Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glutamate decarboxylase (EC 4.1.1.15, GAD) activity was studied in the brain of 12-day-old and adult rats treated with 3-mercaptopropionic acid (3-MPA), an inhibitor of GAD competitive with glutamate. Control GAD activity in the brains of immature animals (91.8 +/- 18.2 nmol/h/mg of protein) was lower than that of the adult rats (228 +/- 37.5 nmol/h/mg of protein). Brain GAD inhibition in adult rats was 58% at the onset of seizures (9 min on the average after administration of 70 mg 3-MPA/kg). At the same time, 3-MPA-treated young rats exhibited 76% inhibition of GAD despite the fact that at 9 min these animals were not yet having seizures. At the onset of seizures (19 min after 3-MPA on the average) their GAD activity remained at the same level. The difference between the groups was not related to the presence of the coenzyme pyridoxal-5'-phosphate in the enzyme assay. The inhibition of GAD by 3-MPA in vitro in the immature and adult brains was similar (Ki at 5.1 microM and 4.8 microM concentrations of 3-MPA, respectively). Identical values were found for Km of GAD (at 4.5 mM concentration of L-glutamate). Calculations based on the results suggest that 3-MPA enters the immature brain more easily than the brain of the adult animals. While GAD inhibition by 3-MPA is the primary cause of seizures, their onset is influenced by other factors, in which the immature brain differs from the adult one and which may include less sensitivity to GABA decrease due to relative overactivity of the GABA system.
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PMID:Differences between immature and adult rats in brain glutamate decarboxylase inhibition by 3-mercaptopropionic acid. 779 89

Pyridoxine-dependent seizures are a disorder of GABA metabolism probably due to a defective binding of pyridoxal phosphate coenzyme (PALP) with glutamate decarboxylase (GAD), the rate-limiting enzyme in GABA synthesis. The resulting GABA deficiency causes severe epilepsy in infancy. We report on a boy with seizures starting soon after birth, and only controlled by pyridoxine at pharmacological dosages. After two months without seizures, a CT scan showed hypodense white matter in frontal and occipital lobes suggestive of a retarded or defective myelination. We are not aware of other descriptions of such morphological abnormalities in a patient with this disorder.
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PMID:Pyridoxine-dependent seizures associated with white matter abnormalities. 788 36

gamma-Aminobutyric acid (GABA) levels and the activity of glutamate decarboxylase were measured in homogenates of rat brain cortical tissue, at different times after chronic intracortical infusion of GABA in vivo during 2, 6 or 24 h. Cortical electrical activity was also recorded. As previously described, about 1 h after cessation of the infusion epileptic discharges were observed (GABA-withdrawal syndrome), which lasted for several days. At zero time after cessation of the infusion, before the appearance of seizures, GABA levels were increased 3-6-fold and glutamate decarboxylase activity was decreased 27-48% in the infused cortex, as compared to the contralateral cortex or to tissue from control intact rats. During epileptic discharges GABA levels gradually returned to normal values. In contrast, glutamate decarboxylase activity remained decreased during seizures and returned to normal only after recovery from the GABA-withdrawal syndrome. These results suggest that the persistent decrease in the activity of the decarboxylase is due probably to a lowered amount of the enzymatic protein, occurring as a consequence of a temporarily elevated intracellular GABA concentration. The decreased rate of GABA synthesis might be involved in the pathophysiology of the GABA-withdrawal syndrome.
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PMID:Decrease of glutamate decarboxylase activity after in vivo cortical infusion of gamma-aminobutyric acid. 806

In this study the effect of the anti-inflammatory drugs indomethacin, ibuprofen, ebselen (PZ 51, 2-phenyl-1,2-benzoisoselenazol-3(2H)-one), and BW755C (3-amino-1-(m-(trifluoromethyl-phenyl)-2-pyrazoline) on kainic acid (KA)-induced behavioral and neurochemical changes in rats was investigated. Rats injected with KA (10 mg/kg s.c.) developed seizure activity with a 20% mortality within the first 4 h and neuronal degeneration in the limbic system after 3 days. Pretreatment with the cyclooxygenase inhibitor indomethacin (10 mg/kg i.p.) augmented KA-induced epileptic activity and increased the mortality in status epilepticus to 80%. Another cyclooxygenase inhibitor, ibuprofen (20 mg/kg i.p.), and the lipoxygenase inhibitor ebselen (20 mg/kg i.p.) showed no effect on KA-induced symptoms and neurochemical changes. Application of the cyclooxygenase/lipoxygenase inhibitor BW755C (40 mg/kg i.p.) reduced the severity of seizures and protected significantly from irreversible brain lesions induced by KA. The marked reduction of glutamate decarboxylase (GAD; 53.3 +/- 12.2% of control) and choline acetyltransferase (ChAT; 60.9 +/- 9.1% of control) activities in amygdala/pyriform cortex and GAD activity in hippocampus (69.4 +/- 5.6% of control) observed 3 days after KA injection was abolished by BW755C treatment. Histopathological analyses of brain tissue showed that treatment with BW755C prevented the KA-induced nerve cell degeneration, edema, hemorrhages, and tissue necrosis in amygdala/pyriform cortex.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The cyclooxygenase and lipoxygenase inhibitor BW755C protects rats against kainic acid-induced seizures and neurotoxicity. 806 64

