A CSF and postmortem brain study of D-serine metabolic parameters in schizophrenia.

Clinical trials demonstrated that D-serine administration improves schizophrenia symptoms, raising the possibility that altered levels of endogenous D-serine may contribute to the N-methyl D-aspartate receptor hypofunction thought to play a role in the disease. We hypothesized that cerebro-spinal fluid (CSF) D-serine levels are decreased in the patients due to reduced synthesis and/or increased degradation in brain. We now monitored amino acid levels in CSF from 12 schizophrenia patients vs. 12 controls and in postmortem parietal-cortex from 15 control subjects and 15 each of schizophrenia, major-depression and bipolar patients. In addition, we monitored postmortem brain serine racemase and D-amino acid oxidase protein levels by Western-blot analysis. We found a 25% decrease in D-serine levels and D/L-serine ratio in CSF of schizophrenia patients, while parietal-cortex D-serine was unaltered. Levels of L-serine, L-glutamine and L-glutamate were unaffected. Frontal-cortex (39%) and hippocampal (21%) serine racemase protein levels and hippocampal serine racemase/D-amino acid oxidase ratio (34%) were reduced. Hippocampal D-amino-acid-oxidase protein levels significantly correlated with duration of illness (r=0.6, p=0.019) but not age. D-amino acid oxidase levels in patients with DOI>20 years were 77% significantly higher than in the other patients and controls. Our results suggest that reduced brain serine racemase and elevated D-amino acid oxidase protein levels may contribute to the lower CSF D-serine levels in schizophrenia.

Congenital microcephaly and seizures due to 3-phosphoglycerate dehydrogenase deficiency: outcome of treatment with amino acids.

Congenital microcephaly, intractable seizures and severe psychomotor retardation characterize 3-phosphoglycerate dehydrogenase (3-PGDH) deficiency, a disorder of L-serine biosynthesis. The enzyme defect results in low concentrations of serine and to a variable degree of glycine in plasma and cerebrospinal fluid. Short-term beneficial effects have been reported of oral treatment with the deficient amino acids. In this paper, we report the first follow-up data of amino acid therapy in five patients treated for 3-7.5 years. Different treatment regimes were used, but a favourable response to amino acids was observed in all patients. A major reduction in seizure frequency occurred in all patients; two patients became free of seizures. Amino acids were well tolerated and no adverse effects were documented. A progress of psychomotor development was only observed in one patient, diagnosed early and treated with a high dosage of L-serine. A favourable outcome of 3-PGDH deficiency depends on early diagnosis and treatment.

IV glycine and oral D-cycloserine effects on plasma and CSF amino acids in healthy humans.

BACKGROUND: The amino acid glycine, modulates neurotransmission via actions at GLY-A receptor and GLY-B receptor. The latter are coagonist sites associated with N-Methyl-D-Aspartate (NMDA) glutamate receptors. The central bioavailability of peripherally administered glycine has not been adequately characterized in humans. METHODS: Healthy human subjects were administered either oral D-cycloserine (50 mg or placebo) and intravenous glycine (saline, 100 mg/kg or 200 mg/kg) in random order over 4 test days under double-blind conditions. Cerebrospinal fluid was collected by lumbar puncture performed on the first test day was analyzed to determine amino acid levels. The acoustic startle response was measured on the second test day. RESULTS: Intravenous glycine dose-dependently increased both serum and CSF glycine and serine levels. Neither glycine nor DCS produced any significant effects on behavior, cognition or the acoustic startle response. Neither IV glycine nor DCS were associated with any toxicity. CONCLUSIONS: Thus, peripheral glycine administration raised CSF glycine levels without producing any clear central nervous system effects. Glycine and D-cycloserine did not worsen cognitive test performance and did not induce behavioral symptoms on their own. The possibility that glycine and D-cycloserine enhanced cognitive test performance cannot be excluded given the psychometric limitations of the test battery.

An assessment of progression of brain edema with amino acid levels in cerebrospinal fluid and changes in electroencephalogram in an adult cat model of cold brain injury.

We investigated the relationship between the changes of the electroencephalogram (EEG) and concentration of amino acids (AAs) in cerebrospinal fluid (CSF) using a model of cold brain injury. A cold injury was made over the motor area of anesthetized adult cats (n = 45). The AAs in CSF from cisterna magna and in the blood were assayed by liquid chromatography. Frequency components and spike discharges/100 s in EEG were evaluated. Data were obtained before production of the lesion and every hour for 8 hours after the lesion was made. The AA-levels and EEG after the lesion was made were compared with those obtained in the controls and the sham operation group: S-group (n = 10) which were not significantly different. Glutamate and aspartate were not detected but methionine and serine were detected in the control CSF and S-group. These AAs increased during the first 4 hours (p < 0.05) and decreased thereafter. Significant increases in spike discharge and disappearance of fast wave (p < 0.02), and increase in AAs were concurrently detected. The AAs originated from necrosis in the lesion. During the next 4 hours, increase of phenylalanine, tyrosine, and valine continued (p < 0.05). Slow wave components (p < 0.02) and precursor AAs of neurotransmitters in CSF increased in association with expansion of edema fluid. In conclusion, our findings showed that changes in the concentration of AAs in CSF are useful indices of progression of edema associated with brain contusion.