Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038220 (status epilepticus)
 7,272 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the present study glutamate decarboxylase immunoreactivity (GAD-IR) was used to quantify GABAergic neurons in the hippocampus of rats exhibiting spontaneous recurrent seizures following pilocarpine-induced status epilepticus. Histological examination demonstrated marked neuronal damage to hippocampal neurons. However, in the same region, GAD-IR neurons were preserved. The present data demonstrate a selective resistance of GABAergic neurons to status epilepticus-induced neuronal damage, suggesting that loss of hippocampal GABAergic neurons does not underlie the recurrence of seizures in these animals.
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PMID:GAD-immunoreactive neurons are preserved in the hippocampus of rats with spontaneous recurrent seizures. 212 65

Pilocarpine, given intraperitoneally to rats, reproduces the neuropathological sequelae of temporal lobe epilepsy and provides a relevant animal model for studying mechanisms of buildup of convulsive activity and pathways operative in the generalization and propagation of seizures within the forebrain. In the present study, the effects of manipulating the activity of the gamma-aminobutyric acid (GABA)-mediated synaptic inhibition within the substantia nigra on seizures produced by pilocarpine in rats, were investigated. In animals pretreated with microinjections of isoniazid, 150 micrograms, an inhibitor of activity of the GABA-synthesizing enzyme, L-glutamic acid decarboxylase, into the substantia nigra pars reticulata (SNR), bilaterally, non-convulsant doses of pilocarpine, 100 and 200 mg/kg, resulted in severe motor limbic seizures and status epilepticus. Electroencephalographic and behavioral monitoring revealed a profound reduction of the threshold for pilocarpine-induced convulsions. Morphological analysis of frontal forebrain sections with light microscopy revealed seizure-related damage to the hippocampal formation, thalamus, amygdala, olfactory cortex, substantia nigra and neocortex, which is typically observed with pilocarpine in doses exceeding 350 mg/kg. Bilateral intrastriatal injections of isoniazid did not augment seizures produced by pilocarpine, 200 mg/kg. Application of an irreversible inhibitor of GABA transaminase, gamma-vinyl-GABA (D,L-4-amino-hex-5-enoic acid), 5 micrograms, into the SNR, bilaterally, suppressed the appearance of electrographic and behavioral seizures produced by pilocarpine, 380 mg/kg. This treatment was also sufficient to protect animals from the occurrence of brain damage. Microinjections of gamma-vinyl-GABA, 5 micrograms, into the dorsal striatum, bilaterally, failed to prevent the development of convulsions produced by pilocarpine, 380 mg/kg. The results demonstrate that the threshold for pilocarpine-induced seizures in rats is subjected to the regulation of the GABA-mediated synaptic inhibition within the substantia nigra.
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PMID:Susceptibility to seizures produced by pilocarpine in rats after microinjection of isoniazid or gamma-vinyl-GABA into the substantia nigra. 370 28

