology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
Camilo
C
Rojas
Johns Hopkins Drug Discovery Program, Johns Hopkins School of Medicine, Baltimore, MD, USA.
Jesse
J
Alt
Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA.
Nancy A
NA
Ator
Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA.
Heather
H
Wilmoth
Johns Hopkins Drug Discovery Program, Johns Hopkins School of Medicine, Baltimore, MD, USA.
Rana
R
Rais
Johns Hopkins Drug Discovery Program, Johns Hopkins School of Medicine, Baltimore, MD, USA.
Niyada
N
Hin
Pfizer Neuroscience Research Unit, Cambridge, MA, USA.
Michael
M
DeVivo
Pfizer Neuroscience Research Unit, Cambridge, MA, USA.
Michael
M
Popiolek
Johns Hopkins Drug Discovery Program, Johns Hopkins School of Medicine, Baltimore, MD, USA Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
Takashi
T
Tsukamoto
Johns Hopkins Drug Discovery Program, Johns Hopkins School of Medicine, Baltimore, MD, USA Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA bslusher@jhmi.edu.
Barbara S
BS
Slusher
D000284:Administration, Oral; D000409:Alanine / Q000008:administration & dosage* / Q000097:blood / Q000134:cerebrospinal fluid; D000818:Animals; D003605:D-Amino-Acid Oxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007555:Isoxazoles / Q000494:pharmacology; D008297:Male; D010215:Papio; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013045:Species Specificity
C531067:5-chlorobenzo(d)isoxazol-3-ol; D004791:Enzyme Inhibitors; D007555:Isoxazoles; D016194:Receptors, N-Methyl-D-Aspartate; D003605:D-Amino-Acid Oxidase; D000409:Alanine
D-amino acid oxidase inhibition; NMDA receptor; Schizophrenia