Effects of Vigabatrin (γ-vinyl GAB A) on Neuro transmission-Related Amino Acids and on GAB A nd Benzodiazepine Receptor Binding in Rats

The effect of 12-day intraperitoneal i.p. administration of vigabatrin (GVG, gamma-vinyl GABA) to rats on the neurotransmission-related amino acids in various brain regions (cortex, hippocampus, cerebellum, and spinal cord), cisternal fluid (CSF) and blood was studied. Results showed that GVG administration increased the levels of GABA in cortical and subcortical regions of the brain and CSF without affecting GABA and benzodiazepine receptors in the cortex. In addition, a dose-dependent decrease was noted in the concentration of glutamate in the hippocampus and in the concentrations of aspartate and glutamine in the cortex, hippocampus, and cerebellum. The changes in the levels of amino acids in the brain, except for that of GABA, were not reflected in the CSF, however, and the levels of amino acids in discrete brain regions did not show any correlation with those in the serum or in the CSF. The results suggest that GVG administration might suppress development and spread of seizures not only by elevating the level of the inhibitory amino acid GABA, but also by decreasing the levels of excitatory amino acids in the brain.     

Schizophrenia, tardive dyskinesia, and brain GABA

We measured the contents of gamma-aminobutyric acid (GABA) and of other amino compounds in five regions of autopsied brain from 18 patients with schizophrenia and from a large group of adult control subjects dying without any neurological or psychiatric disorder. In addition, concentrations of GABA were measured in the cerebrospinal fluid (CSF) of living schizophrenic patients and control subjects. No deficiency of GABA was found in the frontal cortex, caudate nucleus, putamen, nucleus accumbens, or medial dorsal thalamus of patients dying with schizophrenia, nor were GABA concentrations low in the CSF of living schizophrenic patients. These results do not confirm our earlier report of low levels of GABA in the nucleus accumbens and thalamus of some schizophrenic patients. We do not find neurochemical evidence favoring an involvement of GABAergic neuronal hypofunction in the etiology either of schizophrenia or of neuroleptic-induced tardive dyskinesia.     

Dominantly inherited apathy, central hypoventilation, and Parkinson's syndrome: clinical, biochemical, and neuropathologic studies of 2 new cases

We describe 2 new patients from a family in which 10 persons in 3 successive generations had a dominant neuropsychiatric disorder characterized by apathy, central hypoventilation, and parkinsonism. Neuropathologically, both patients showed severe neuronal loss and reactive gliosis in the substantia nigra. Neurochemical studies showed a marked depletion of dopamine in substantia nigra, putamen, and caudate nucleus, as well as reduction in serotonin content in the substantia nigra. Glutamate contents were low in frontal cortex and thalamus, and gamma-aminobutyric acid (GABA) contents were low in thalamus and substantia nigra of both patients. In addition, phosphoethanolamine contents were reduced in all brain regions of both patients, especially in the substantia nigra. One patient with severe symptoms had low levels of homovanillic acid, 5-hydroxyindoleacetic acid, and GABA in his CSF repeatedly for 3 years before death (aged 58), while the 2nd patient died (aged 51) of an unrelated cause before developing any symptoms of the familial disorder. Because brain deficiencies of multiple neurotransmitters appear to be involved, this disorder is unlikely to respond to treatment; however, neurochemical studies of CSF may make presymptomatic diagnosis feasible.     

gamma-Aminobutyric acid (GABA) and sepsis-related encephalopathy

In order to determine whether disturbances in GABA homeostasis might play a role in the pathogenesis of sepsis-related encephalopathy, serum and brain tissue GABA concentrations from six areas of the brain (cortex, diencephalon, striatum, hippocampus, midbrain, and pons-medulla) were determined in a rat model of bacterial sepsis (cecal ligation and perforation). The results were compared to those obtained from sham operated control animals. All septic animals demonstrated clinical signs of encephalopathy and had elevated serum GABA levels (0.92 +/- 0.3 uM versus 0.48 +/- 0.15 in controls, p less than 0.01). GABA content in the specific subcompartments of the brain, however, were similar in the two groups. These results indicate that although serum GABA levels are elevated during sepsis, GABA is unlikely to play an important role in the pathogenesis of sepsis-related encephalopathy.     

