Lack of Effect of Sodium Benzoate at Reported Clinical Therapeutic Concentration on D-Alanine Metabolism in Dogs

Cognitive decline and psychosis have been hypothesized to be mediated by N-methyl-D-aspartate receptor (NMDAR) hypofunction. Consistent with this hypothesis, chronic treatment with D-alanine, a coagonist at the glycine site of the NMDAR, leads to an improvement of positive and cognitive symptoms in schizophrenic patients. D-alanine is oxidized by D-amino acid oxidase (DAAO); thus, an inhibitor of DAAO would be expected to enhance D-alanine levels and likewise lead to desirable clinical outcomes. Sodium benzoate, on the basis of D-amino acid inhibition, was observed to display beneficial clinical effects in schizophrenic and Alzheimer's patients. However, in the clinical pilot studies using sodium benzoate, D-amino acids were not quantified to verify that sodium benzoate's efficacy was mediated through DAAO inhibition. In this study, D-alanine content was monitored in cerebral spinal fluid (CSF) of dogs treated with daily injections of D-alanine (30 mg/kg) alone and in combination with sodium benzoate (30 mg/kg) for seven consecutive days. We reasoned that the cerebral spinal fluid D-alanine quantity is reflective of the brain D-alanine levels and it would increase as a consequence of DAAO inhibition with sodium benzoate. We found that D-alanine treatment lead to maximal concentration of 7.51 mu M CSF D-alanine level; however, coadministration of sodium benzoate and D-alanine did not change CSF D-alanine level beyond that of D-alanine treatment alone. As a consequence, we conclude that clinical efficacy associated with chronic administration of sodium benzoate in schizophrenic and Alzheimer's patients is likely not mediated through inhibition of DAAO.