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Background and Purpose: Ischemia elicits the rapid release of various amino acid neurotransmitters. A glutamate surge activates N-methyl-d-aspartate (NMDA) glutamate receptors, triggering deleterious processes in neurons. Although glycine is a coagonist of the NMDA receptor, the effect of extracellular glycine concentration on ischemic injury remains controversial. To approach this issue, we examined ischemic injury in mice with genetically altered activities of the glycine cleavage multienzyme system (GCS), which plays a fundamental role in maintaining extracellular glycine concentration., Methods: A mouse line with increased GCS activity (340% of C57BL/6 control mice) was generated by transgenic expression of glycine decarboxylase, a key GCS component (high-GCS mice). Another mouse line with reduced GCS activity (29% of controls) was established by transgenic expression of a dominant-negative mutant of glycine decarboxylase (low-GCS mice). We examined neuronal injury after transient occlusion of the middle cerebral artery in these mice by measuring extracellular amino acid concentrations in microdialysates., Results: High-GCS and low-GCS mice had significantly lower and higher basal concentrations of extracellular glycine than did controls, respectively. In low-GCS mice, the extracellular glycine concentration reached 2-fold of control levels during ischemia, and infarct volume was significantly increased by 69% with respect to controls. In contrast, high-GCS mice had a significantly smaller infarct volume (by 21%). No significant difference was observed in extracellular glutamate concentrations throughout the experiments. An antagonist for the NMDA glycine site, SM-31900, attenuated infarct size, suggesting that glycine operated via the NMDA receptor., Conclusions: There is a direct correlation between ischemic injury and extracellular glycine concentration maintained by the GCS.

Objective: To investigate the effect of vigabatrin (VGB; gamma-vinyl gamma-aminobutyric acid [GABA]), a selective irreversible GABA-transaminase inhibitor, on cerebral metabolic rate for glucose (CMRGlc) and cerebral blood flow (CBF) measured with 18F-fluorodeoxyglucose (FDG) PET and 15O water PET., Background: Antiepileptic drugs (AEDs) reduce CMRGlc to varying degrees. Phenobarbital causes a mean decrease of 30 to 40%. Phenytoin, carbamazepine (CBZ), and valproate (VPA) cause milder reductions in CMRGlc. The combination of VPA with CBZ results in a greater decrease than either drug alone. The effect of novel AEDs on both CBF and CMRGlc has not been studied extensively., Methods: Fourteen patients with refractory complex partial seizures on CBZ monotherapy for 4 weeks were included in the study. All patients had baseline 18F-FDG and 15O water PET studies followed by double-blind randomization to placebo (PLC) or VGB while on continuous CBZ treatment. PET scans were repeated after an interval of 2 months on target dose of VGB (50 mg/kg) or PLC. Quantitative PET data analysis was performed using a region of interest template. Significance was tested with the Wilcoxon rank sum test., Results: No statistically significant difference in age, duration of epilepsy, or CBZ levels was observed in the two patient groups. VGB reduced global CMRGlc by 8.1+/-6.5% and global CBF by 13.1+/-10.4%. The change in CMRGlc was different in patients taking VGB compared with those on PLC (p < 0.04). VGB patients showed regional decreases in both CMRGlc and CBF, particularly in temporal lobes. CSF total GABA increased in the VGB patient group (1.48+/-1.06 versus 4.03+/-4.19 nm/mL). The increase differed from the PLC group (p < 0.03). We found a strong relation between decreased total CSF GABA and increased CMRGlc in the VGB patient group (R2 = 0.82, p < 0.01)., Conclusions: Vigabatrin (VGB) causes mild reductions in both cerebral blood flow (CBF) and cerebral metabolic rate for glucose (CMRGlc) in contrast to other drugs such as barbiturates, which are direct agonists at the gamma-aminobutyric acid-benzodiazepine receptor complex. Conventional AEDs depress CBF and CMRGlc to a greater degree than does VGB. The relatively mild reduction could be due to pre- as well as postsynaptic effects or a use-dependent mechanism.

Carbamazepine was administered to nine patients with manic-depressive illness at doses ranging from 600 to 1600 mg per day, achieving blood levels between 6 and 11 microgram per milliliter. Compared to medication-free values, GABA levels in the cerebrospinal fluid (CSF) were not significantly altered by an average of 30 days' treatment with carbamazepine. These preliminary data do not support a major effect of carbamazepine on brain GABA as reflected in CSF as a mechanism for its anticonvulsant or psychotropic effects.

The mean CSF GABA level in 22 children with infantile spasms was significantly lower than in 35 controls. There was no significant difference between the CSF GABA levels in untreated children and those treated with anticonvulsants, or between uncontrolled and temporarily controlled patients. After treatment with ACTH, CSF GABA levels were lower than before treatment, and seizures disappeared. Brain GABAergic neuronal function may be disturbed in children with infantile spasms, but the decreased CSF GABA level does not directly correlate with the seizures of infantile spasms.

The valid measurement of GABA concentration in the CSF for studying in vivo alterations of central nervous system GABAergic activity requires that consideration be given to several factors that affect GABA concentration. These factors include in vivo variables such as the caudocranial concentration gradient in CSF, age, sex, precursor intake, medications, and physical activity, as well as in vitro alterations that can occur during collection, storage, preparation of sample, and analysis. The influence of these factors can be minimized with proper methodology.