Cerebrospinal fluid content of diazepam binding inhibitor in chronic hepatic encephalopathy

The neuropeptide diazepam binding inhibitor (DBI) is an endogeneous allosteric modulator of gamma-aminobutyric acid (GABA) receptors at the benzodiazepine recognition site. Recent theories on the neurochemical cause for hepatic encephalopathy have implicated activation of inhibitory neurotransmitter GABA systems. In 20 patients with hepatic disease, blood and cerebrospinal fluid (CSF) levels of ammonia and amino acids were measured. As in previous studies there was a selective elevation of CSF amino acids as well as a correlation between CSF glutamine levels and encephalopathy. CSF DBI levels were maximally elevated 5-fold in patients with hepatic encephalopathy, but they were normal in those patients with liver disease not associated with changes in mental status and in patients with nonhepatic encephalopathy. Levels of DBI correlated with the clinical staging of hepatic encephalopathy. These data suggest that DBI may participate in the modulation of cerebral function in hepatic encephalopathy.     

Preliminary evidence of low cortical GABA levels in localized 1H-MR spectra of alcohol-dependent and hepatic encephalopathy patients.

OBJECTIVE: The aim of the study was to compare levels of neuroactive amino acids in the cerebral cortex of healthy subjects, recently detoxified alcohol-dependent patients, and patients with hepatic encephalopathy. METHOD: Metabolite levels were measured in the occipital cortex by using spatially localized 1H-MRS. Five recently detoxified alcohol-dependent and five hepatic encephalopathy patients with alcohol and non-alcohol-related disease were compared with 10 healthy subjects. RESULTS: The combined level of gamma-aminobutyric acid (GABA) plus homocarnosine was lower in the alcohol-dependent and hepatic encephalopathy patients than in the healthy subjects. CONCLUSIONS: The findings suggest that GABA-ergic systems are altered in both alcohol-dependent and hepatic encephalopathy patients.     

抗GABA(B)R脑炎临床、脑电图及随访研究

目的分析抗GABA(B)R脑炎临床,影像学及脑电图(EEG)特征。方法 5例血清和脑脊液(CSF)抗GABA(B)R抗体阳性的抗GABA(B)R脑炎,分析CSF白细胞数、头颅磁共振(MRI)、24h长程视频脑电图(VEEG)和预后特点。结果 5例抗GABA(B)R脑炎中,精神行为异常2例,意识障碍2例,CSF白细胞数增高4例,癫痫发作5例,其中癫痫持续状态4例(80%)。24h VEEG监测3例各导可见多量阵发性长程持续5~30s、4~6Hzθ节律,并前额、额、前颞可见尖波或复合性慢波。未见异常2例。头颅MRI异常1例,累及海马、额叶皮质。呼吸衰竭1例,行气管插管,未用呼吸机辅助呼吸。1例合并血和CSF抗Hu抗体阳性并发肺癌。随访半年死亡3例(60%),完全正常2例(40%)。结论抗GABA(B)R脑炎是以癫痫发作为特点的疾病,本组5例患者均早期出现严重的癫痫发作。预后与癫痫的严重程度和是否合并肿瘤有关。     

Effects of subchronic treatment of methamphetamine haloperidol on the rat brain levels of GABA, glutamate and aspartate

Centrally active amino acids (GABA, glutamate, aspartate) were assayed enzyme-fluorometrically in five brain regions of the rat after a 16-day administration of methamphetamine (2.5 mg/kg, i.p.) and haloperidol (2.5 mg/kg, i.p.), or both agents together. Methamphetamine caused no statistically-significant changes in the GABA contents in any brain areas, a significant decrease in the glutamate content of the striatum, hippocampus and midbrain and an increase in the aspartate content of the hypothalamus. Haloperidol treatment resulted in no changes in the GABA content, a significant decrease in the glutamate content of the striatum and a significant increase in the aspartate content in the frontal cortex. The treatment with both agents caused a significant decrease in the GABA content of the hypothalamus. The combined administration normalized a lowering of the glutamate levels in the striatum caused by methamphetamine and haloperidol, respectively, and increased the level of aspartate in the hypothalamus caused by methamphetamine and in the frontal cortex caused by haloperidol.     

