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

Pretreatment of adult male Sprague-Dawley rats with a single dose of gamma-vinyl GABA (GVG) (1200 mg/kg, IP) or gamma-acetylenic GABA (GAG) (100 mg/kg, IP) did not affect the threshold of metrazol-activated generalized seizures, but increased their duration to the point of status epilepticus. In rats with epilepsy kindled by amygdaloid stimulation, a single dose of GVG (800 mg/kg, IP) and five subsequent daily administrations of GAG (80 mg/kg, IP) tended to reduce the motor manifestations of seizures leaving unaffected their electrographic pattern. The effects of GVG and GAG are attributed in part to decreased arousal. Practical implications of these findings are discussed.
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PMID:Effects of gamma-acetylenic GABA and gamma-vinyl GABA on metrazol-activated, and kindled seizures. 50 7

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

The effects of bilateral microinjection of gamma-vinyl GABA (GVG, an irreversible inhibitor of GABA-T) were tested during the development of seizures induced by i.p. administration of 10 mg/kg of kainic acid. Intrahippocampal injection of GVG prevents the development of the seizures at an early stage in about half of the cases. In the remaining animals status epilepticus comparable to that of controls develops. Intra-amygdaloid injection reduces the severity of the seizures from the first motor limbic signs. Finally, intranigral injection prevents the appearance of convulsive status epilepticus or, when it develops, reduces its duration. The role that these three structures could play in the electro-clinical development of kainic acid-induced seizures is discussed.
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PMID:[Role of the hippocampus, amygdala and the substantia nigra in the evolution of status epilepticus induced by systemic injection of kainic acid in the rat]. 652 78

We studied the neuroprotective effect of vigabatrin (gamma-vinyl GABA, VGB) in the rat hippocampus after status epilepticus (SE) induced by kainic acid (KA). Rats were treated with VGB (500 or 1000 mg/kg, i.p.) 24 h before KA injection (9 mg/kg, i.p.). The lower dose of VGB had no effect on the generation or severity of convulsions. However, VGB decreased neuronal damage in the CA3a (P < 0.05) and CA1 (P < 0.01) subfields of the hippocampus. The higher dose of VGB attenuated the severity of convulsions (P < 0.05) but had no effect on the development or generalization of convulsions. This finding may have clinical implications in the prevention of neuronal damage induced by drug refractory seizures or SE.
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PMID:Vigabatrin protects against kainic acid-induced neuronal damage in the rat hippocampus. 747 43

The metabolism of GABA and other amino acids was studied in the substantia nigra, the hippocampus and the parietal cortex of rats following microinjections of GAMMA-vinyl-GABA during status epilepticus induced by lithium and pilocarpine. GABA metabolism showed striking regional variations. In controls, both GABA concentration and rate of GABA synthesis were highest in the substantia nigra and lowest in cortex, as expected. In substantia nigra, status epilepticus resulted in a 2 1/2 fold decline in the rate of GABA synthesis and in a 307% increase in the turnover time of the GABA pool. In hippocampus, the rate of GABA synthesis was not altered significantly, but the turnover time of the GABA pool was 284% of controls, and the size of that pool increased to 208% of controls. By contrast, in cortex, where seizure activity is limited in this model, the rate of GABA synthesis increased to 230% of controls while pool size and turnover time did not change. Aspartate concentration decreased in all three brain regions. These data suggest that the observed reduction of the rate of GABA synthesis in substantia nigra could play a key role in seizure spread in this model of status epilepticus.
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PMID:GABA metabolism in the substantia nigra, cortex, and hippocampus during status epilepticus. 847 71

A variety of cerebral insults induce neuronal damage to the hippocampal formation. The somatostatin-immunoreactive (SOM-ir) neurones in the dentate hilus are particularly vulnerable. In the present study, we demonstrated that augmentation of hippocampal GABAergic inhibition by chronic infusion of gamma-vinyl GABA prevented the delayed seizure-induced damage to hilar SOM-ir neurones. Selective lesions of the cholinergic, serotonergic or noradrenergic pathways to the hippocampus did not attenuate the seizure-induced loss of SOM-ir neurones; rather, the damage was exacerbated by the cholinergic lesion. It is, therefore, the intrahippocampal GABAergic circuitries, rather than the selective subcortical pathways, that are critical for neuroprotection after seizures. Enhanced GABAergic inhibition in the hippocampus prevented damage to hilar SOM-ir neurones, even when started 2 days after status epilepticus. GABAergic agents may thus provide an alternative treatment for delayed neuronal damage caused by cerebral insults.
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PMID:Seizure-induced damage to the hippocampus is prevented by modulation of the GABAergic system. 890 19