CSF levels of GABA were investigated in a group of Parkinson patients without drug treatment and a group of Parkinson patients under treatment with L-DOPA or anticholinergics. Probenecid results in an elevation of CSF GABA levels in healthy persons. The results indicate a significant decrease of GABA levels in CSF in untreated Parkinson patients. Parkinson patients treated with L-DOPA or anticholinergics show nearly normal CSF GABA levels. This may suggest that the altered GABA function in Parkinson's disease is secondary to changes in the dopamine system.

Evidence suggesting a reduction of cerebral gamma-aminobutyric acid (GABA) neurons in Alzheimer's disease has been reported. To evaluate the possible contribution of GABA system dysfunction to the intellectual decline associated with this disorder, a controlled therapeutic trial of a potent and specific GABA agonist, THIP [4,5,6,7-tetrahydroisoxazolo(5,4,-c)pyridin-3-ol], was undertaken. Six Alzheimer patients with mild to moderately severe dementia and low spinal-fluid GABA levels received THIP at maximum individually tolerated dosage. No significant change in cognitive function could be discerned, despite attainment of dose levels that produced centrally mediated adverse effects similar to those of other GABA agonists. The results support the views that pharmacologic attempts to stimulate central GABA-mediated synaptic function may not confer therapeutic benefit to patients with Alzheimer's disease and that a GABA system deficit may not serve as a critical determinant of the dementia that characterizes this disorder.

The use of cerebrospinal fluid (CSF) analysis for studying in vivo alterations in central neuronal activity requires a relatively sophisticated knowledge of CSF physiology and pathology. Ventriculospinal concentration gradients, circadian rhythms, physical activity, stress, medications, precursor intake, concomitant illness, obstructed CSF circulation, age, and sex alter the baseline neurochemical composition of CSF. Differential probenecid blockade of the egress of acidic monoamine metabolites and cyclic nucleotides from the CSF may complicate interpretations of their accumulations. Degradation of CSF constituents during collection, storage, and analysis may introduce errors in quantification. These sources of CSF variability can be minimized with proper methodolology.

In a patient with a syndrome of continuous muscle fiber activity, peripheral nerve block completely abolished the EMG discharges. Reduction of spontaneous discharges by epidural block and demonstration of a silent period after the H response suggested that the disorder may originate in the spinal cord or ventral roots, sparing inhibitory influences on the alpha-motoneuron to some extent. GABA (gamma-aminobutyric acid) content in CSF was remarkably increased. Therapeutically, dantrolene sodium was as effective as phenytoin or carbamazepine.

Gamma-Aminobutyric acid (GABA) has been implicated in the neurochemistry of epilepsy. Lumbar cerebrospinal fluid (CSF) GABA concentrations determined using an ion-exchange fluorometric assay reflect brain GABA content. The mean lumbar CSF GABA concentration among 21 medicated patients with intractable seizures was significantly lower (p less than 0.001) than that of 20 unmedicated normal volunteers. Patients with generalized tonic-clonic (grand mal) and complex partial (psychomotor) seizures had significantly lower (p less than 0.05) CSF GABA concentrations than those with simple partial (focal sensory/motor) seizures. Although lumbar CSF GABA levels in our seizure patients did not significantly correlate with serum concentrations of phenytoin, phenobarbital, or primidone, additional study of medication-free epileptic patients may be required to evaluate the possibility of anticonvulsant-drug-induced CSF GABA alterations.

Patients with amyotrophic lateral sclerosis have increased levels of the neutrotransmitter norepinephrine in blood and cerebrospinal fluid and depressed levels of the inhibitory neurotransmitter gamma-aminobutyric acid in cerebrospinal fluid. These neurochemical alterations are most marked in patients bedridden with advanced disease, appear interrelated, and lead to cardiovascular alterations in patients with amyotrophic lateral sclerosis.

gamma-Aminobutyric acid (GABA) levels were measured by a radioreceptor assay in cerebrospinal fluid (CSF) specimens from two groups of subjects, one without evidence of neurological or psychiatric disease and one with a variety of neurological disorders for which GABA involvement is not known. Mean GABA concentrations in CSF for the two groups were 117 +/- 10 and 127 +/- 7.4 pmol/ml (means +/- SE for 17 and 41 individuals, respectively). These values were about half of most previously reported mean CSF GABA control values, a fact which may be attributed, at least in part, to a reduction of artifactual increase in GABA levels during sampling, storing, and thawing of CSF samples and GABA analysis. Age and sex had no significant influence on CSF GABA concentration.

We measured levels of gamma-aminobutyric acid (GABA) in the CSF and in the autopsied brain of patients with dialysis encephalopathy. GABA concentrations were low in the CSF of three of five living patients. Mean GABA content was reduced by 30 to 50% in five brain regions (frontal, occipital, and cerebellar cortex, caudate nucleus, and medial dorsal thalamus) in five fatal cases. GABA content was normal in brain regions where GABA is characteristically reduced in Huntington's disease. Choline acetyltransferase activity was diminished (by 25 to 35%) in cerebral cortex of the dialysis encephalopathy patients.

Cerebrospinal fluid gamma-aminobutyric acid (CSF GABA) was analyzed in 151 patients who underwent evaluation for central nervous system disease. CSF GABA was not detected in 19 of these patients, who had no evidence of neurologic disease and who served as controls. GABA was most frequently detected in patients with cerebrovascular disease, and was detected only in Parkinson's syndrome of atherosclerotic origin and dementia of multi-infarct type. CSF GABA was not detected in Alzheimer's disease or Huntington's disease. Patients with grand mal seizures exhibited CSF GABA elevation within 24 hours of the ictus. In patients with multiple sclerosis GABA detection was related to the presence or exacerbation of spinal cord lesions. Further study is necessary to evaluate the significance of elevated CSF GABA in central nervous system disease.