Effects of Subchronic Treatment of Methamphetamine Haloperidol on the Rat Brain Levels of GABA, Glutamate and Aspartate

Abstract: Centrally active amino acids (GABA, glutamate, asparate) were assayed enzyme-fluorometrically in five brain regions of the rat after a 16-day administration of methamphetamine (2.5 mg/kg, i.p.) and haloperidol (2.5 mg/kg, i.p.), or both agents together. Methamphetamine caused no statistically-significant changes in the GABA contents in any brain areas, a significant decrease in the glutamate content of the striatum, hippocampus and midbrain and an increase in the aspartate content of the hypothalamus. Haloperidol treatment resulted in no changes in the GABA content, a significant decrease in the glutamate content of the striatum and a significant increase in the aspartate content in the frontal cortex. The treatment with both agents caused a significant decrease in the GABA content of the hypothalamus. The combined administration normalized a lowering of the glutamate levels in the striatum caused by methamphetamine and haloperidol, respectively, and increased the level of aspartate in the hypothalamus caused by methamphetamine and in the frontal cortex caused by haloperidol.     

Impaired brain GABA in focal dystonia.

Patients with task-specific dystonia (writer's cramp) have impaired cortical inhibition likely arising from striatal dysfunction. However, the levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in the brains of these patients are not known. In this study, we evaluated 7 patients with right-sided focal, task-specific dystonia and 17 normal control subjects. A novel method using two-dimensional J-resolved magnetic resonance spectroscopy revealed that brain GABA levels are decreased in specific brain regions of the focal dystonia patients compared to normal controls. A significant decrease in GABA level was observed in the sensorimotor cortex and lentiform nuclei contralateral to the affected hand, while there was only a small nonsignificant decrease in the ipsilateral sensorimotor cortex and lentiform nuclei. GABA changes in the posterior occipital region of patients were not significant. The impaired cortical GABA level correlates with prior physiologic studies showing reduced intracortical inhibition. Reduced GABA in the striatum is consistent with striatal dysfunction since GABA is a principal neurotransmitter in that region. The reduction of brain GABA in dystonia patients may explain the clinical symptomatology of focal dystonia. Magnetic resonance spectroscopy may be a useful noninvasive tool in the evaluation of regional brain GABA changes and in monitoring the effects of various therapies.     

Brain benzodiazepine receptor binding and purine concentration in Lesch-Nyhan syndrome

Benzodiazepine receptor [( 3H]flunitrazepam) binding and purine concentration were measured in autopsied cerebral cortex of 4 patients who died with Lesch-Nyhan syndrome. Receptor density was normal in all 4 regions of Lesch-Nyhan cortex examined. However, an enhancement of benzodiazepine receptor affinity (25% reduction in Kd) was found in well-washed parietal and occipital cortex homogenates. Maximal gamma-aminobutyric acid (GABA) stimulation of [3H]flunitrazepam binding was normal in temporal, parietal and occipital cortex but markedly reduced (by 50-80%) in frontal cortex. Increased sensitivity to hypoxanthine inhibition (30% reduction in Ki) was also observed in parietal cortex. The concentrations of the purines hypoxanthine, xanthine and inosine in Lesch-Nyhan parietal cortex were about twice the values measured in control material matched for postmortem time. We suggest that the above-normal concentrations of purines estimated to be present in Lesch-Nyhan brain may be sufficient to significantly affect the ability of the benzodiazepine receptor to modulate GABA-mediated brain mechanisms.     

Normal prefrontal gamma-aminobutyric acid levels in remitted depressed subjects determined by proton magnetic resonance spectroscopy.