We have previously shown that short-lasting reduction of cerebral blood flow by bilateral clamping of carotid arteries (BCCA) results in long-lasting increase in regional GABA concentration and decrease in seizure susceptibility in rats. In the present experiments, the effect of BCCA on GABA turnover and the enzymes involved in GABA synthesis and degradation were studied in rats. Regional GABA turnover was measured by means of GABA accumulation induced by the GABA-transaminase (GABA-T) inhibitor aminooxyacetic acid (AOAA). Fourteen days after BCCA, GABA turnover was significantly increased in hippocampus, substantia nigra and cortex, but not different from sham-operated controls in several other brain regions, including striatum, hypothalamus and cerebellum. The activity of glutamate decarboxylase (GAD) measured ex vivo did not show any changes in investigated structures, while the activity of GABA-T was slightly increased in hippocampus. The increased GABA turnover in some brain regions may explain our previous findings of increased GABA content in these brain regions and decreased sensitivity of BCCA treated animals to the GABAA-receptor antagonist bicuculline.
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PMID:Influence of short-lasting bilateral clamping of carotid arteries (BCCA) on GABA turnover in rat brain structures. 817 78

We have previously shown that in the adult rat the inhibition of brain glutamate decarboxylase (GAD) activity by pyridoxal phosphate-gamma-glutamyl hydrazone (PLPGH) administration does not result in convulsions, whereas in the adult mouse intense convulsions invariably occur. In the present study we report that, surprisingly, immature rats from 2 to 20 days of age treated with PLPGH (80 mg/kg) showed generalized tonic-clonic convulsions, whereas no convulsions at all were present in 30 days-old or older rats. GAD activity, measured by enzymic determination of GABA formed in forebrain homogenates, was inhibited by about 60% at the time of convulsions in 15 days-old and younger rats, whereas the inhibition was between 40 and 50% in older animals. The addition of the coenzyme pyridoxal 5'-phosphate to the incubation medium completely reversed this inhibition. In all treated animals GABA levels were lower compared to controls. The results indicate that the susceptibility of GAD in vivo to a diminished cofactor concentration decreases with age. It seems possible that changes in the expression of enzyme forms are reflected in developmental variations in the susceptibility to seizures induced by vitamin B6 depletion, but alterations of other B6-dependent biochemical pathways cannot be discarded.
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PMID:Convulsions and inhibition of glutamate decarboxylase by pyridoxal phosphate-gamma-glutamyl hydrazone in the developing rat. 818 28

The convulsant action of 3-mercaptopropionic acid (3-MPA), a known inhibitor of glutamate decarboxylase activity, was studied in 7-, 12-, 18- and 25-day-old rats and in adult animals. 3-MPA elicited predominantly clonic, minimal seizures as well as generalized tonic-clonic (major) seizures at all developmental stages studied. The CD50 for major seizures did not change during development; CD50 for minimal seizures was significantly lower in 18-day-old rats than in older animals. Latency to the onset of seizures was shortest in 18-day-old rats and extremely long in 12- and, especially, in 7-day-old rats. This long latency might signify either changing molecular properties of glutamate decarboxylase during development or slow turnover of GABA at early postnatal stages. Electrocorticographic recordings demonstrated sharp EEG components in the frontal region as a first sign of 3-MPA action, and seizure patterns exhibited similar developmental changes as found with other seizure models (a decrease in duration of individual graphoelements and an increase in synchronization among various cortical regions). This indicates the primary importance of brain maturation in the expression of epileptic EEG phenomena. The correlation between EEG and motor phenomena was poor in the youngest animals and it ameliorated with age, but it never became perfectly coincidental.
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PMID:Motor and electrocorticographic epileptic activity induced by 3-mercaptopropionic acid in immature rats. 824 36

In order to identify lasting alterations in gamma-aminobutyric acid (GABA) neurons in the kindling model of epilepsy, immunocytochemical techniques were used to quantify the number of GABA-immunoreactive (IR) neurons in different regions of the hippocampal formation (HCF) of amygdala-kindled rats, 40 days after the last fully kindled seizure. A new, highly specific monoclonal GABA antibody was used for these experiments. Unexpectedly, the antibody not only stained neurons in CA1, CA3, and hilus, but also intensively stained granule cells (GCs) in the dentate gyrus (DG) of both kindled rats and non-kindled controls, indicating that GCs may be capable of synthesizing GABA. Comparison with a polyclonal GABA and a glutamate decarboxylase antibody showed that staining of GCs with the monoclonal GABA antibody was much more intense. The number of GABA-IR cells that were counted in different regions of the HCF, including the DG, did not differ significantly between kindled rats and controls, which does not support the hypothesis of loss of hippocampal GABAergic neurons to explain the permanency of kindled epileptogenesis.
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PMID:Immunocytochemical localization of GABA immunoreactivity in dentate granule cells of normal and kindled rats. 882 58