1. DL-C-Allyglycine, 4-deoxypyridoxine hydrochloride and 3-mercaptopropionic acid have been studied with reference to their convulsant effects in mice and in baboons (Papio papio) with photosensitive epilepsy, and their action on the cerebral enzyme synthesizing gamma-aminobutyric acid (L-glutamate-1-carboxy-lyase).2. In mice, the ED(50) values for seizures following intraperitoneal injection were allylglycine 1.0 mmol/kg body weight, 4-deoxypyridoxine 1.1 mmol/kg and 3-mercaptopropionic acid 0.27 mmol/kg. Latency to seizure onset was longest after allylglycine (44-240 min), intermediate after 4-deoxypyridoxine (9-114 min) and shortest after 3-mercaptopropionic acid (2.5-8 min).3. In Papio papio intravenous administration of subconvulsant doses of allylglycine (0.87-3.1 mmol/kg), or of 4-deoxypyridoxine (0.21-0.53 mmol/kg) enhanced the occurrence and persistence of myoclonic responses to intermittent photic stimulation, and augmented the associated electroencephalographic abnormalities, without modifying their character or distribution. Higher doses produced brief seizures recurring at regular intervals, between 2-14 h after allylglycine (4.0-4.3 mmol/kg) or 1-4 h after 4-deoxypyridoxine (0.53-0.87 mmol/kg). Electroencephalographically these seizures originated unilaterally in the occipital or posterior parietal cortex.4. In Papio papio photically-induced epileptic responses were enhanced 5-10 min after the intravenous injection of 3-mercaptopropionic acid (0.09-0.28 mmol/kg). A sequence of brief generalized seizures followed by complete recovery occurred 4-17 min after the injection of 3-mercaptopropionic acid (0.28-0.38 mmol/kg). Fatal status epilepticus followed the injection of 3-mercaptopropionic acid (0.57-0.75 mmol/kg). E.E.G. records showed generalized cortical involvement at the onset of the seizures.5. L-Glutamate 1-carboxy-lyase (GAD) activity was determined in whole brain homogenates from mice killed at various intervals after receiving i.p. a convulsant dose of one of the compounds. Inhibition of GAD activity was evident 30-60 min before seizure onset following allylglycine or 4-deoxypyridoxine administration, and was maximal (40-60%) just before or during seizure activity. Addition of pyridoxal phosphate to the brain homogenate relieved inhibition produced by 4-deoxypyridoxine but not that produced by allylglycine. Inhibition of GAD activity in brain homogenates from animals killed 2 or 4 min after injection of a convulsant dose of 3-mercaptopropionic acid varied from 0-49% depending on the dose of 3-mercaptopropionic acid and the concentration of substrate in the assay system.6. Kinetic analysis of the inhibition of GAD activity following direct addition of the compounds to mouse brain homogenates indicated that 3-mercaptopropionic acid (0.01-0.5 mM) was competitive with respect to the substrate. A comparable percentage inhibition of GAD activity was obtained only with much higher concentrations of 4-deoxypyridoxne, i.e. 10-50 mM. Allylglycine in vitro was a very weak inhibitor of GAD activity.7. Three biochemically different mechanisms underlie the inhibition of cerebral GAD activity that precedes seizures induced by ailylglycine, 4-deoxypyridoxine and 3-mercaptopropionic acid. The data are consistent with a critical reduction in the rate of synthesis of gamma-aminobutyric acid being responsible for the onset of seizures.
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PMID:Seizures induced by allylglycine, 3-mercaptopropionic acid and 4-deoxypyridoxine in mice and photosensitive baboons, and different modes of inhibition of cerebral glutamic acid decarboxylase. 420 45

The anticonvulsive effect of midazolam was studied in rats and mice brains. Microiontophoretically applied midazolam (0.2M, pH 3.5) potentiated the GABA effect at the single neurone level, and inhibited neuronal firing in the rat cuneate neurones. Midazolam administered intraperitoneally (15 mg/kg) increased the primary afferent depolarization for at least two hours. Three mg/kg of midazolam slightly increased the glutamate decarboxylase activities in the mice cerebrum and the increase was statistically significant (p less than 0.05). The authors reported a case of clinical application of midazolam: a status epilepticus was successfully treated with it, while intravenous diazepam of 30 mg failed to control the status.
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PMID:Potentiation of GABA by midazolam and its therapeutic effect against status epilepticus. 667 38