BACKGROUND: There is growing evidence that the brain gamma-aminobutyric acid (GABA) system is involved in depression. Lowered plasma GABA levels were identified as a traitlike abnormality found in patients with remitted unipolar depression and in healthy first-degree relatives of patients with unipolar depression. Major depressive disorder has been associated with neuroimaging and neuropathological abnormalities in the prefrontal cortex by various types of evidence. As a result, the current study investigates whether GABA levels in the prefrontal cortex differ between unmedicated subjects with remitted major depressive disorder (rMDD) and healthy control subjects. METHODS: Sixteen rMDD subjects and 15 healthy control subjects underwent magnetic resonance spectroscopy. We used a 3 Tesla GE whole body scanner with a homogeneous resonator coil providing a homogenous radiofrequency field and capability of obtaining measurement from the prefrontal cortex. Gamma-aminobutyric acid levels were measured in the ventromedial prefrontal cortex and dorsolateral/anterior medial prefrontal cortex. RESULTS: There was no difference in GABA concentrations between rMDD subjects and healthy control subjects in the ventromedial prefrontal cortex and dorsolateral/anterior medial prefrontal cortex. Secondary analyses provided preliminary evidence for a negative relationship between the glutamate/glutamine (Glx)/GABA ratio and age of onset of major depression in the ventromedial prefrontal cortex. CONCLUSIONS: This result suggests that GABA levels in the prefrontal cortex, if found to be reduced in symptomatic depression, do not represent a persistent characteristic of major depression. Further research is needed to determine brain GABA levels in different brain regions, in different stages of depressive illness, and in different depressive subtypes.     

Brain gamma-aminobutyric acid changes in stiff-person syndrome

BACKGROUND: Patients with stiff-person syndrome (SPS) have circulating antibodies against glutamic acid decarboxylase, the rate-limiting enzyme responsible for the synthesis of gamma-aminobutyric acid (GABA). Although the patients' symptoms of stiffness and unexpected spasms can be explained on the basis of reduced or impaired inhibitory neurotransmitters, such as GABA, it is unclear whether the level of GABA in the brains of these patients is reduced and, if so, whether the reduction is due to anti-glutamic acid decarboxylase antibodies. OBJECTIVE: To measure GABA levels in the brains of patients with SPS. DESIGN: Prospective case-control study. SETTING: National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Md. PATIENTS: Eight patients with SPS with high titers of circulating anti-glutamic acid decarboxylase antibodies and typical clinical symptoms of SPS and 16 control subjects. MAIN OUTCOME MEASURES: Results of brain magnetic resonance imaging and magnetic resonance spectroscopy, which measures GABA levels in specific brain regions. RESULTS: No abnormalities were noted on brain magnetic resonance images. A prominent and significant decrease in GABA level was, however, observed in the sensorimotor cortex and a smaller decrease in the posterior occipital cortex but not in the cingulate cortex or pons. CONCLUSIONS: The reduction of brain GABA in patients with SPS supports the clinical symptoms and indicates that the inhibitory GABAergic pathways are involved in the disease. Regardless of the responsible autoantigens, in SPS autoantibodies block the function of GABAergic neurons and interfere with the synthesis of GABA but do not cause structural changes in the brain.     

Neurotransmitter changes in Alzheimer's disease: implications to diagnostics and therapy