The effects of the administration of two doses (1,000 and 1,500 mg kg-1) of gamma-vinyl-GABA (GVG), have been tested in pubescent rats, systemically injected with kainic acid (KA). The changes in spontaneous behaviour before KA injection, the behavioural and epileptic manifestations (Wet Dog Shakes, Limbic Seizures and Status Epilepticus) and the lethality rate caused by KA were taken into account and compared to those observed in controls and in carbamazepine (CBZ) or phenytoin (PHT) treated animals. While GVG appeared to reduce the incidence of the epileptic manifestations and the subsequent mortality, particularly when higher doses of the drug were used, CBZ exerted a proconvulsant action and PHT did not substantially modify the parameters considered. Moreover, GVG, but not CBZ and PHT, induced remarkable sedative effects which disappeared within 48 h. The different anticonvulsant profile of GVG, CBZ and PHT were correlated to their different modes of action, since GVG acts by enhancing the inhibitory GABA-mediated processes, while CBZ and PHT act by reducing the excitatory processes.
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PMID:Vigabatrin versus carbamazepine and phenytoin in kainic acid-treated pubescent rats. 934 35

Selective neuronal damage and mossy fiber sprouting may underlie epileptogenesis and spontaneous seizure generation in the epileptic hippocampus. It may be beneficial to prevent their development after cerebral insults that are known to be associated with a high risk of epilepsy later in life in humans. In the present study, we investigated whether chronic treatment with an anticonvulsant, vigabatrin (gamma-vinyl GABA), would prevent the damage to hilar neurons and the development of mossy fiber sprouting. Vigabatrin treatment was started either 1 h, or 2 or 7 days after the beginning of kainic acid-induced (9 mg/kg, i.p.) status epilepticus and continued via subcutaneous osmotic minipumps for 2 months (75 mg/kg per day). Thereafter, rats were perfused for histological analyses. One series of horizontal sections was stained with thionine to estimate the total number of hilar neurons by unbiased stereology. One series was prepared for somatostatin immunohistochemistry and another for Timm histochemistry to detect mossy fiber sprouting. Our data show that vigabatrin treatment did not prevent the decrease in the total number of hilar cells, nor the decrease in hilar somatostatin-immunoreactive (SOM-ir) neurons when SOM-ir neuronal numbers were averaged from all septotemporal levels. However, when vigabatrin was administered 2 days after the onset of status epilepticus, we found a mild neuroprotective effect on SOM-ir neurons in the septal end of the hippocampus (92% SOM-ir neurons remaining; P < 0.05 compared to the vehicle group). Vigabatrin did not prevent mossy fiber sprouting regardless of when treatment was started. Rather, sprouting actually increased in the septal end of the hippocampus when vigabatrin treatment began 1 h after the onset of status epilepticus (P < 0.05 compared to the vehicle group). Our data show that chronic elevation of brain GABA levels after status epilepticus does not have any substantial effects on neuronal loss or mossy fiber sprouting in the rat hippocampus.
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PMID:Effects of vigabatrin treatment on status epilepticus-induced neuronal damage and mossy fiber sprouting in the rat hippocampus. 1002 67

In temporal lobe epilepsy (TLE), the nature of the structures involved in the development of the epileptogenic circuit is still not clearly identified. In the lithium-pilocarpine model, neuronal damage occurs both in the structures belonging to the circuit of initiation and maintenance of the seizures (forebrain limbic system) as well as in the propagation areas (cortex and thalamus) and in the circuit of remote control of seizures (substantia nigra pars reticulata). In order to determine whether protection of some brain areas could prevent the epileptogenesis induced by status epilepticus (SE) and to identify the cerebral structures involved in the genesis of TLE, we studied the effects of the chronic exposure to Vigabatrin (gamma-vinyl-GABA, GVG) on neuronal damage and epileptogenesis induced by lithium-pilocarpine SE. The animals were subjected to SE and GVG treatment (250 mg/kg) was initiated at 10 min after pilocarpine injection and maintained daily for 45 days. These pilo-GVG rats were compared with rats subjected to SE followed by a daily saline treatment (pilo-saline) and to control rats not subjected to SE (saline-saline). GVG treatment induced a marked, almost total neuroprotection in CA3, an efficient protection in CA1 and a moderate one in the hilus of the dentate gyrus while damage in the entorhinal cortex was slightly worsened by the treatment. All pilo-GVG and pilo-saline rats became epileptic after the same latency. Glutamic acid decarboxylase (GAD67) immunoreactivity was restored in pilo-GVG rats compared with pilo-saline rats in all areas of the hippocampus, while it was increased over control levels in the optical layer of the superior colliculus and the substantia nigra pars reticulata. Thus, the present data indicate that neuroprotection of principal cells in the Ammon's horn of the hippocampus is not sufficient to prevent epileptogenesis, suggesting that the hilus and extra-hippocampal structures, that were not protected in this study, may play a role in the genesis of spontaneous recurrent seizures in this model. Furthermore, the study performed in non-epileptic rats indicates that chronic treatment with a GABAmimetic drug upregulates the expression of the protein GAD67 in specific areas of the brain, independently from the seizures.
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PMID:Vigabatrin protects against hippocampal damage but is not antiepileptogenic in the lithium-pilocarpine model of temporal lobe epilepsy. 1167 25