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

This study determined whether there were differences in hippocampal neuron loss and synaptic plasticity by comparing rats with spontaneous epilepsy after limbic status epilepticus and animals with a similar frequency of kindled seizures. At the University of Virginia, Sprague-Dawley rats were implanted with bilateral ventral hippocampal electrodes and treated as follows; no stimulation (electrode controls; n=5): hippocampal stimulation without status (stimulation controls; n=5); and limbic status from continuous hippocampal stimulation (n=12). The limbic status group were electrographically monitored for a minimum of four weeks. Four rats had no recorded chronic seizures (status controls), and all three control groups showed no differences in hippocampal pathology and were therefore incorporated into a single group (controls). Eight limbic status animals eventually developed chronic epilepsy (spontaneous seizures) and an additional eight rats were kindled to a similar number and frequency of stage 5 seizures (kindled) as the spontaneous seizures group. At the University of California (UCLA) the hippocampi were processed for: (i) Niss1 stain for densitometric neuron counts; (ii) neo-Timm's histochemistry for mossy fiber sprouting; and (iii) immunocytochemical staining for glutamate decarboxylase, N-methyl-D-aspartate receptor subunit 2, AMPA receptor subunit 1 and the GABA(A) receptor. In the fascia dentata inner and outer molecular layers the neo-Timm's stain and immunoreactivity was quantified as gray values using computer image analysis techniques. Statistically significant results (P<0.05) showed the following. Compared to controls and kindled animals, rats with spontaneous seizures had: (i) lower neuron counts for the fascia dentata hilus, CA3 and CA1 stratum pyramidale; (ii) greater supragranular inner molecular layer mossy fiber staining; and (iii) greater glutamate decarboxylase immunoreactivity in both molecular layers. Greater supragranular excitatory mossy fiber and GABAergic axon sprouting correlated with: (i) increases in N-methyl-D-aspartate receptor subunit 2 inner molecular layer staining; (ii) more AMPA receptor subunit 1 immunoreactivity in both molecular layers; and (iii) greater outer than inner molecular layer GABA(A) immunoreactivity. Furthermore, in contrast to kindled animals, rats with spontaneous seizures showed that increasing seizure frequency per week and the total number of natural seizures positively correlated with greater Timm's and GABAergic axon sprouting, and with increases in N-methyl-D-aspartate receptor subunit 2 and AMPA receptor subunit 1 receptor staining. In this rat limbic status model these findings indicate that chronic seizures are associated with hippocampal neuron loss, reactive axon sprouting and increases in excitatory receptor plasticity that differ from rats with an equal frequency of kindled seizures and controls. The hippocampal pathological findings in the limbic status model are similar to those in humans with hippocampal sclerosis and mesial temporal lobe epilepsy, and support the hypothesis that synaptic reorganization of both excitatory and inhibitory systems in the fascia dentata is an important pathophysiological mechanism that probably contributes to or generates chronic limbic seizures.
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PMID:In contrast to kindled seizures, the frequency of spontaneous epilepsy in the limbic status model correlates with greater aberrant fascia dentata excitatory and inhibitory axon sprouting, and increased staining for N-methyl-D-aspartate, AMPA and GABA(A) receptors. 913 Jul 82

Studies of neuroactive amino acids and their regulatory enzymes in surgically excised focally epileptic human brain are reviewed. Concentrations of glutamate, aspartate and glycine are significantly increased in epileptogenic cerebral cortex. The activities of the enzymes, glutamate dehydrogenase and aspartate aminotransferase, involved in glutamate and aspartate metabolism are also increased. Polyamine synthesis is enhanced in epileptogenic cortex and may contribute to the activation of N-methyl-D-aspartate (NMDA) receptors. Nuclear magnetic resonance spectroscopy (NMRS) reveals that patients with poorly controlled complex partial seizures have a significant diminution in occipital lobe gamma aminobutyric acid (GABA) concentration. The activity of the enzyme GABA-aminotransaminase (GABA-T) which catalyzes GABA degradation is not altered in epileptogenic cortex. NMRS studies show that vigabatrin, a GABA-T inhibitor and effective antiepileptic, significantly increases brain GABA. Glutamate decarboxylase (GAD), responsible for GABA synthesis, is diminished in interneurons in discrete regions of epileptogenic cortex and hippocampus. In vivo microdialysis performed in epilepsy surgery patients provides measurements of extracellular amino acid levels during spontaneous seizures. Glutamate concentrations are higher in epileptic hippocampi and increase before seizure onset reaching potentially excitotoxic levels. Frontal or temporal cortical epileptogenic foci also release aspartate, glutamate and serine particularly during intense seizures or status epilepticus. GABA in contrast, exhibits a delayed and feeble rise in the epileptic hippocampus possibly due to a reduction in the number and/or efficiency of GABA transporters.
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PMID:Neuroactive amino acids in focally epileptic human brain: a review. 1055 79

Several lines of evidence suggest that the binding affinity of glutamate decarboxylase (GAD) to the active form of pyridoxine is low in cases of pyridoxine-dependent seizures (PDS) and that a quantitative imbalance between excitatory (i.e. glutamate) and inhibitory (i.e. gamma-aminobutyric acid, GABA) neurotransmitters could cause refractory seizures. However, inconsistent findings with GAD insufficiency have been reported in PDS. We report a case of PDS that is not accompanied by an elevated cerebrospinal fluid (CSF) glutamate concentration. Intravenous pyridoxine phosphate terminated generalized seizures which were otherwise refractory to conventional anti-epileptic medicines. No seizure occurred once oral pyridoxine (13.5 mg/kg per day) was started in combination with phenobarbital sodium (PB, 3.7 mg/kg per day). The electroencephalogram (EEG) normalized approximately 8 months after pyridoxine was started. The patient is gradually acquiring developmental milestones during the 15 months follow-up period. The CSF glutamate and GABA concentrations were determined on three separate occasions: (1) during status epilepticus; (2) during a seizure-free period with administration of pyridoxine and PB; and (3) 6 days after suspension of pyridoxine and PB and immediately before a convulsion. The CSF glutamate level was below the sensitivity of detection (<1.0 microM) on each of the three occasions; the CSF GABA level was within the normal range or moderately elevated. The CSF and serum concentrations of vitamin B6-related substances, before pyridoxine supplementation, were within the normal range. We suggest that (1) PDS is not a discrete disease of single etiology in that insufficient activation of GAD may not account for seizure susceptibility in all cases and (2) mechanism(s) of anti-convulsive effect of pyridoxine, at least in some cases, may be independent of GAD activation.
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PMID:CSF glutamate/GABA concentrations in pyridoxine-dependent seizures: etiology of pyridoxine-dependent seizures and the mechanisms of pyridoxine action in seizure control. 1122 25