Changes in the cholinergic, serotonergic, noradrenergic, dopaminergic, GABAergic and somatostatinergic neurons were investigated to determine their roles in Alzheimer's disease (AD). Markers for these systems were analyzed in postmortem brain samples from 20 patients with AD and 14 controls. In the CSF study, markers for the cholinergic neurons (choline esterase, ChE) and for the somatostatinergic neurons (somatostatin-like immunoreactivity, SLI) were assayed for 93 and 75 probable AD patients and 29 and 19 controls, respectively. Activity of choline acetyltransferase (CAT) was decreased by 50-85% in four cortical areas and hippocampus in patients with AD, but not in other areas of the brain, indicating a profound deficit in the function of cholinergic projections ascending from the nucleus basalis to the cerebral cortex and hippocampus in AD. Muscarinic receptor binding was reduced by 18% in the frontal cortex but not in other areas of the brain in AD. Serotonin (5HT) concentrations were reduced (by 21-37%) in hippocampal cortex, hippocampus and striatum; and 5HT metabolite levels were lowered (by 39-54%) in three cortical areas, thalamus and putamen in AD patients. Concentrations of noradrenaline (NA) were reduced (18-36%) in frontal and temporal cortex and putamen. These data imply that serotonergic and noradrenergic projections are also affected in AD but less than the cholinergic neurons. Dopamine (DA) concentrations in AD patients were reduced by 18-27% in temporal and hippocampal cortex and hippocampus, while HVA, the metabolite of DA, was unaltered. Glutamic acid decarboxylase activity was not altered in AD. SLI was decreased (28-42%) in frontal, temporal and parietal cortex, but not in thalamus and putamen in patients with AD. Frontal tangle scores correlated most strongly with cortical CAT activity reduction and less so with decreases of 5HT, NA and DA, indicating a closer correlation with the cholinergic changes and severity of AD than with other neurotransmitter deficiencies. ChE activity and SLI were reduced by 20% and 35%, respectively, in CSF of the whole group of AD patients as compared to the controls. Comparison of CSF findings between four subgroups of dementia severity indicated that the SLI was already reduced in the group of mildest AD (-31%), while ChE activity was not. Although ChE activity in CSF declined in relation to dementia severity, however, the maximal reduction was only modest (-30%). On the other hand, SLI in CSF showed only a slight further reduction (up to -41%) as the dementia become more severe.(ABSTRACT TRUNCATED AT 400 WORDS)     

The relationship between GABA concentrations in brain and cerebrospinal fluid

GABA concentrations in cerebrospinal fluid (CSF) and brain of rats and cats were determined before and after intraperitoneal injection of three drugs that increase brain GABA levels. GABA exists in the CSF in two forms: free and conjugated GABA. In the CSF of untreated animals, there is very little free GABA (65 ± 12pmol/ml) but considerable amounts of conjugated GABA (2885 ± 100pmol/ml). After IP administration of γ-vinyl GABA to rats, CSF concentrations of both free and conjugated GABA rise in a dose-dependent manner. There is an exponential correlation (r = 0.92, P < 0.001) between rat whole brain GABA concentrations and free GABA in the CSF. Concentrations of brain GABA and conjugated CSF GABA are linearly correlated (r = 0.84, P < 0.001). γ-Acetylenic GABA has qualitatively similar effects to γ-vinyl GABA. Treatment with ethanolamine-O-sulfate i.p. at a dose not affecting brain GABA concentrations markedly increases serum GABA, leaves conjugated CSF GABA unchanged and significantly elevates free GABA in the CSF.These findings suggest that total CSF GABA concentrations are related primarily to brain GABA levels and are minimally affected by the changes in the peripheral GABA concentrations. Determination of the levels of free and conjugated GABA in the CSF may be useful for the estimation of brain GABA concentration in patients on therapy intended to alter brain GABA levels.     

Elevation of brain GABA levels with vigabatrin (γ-vinylGABA) differentially affects GAD65 and GAD67 expression in various regions of rat brain

Previous studies have demonstrated that the expression of one of the isoforms of glutamate decarboxylase, GAD₆₇, is selectively reduced in cultured cortical neurons and in rat cerebral cortex when the concentration of GABA is elevated. We asked whether the expression of GAD₆₇ was similarly affected by elevated GABA throughout the brain. The concentration of GABA in rat brain was increased by inhibiting GABA transaminase (GABA-T) with vigabatrin (γ-vinylGABA, GVG), an antiepileptic drug and selective inhibitor of GABA-T. Rats were injected with saline or vigabatrin (150 mg/kg) daily for 5 days, and the effects of accumulated GABA on total GAD activity and the expression of GAD₆₅ and GAD₆₇ proteins were determined in twelve brain regions. The GABA concentration was significantly elevated in all regions except amygdala and olfactory bulb after vigabatrin treatment. Total GAD activity was significantly lower than controls in six regions: cerebellum, frontal cortex, thalamus, substantia nigra, ventral tegmentum, and the remaining midbrain. The decrease in GAD activity was largest in cerebellum and thalamus (33% and 29%), while the changes in the other four areas were 15–18%. Vigabatrin treatment significantly reduced GAD₆₇ protein in all regions except olfactory bulb, whereas GAD₆₅ protein decreased significantly only in cerebellum. The failure to detect significant changes in GAD activity in regions having a significant change in GAD₆₇ levels is attributable to the small contribution of GAD₆₇ to total GAD in those regions. It is evident that there are marked regional differences in the effects of tissue GABA levels on the expression of GAD₆₇. J. Neurosci. Res. 52:736–741, 1998. © 1998 Wiley-Liss, Inc.     