The excitatory, glutamatergic granule cells of the hippocampal dentate gyrus are presumed to play central roles in normal learning and memory, and in the genesis of spontaneous seizure discharges that originate within the temporal lobe. In localizing the two GABA-producing forms of glutamate decarboxylase (GAD65 and GAD67) in the normal hippocampus as a prelude to experimental epilepsy studies, we unexpectedly discovered that, in addition to its presence in hippocampal nonprincipal cells, GAD67-like immunoreactivity (LI) was present in the excitatory axons (the mossy fibers) of normal dentate granule cells of rats, mice, and the monkey Macaca nemestrina. Using improved immunocytochemical methods, we were also able to detect GABA-LI in normal granule cell somata and processes. Conversely, GAD65-LI was undetectable in normal granule cells. Perforant pathway stimulation for 24 hours, which evoked population spikes and epileptiform discharges in both dentate granule cells and hippocampal pyramidal neurons, induced GAD65-, GAD67-, and GABA-LI only in granule cells. Despite prolonged excitation, normally GAD- and GABA-negative dentate hilar neurons and hippocampal pyramidal cells remained immunonegative. Induced granule cell GAD65-, GAD67-, and GABA-LI remained elevated above control immunoreactivity for at least 4 days after the end of stimulation. Pre-embedding immunocytochemical electron microscopy confirmed that GAD67- and GABA-LI were induced selectively within granule cells; granule cell layer glia and endothelial cells were GAD- and GABA-immunonegative. In situ hybridization after stimulation revealed a similarly selective induction of GAD65 and GAD67 mRNA in dentate granule cells. Neurochemical analysis of the microdissected dentate gyrus and area CA1 determined whether changes in GAD- and GABA-LI reflect changes in the concentrations of chemically identified GAD and GABA. Stimulation for 24 hours increased GAD67 and GABA concentrations sixfold in the dentate gyrus, and decreased the concentrations of the GABA precursors glutamate and glutamine. No significant change in GAD65 concentration was detected in the microdissected dentate gyrus despite the induction of GAD65-LI. The concentrations of GAD65, GAD67, GABA, glutamate and glutamine in area CA1 were not significantly different from control concentrations. These results indicate that dentate granule cells normally contain two "fast-acting" amino acid neurotransmitters, one excitatory and one inhibitory, and may therefore produce both excitatory and inhibitory effects. Although the physiological role of granule cell GABA is unknown, the discovery of both basal and activity-dependent GAD and GABA expression in glutamatergic dentate granule cells may have fundamental implications for physiological plasticity presumed to underlie normal learning and memory. Furthermore, the induction of granule cell GAD and GABA by afferent excitation may constitute a mechanism by which epileptic seizures trigger compensatory interictal network inhibition or GABA-mediated neurotrophic effects.
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PMID:Basal expression and induction of glutamate decarboxylase and GABA in excitatory granule cells of the rat and monkey hippocampal dentate gyrus. 888 46

Circumscribed cortical lesions are frequently encountered in patients with chronic focal epilepsies. However, the pathogenesis of seizures is poorly understood. To determine whether the perilesional cortex shows evidence for abnormal excitatory or inhibitory neurochemical activity, we immunohistochemically examined the distribution of the alpha 1 subunit of the GABAA receptor (GABAR), the N-methyl-D-aspartate receptor subunit 1 (NR1), and glutamate decarboxylase (GAD) in 30 surgical specimens of neocortical epilepsy-associated lesions. These comprised 7 low-grade gliomas, 2 gangliogliomas, 2 dysembryoplastic neuroepithelial tumors, 4 glioneuronal malformations, 5 vascular malformations, and 10 glial or gliomesodermal scars. All specimens originated from patients with chronic pharmacoresistant epilepsy. In 73% of the cases there was a distinct difference in immunoreactivity for GABAR, GAD or NR1 between the perilesional zone and the normal cortex. With each of the markers there was reduced perilesional immunoreactivity in 30% of the specimens. Increased staining of GAD was seen in 17%, for GABAR in 7%, and for NR1 in 13% of the cases. The age at surgery, onset of seizures, epilepsy duration, and maximal seizure frequency did not differ significantly between patients with normal and those with altered perilesional immunoreactivity patterns. Although the perilesional changes for GAD, GABAR or NR1 were heterogeneous, they suggest a disturbed balance between excitatory and inhibitory synaptic transmission which may contribute to the pathogenesis of focal seizures.
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PMID:Perilesional neurochemical changes in focal epilepsies. 892 14


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