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)

The inferior colliculus of the genetically epilepsy-prone rat (GEPR) was examined at the ultrastructural level to determine if any abnormalities exist in the inferior colliculus of the GEPR as compared to the non-epileptic Sprague-Dawley rat. Both routine electron microscopic preparations and glutamate decarboxylase (GAD) and GABA immunocytochemical preparations were examined in the GEPR and compared to previous studies from this laboratory that described the normal ultrastructure of the Sprague-Dawley rat. Cell counts from 2 micron semi-thin sections confirmed our previous observations that showed a large, significant increase in the number of neurons in the inferior colliculus of the GEPR as compared to the Sprague-Dawley rat. Many of the small neurons in the inferior colliculus of the GEPR were found to be smaller than those in the inferior colliculus of the Sprague-Dawley rat. Moreover, the small neurons in the GEPR were frequently clumped in clusters of 3-5. Several ultrastructural abnormalities present in the inferior colliculus of the GEPR have been observed at epileptic foci or in brain regions along the pathway of seizure spread in other experimental models of epilepsy. These changes included the presence of dendrites which are almost completely devoid of organelles, hypertrophy of glial processes, and terminals that contain either swollen vesicles or very few vesicles. Other features that were frequently observed in the GEPR but were rarely found in preparations of Sprague-Dawley rats included an abundance of extra membranes, whorl bodies and multivesicular bodies within somata, dendrites and axons.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The ultrastructure of the central nucleus of the inferior colliculus of the genetically epilepsy-prone rat. 284 97

The neuropeptides somatostatin and neuropeptide Y and the activity of glutamate decarboxylase were determined in the frontal cortex of rats subjected to experimental epilepsy. Two different animal models, (1) rats kindled for 4 weeks by daily injection of pentylenetetrazole, and (2) rats which had undergone strong limbic seizures induced by kainic acid, were used. Decreased seizure threshold, as shown by injection of a subconvulsive dose of pentylenetetrazole, was observed 10 days after the last kindling session and 1 month after injection of kainic acid, respectively. Significantly increased levels of somatostatin (by 60%), neuropeptide Y (135%) and increased activity of glutamate decarboxylase (22%) were found in the frontal cortex of rats previously treated with kainic acid. Separation of somatostatin-like immunoreactivity by size exclusion high-performance liquid chromatography showed a marked increase of immunoreactivity in fractions containing the somatostatin precursor (by 200%) and less prominently of somatostatin-14 and somatostatin-28 (by 60 and 80%, respectively). Michaelis-Menten kinetics of glutamate decarboxylase revealed an increased maximal velocity (Vmax) in the frontal cortex of kainic acid-treated rats, but no change in the Km value was found. Similar results were also obtained in pentylenetetrazole-kindled rats. Injection of cysteamine (100 mg/kg, i.p.) resulting in a 30% decrease of cortical somatostatin in kainic acid-pretreated rats markedly suppressed seizures induced by an otherwise subconvulsive dose of pentylenetetrazole.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Concomitant increase of somatostatin, neuropeptide Y and glutamate decarboxylase in the frontal cortex of rats with decreased seizure threshold. 290 35

The present study was designed to test the hypothesis that chronic gamma-aminobutyric acid (GABA) disinhibition of granule cells could explain permanent kindled epileptogenicity. Quantitative and statistical comparisons of glutamate decarboxylase immunoreactivity (GAD-IR), the synthesizing enzyme for GABA, were made of GAD-IR cells and puncta in stratum granulosum of the fascia dentata. The use of GAD immunocytochemistry in kindled and control tissue was used to allow direct anatomic confirmation that we were measuring changes in GAD-IR which would represent GABA synthesis for release by the recurrent inhibitory system of the fascia dentata. Immediately after the last kindled seizure, optically detected GAD-IR puncta densities were significantly reduced in stratum granulosum. At 3 or 7 days after the last kindled seizure, GAD-IR was normal in puncta, indicating that the transient GAD-IR loss was probably a metabolic response to the recent seizure represented by over-use of GAD needed for synthesis of GABA after a prolonged kindled seizure. When the prolonged kindled seizures were discontinued GAD-IR recovered in the puncta. This transient effect did not occur in other areas such as Ammon's horn (CA3) or substantia nigra. The extent of the GAD-IR loss showed no correlation with the severity of the final behavioral seizure (R = 0.23), or the final afterdischarge (AD) duration in entorhinal cortex (R = 0.17) or motor cortex (R = 0.53). A massed stimulation control group given 19 shorter-duration ADs every 10 min (non-kindling) did not reduce GAD-IR. These findings support the hypothetical model that prolonged kindled seizures release excessive GABA which depletes GAD in axon terminals for 1 day after the seizure. However, such a transient suppression of GAD-IR provides no evidence that disinhibition contributes to the kindling process, because kindling proceeds normally with inter-seizure intervals as long as 1 week. The finding of full recovery of GAD-IR within 1 week does not support the model of loss of GABA inhibition to explain the permanency of kindled epileptogenesis.
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PMID:Recovery of decreased glutamate decarboxylase immunoreactivity after rat hippocampal kindling. 291 45