Glucocorticoids are modulators of GABAA receptors in brain

Modulation of binding of [³H]muscimol, a GABA_A receptor agonist, by natural and synthetic glucocorticoids was investigated in crude synaptosomal membranes and in brain sections of rat. In adrenalectomized (Adx) rats, muscimol binding was reduced by 30–50% in cerebral cortex, cerebellum, thalamus and hippocampus, as compared to sham-operated controls. This decrease was due to reduced binding affinities of GABA receptors for muscimol. In contrast muscimol binding was increased by 38% in the hypothalamus and did not change in the pons-medulla after Adx. Nanomolar concentrations of corticosterone and pregnenolone-sulfate, but not dexamethasone, enhanced muscimol binding in brain regions that were characterized by reduced binding following Adx. This steroid-induced increase in muscimol binding was due to enhanced affinities of GABA receptors.     

Cerebrospinal fluid GABA levels in chronic migraine with and without depression

Psychiatric comorbidity is one of the key elements in chronic migraine (CM) management. Depression is particularly common in these patients, occurring in up to 85%. Preclinical studies have suggested that gamma-aminobutyric acid (GABA) levels may be decreased in animal models of depression. Also, clinical studies have reported low level in mood disorder patients for both plasma and cerebrospinal fluid (CSF) GABA. We hypothesized that low GABA levels in the brain might be related to the depression associated with CM. We studied 14 chronic migraine patients, with or without depression, compared to age-and sex-matched controls. CSF GABA levels were measured by HPLC. CSF GABA levels showed significant lower levels in depressed patients than those without depression. No difference was found when comparing patients versus controls. A GABA deficiency may be the underlying mechanism of depression in CM. Hence, preventive therapies modulating GABA neurotransmission could be used in CM associated with depression.     

Brain MRI findings in acute hepatic encephalopathy in liver transplant recipients

Acute hepatic encephalopathy has significant morbidity and mortality in liver transplant recipients unless it is promptly treated. We evaluated the brain magnetic resonance (MR) imaging findings associated with acute hepatic encephalopathy in transplant recipients. We retrospectively reviewed the clinical and imaging data and outcomes of twenty-five liver transplant patients (16 male; mean age, 49.3 years) with clinically diagnosed acute hepatic encephalopathy and forty liver transplant patients (20 males; mean age, 45.5 years) without neurological symptoms suggestive of hepatic encephalopathy at our institution. Bilateral symmetric hyperintensities of the insular cortex and cingulate gyrus were observed in twenty-one patients (84.00%), bilateral symmetric extensive increased cortical signal intensity (involving two or more regions) was observed in 72.00% of the patients, leptomeningeal enhancement in 73.68%, and visualization of prominent venules in 52.00%. The most common symptom at diagnosis was rigidity (n = 14), and the plasma ammonia levels ranged from 68.63 to 192.16 μmol/L. After active treatment, 17 patients gradually recovered, four patients suffered from mild or moderate neurologic deficits, and four patients with widespread brain edema died. The specific brain MR imaging features were bilateral symmetric increased cortical signal intensity, especially in the insular cortex and cingulate gyrus, leptomeningeal enhancement, visualization of the prominent venules, and widespread brain edema. These features may indicate poor prognosis and should alert radiologists to the possibility of acute hepatic encephalopathy in liver transplant recipients and encourage clinicians to prepare appropriate treatment in advance.