Kainic acid-induced seizures cause a marked increase in the expression of glutamate decarboxylase 67 (GAD67) in granule cells of the dentate gyrus. To determine the possible modes of sequestration of newly formed gamma-aminobutyric acid (GABA), we used in situ hybridization and immunocytochemistry to investigate the expression of several proteins related to GABA in dentate granule cells of rats 4 h to 60 days after kainic acid-induced status epilepticus and in controls. GAD67 and GAD65 mRNA levels were increased by up to 300% and 800%, respectively, in the granule cell layer 6-24 h after kainate injection. Subsequently, increased GAD and GABA immunoreactivity was observed in the terminal field of mossy fibers and in presumed dendrites of granule cells. mRNA of both known plasma membrane GABA transporters (GAT-1 and GAT-3) was expressed in granule cells of control rats. GAT-1 mRNA levels increased (by 30%) 9 h after kainate injection but were reduced by about 25% at later intervals. GAT-3 mRNA was reduced (by 35-75%) in granule cells 4 h to 30 days after kainic acid injection. In contrast, no expression of the mRNA or immunoreactivity of the vesicular GABA transporter was detected in granule cells or in mossy fibers, respectively. GABA transaminase mRNA was only faintly expressed in granule cells, and its levels were reduced (by 60-65%) 12 h to 30 days after kainate treatment. The results indicate that GABA can be taken up and synthesized in granule cells. No evidence for the expression of the vesicular GABA transporter (VGAT) in granule cells was obtained. After sustained epileptic seizures, the markedly increased expression of glutamate decarboxylase and the reduced expression of GABA transaminase may result in increased cytoplasmic GABA concentrations in granule cells. It is suggested that, during epileptic seizures, elevated intracellular GABA and sodium concentration could then result in nonvesicular release of GABA from granule cell dendrites. GABA could then act on GABA-A receptors, protecting granule cells from overexcitation.
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PMID:Expression of plasma membrane GABA transporters but not of the vesicular GABA transporter in dentate granule cells after kainic acid seizures. 1462 Aug 76

GABAergic inhibition of the substantia nigra pars reticulata (SNR) has been shown to suppress seizures in most models of epilepsy, including the amygdala-kindling model of temporal lobe epilepsy (TLE). A dysfunction of this seizure gating mechanism of the SNR may lead to facilitation of seizure propagation in such models. In post-status epilepticus models of TLE, GABAergic neurons in the SNR are damaged, but it is not known whether such damage also occurs in kindling. By using stereological techniques for cell counting in amygdala-kindled rats, we determined the density of SNR neurons that were labeled for GABA by immunohistochemistry or for the two isoforms of the GABA-synthesizing enzyme glutamate decarboxylase (GAD), GAD65 and GAD67, by in situ hybridization (ISH). In addition, GABA neurons in the basolateral amygdala (BLA) were counted. While there was a significant reduction of GAD65 mRNA expressing neurons in the BLA of kindled rats, no alteration in the density of neurons was observed in the anterior or posterior SNR when cells were counted 6 weeks after the last kindled seizure. Our previous finding of reduced GAD and GABA levels in synaptosomes isolated from the SN of kindled rats together with the present observation of unchanged density of SNR neurons in such rats suggest that kindling affects the GABAergic projections from the striatum or globus pallidus to the SNR rather than directly affecting GABA neurons in the SNR.
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PMID:Amygdala-kindling does not induce a persistent loss of GABA neurons in the substantia nigra pars reticulata of rats. 1546 61


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