The kindling model of epilepsy, induced by tetanic stimulation of Schaffer collateral/commisural fibers, was studied in the rat hippocampus. Gamma-aminobutyric acid immunoreactivity was used to quantify the number of GABA-immunoreactive somata per mm2 in CA1 region, 28 days after the last generalized seizure. Comparison of the numbers obtained from kindled animals with those from controls, showed a significant decrease (18%) on the ipsilateral stimulated side but none on the contralateral side. In control rats injection of the GABA-transaminase inhibitor, amino oxyacetic acid (AOAA), led to a 46% increase in the number of cell somata immunoreactive for GABA. This probably results from an accumulation of GABA, reflecting GABA synthesis by glutamate decarboxylase (GAD) activity, in somata of interneurons that had initially a GABA content below the immunocytochemical detection threshold. In kindled rats, 31 days after the last seizure, the number of GABA-immunoreactive cells that could be observed after AOAA-treatment was significantly lower (35% ipsilateral and 25% contralateral) when compared to AOAA-treated controls. This suggests that in kindled animals a GAD dependent increase in GABA content did not take place in a subpopulation of interneurons. The observations for kindled rats are interpreted as a long-term decrease in GABA content and as an alteration in GABA turnover in a subpopulation of interneuron somata, the latter possibly due to a decrease in GAD activity. The long-term enhanced seizure sensitivity, characteristic for kindled animals, may be due to a decreased GABAergic inhibitory control of the neuronal circuitry in the CA1 region of the hippocampus.
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PMID:Decrease in GABA immunoreactivity and alteration of GABA metabolism after kindling in the rat hippocampus. 292 57

The activity of the GABA-synthesizing enzyme glutamate decarboxylase (GAD) was determined in synaptosomal fractions from 12 brain regions of amygdaloid kindled rats. The only significant difference in regional GAD activities between kindled animals and sham-operated controls was a 40% decrease of GAD activity in the substantia nigra. The data suggest that impaired GABAergic function in the nigra may be involved in the initiation and propagation of amygdaloid-kindled seizures.
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PMID:Evidence for impaired GABAergic activity in the substantia nigra of amygdaloid kindled rats. 299 93

Previous studies have indicated that a loss of GABAergic terminals occurs at epileptic foci. The present study was undertaken to investigate if this loss is associated with a loss of GABAergic neuronal somata. Seven juvenile monkeys (M. mulatta) received alumina gel injections to the pre-central gyrus of the left cerebral hemisphere to produce epileptic foci. Four of these monkeys were chosen for further quantitative study. One was sacrificed prior to seizure onset ('pre-seizure'), one had seizures for 3 days ('acute'), and two had a seizure record of one month ('chronic'). Sections of tissue from the epileptic cortex and from the contralateral, non-epileptic cortex were processed for glutamate decarboxylase (GAD) immunocytochemistry at the light microscopic level. Quantitative analysis revealed that a loss of GAD-positive neuronal somata ranging from 24 to 52% occurred at epileptic foci for all monkeys. This decrease was significant (P less than 0.01) for the two chronic monkeys. There was also a slight decrease in GAD-positive neurons 1 cm distal to the focus ('parafocus') in the chronic monkeys, but not in the acute or pre-seizure animals. In addition, small GAD-positive somata (50-150 micron2) were more severely decreased in number at epileptic foci than larger ones (200-250 micron2). As an experimental control, an additional monkey was given a surgical lesion in area 4 of one cerebral hemisphere. It did not display seizure activity prior to sacrifice and did not show a loss of GAD-positive neurons proximal to the control lesions. The results of this study indicate that a loss of GABAergic neuronal somata is associated with a loss of GABAergic terminals at epileptic foci, and that this loss may be more specific for the small GABAergic neurons.
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PMID:A decrease in the number of GABAergic somata is associated with the preferential loss of GABAergic terminals at epileptic foci. 300 43

Although animal models consistently indicate that gamma-amino-butyric acid (GABA) synaptic function (GABA levels, synthesis, uptake and/or receptors) is decreased in seizure states, there is little evidence to date in support of such a hypothesis for human epilepsy. This chapter presents the results of an in-depth study of the activity of the GABA-synthesizing enzyme L-glutamic acid decarboxylase (GAD) in brain tissue removed during neurosurgical resection for intractable epilepsy. The tissue studied is unique in that identified (by stereo EEG) foci were excised (rather than large blocks of tissue containing mixtures of foci and nonepileptic material) and compared with nonepileptic (stereo EEG and morphological definitions) tissue from the same patients. In patients in which there was no indication of a tumor, GAD activity in the foci was low in more than 50% of the patients examined. Furthermore, when the population distribution of GAD was compared in epileptic versus nonepileptic tissue fragments from all patients, the peak distribution of epileptic tissue fragments occurred at much lower GAD activities than for the nonepileptic fragments (0-20 versus 41-80 nmol CO2/mg protein X hr, respectively). A small subgroup of epileptic fragments occurred with a normal GAD distribution, indicating that the presence of an epileptic focus was not invariably associated with low GAD activity. When the low levels of GABA "A" binding sites in these epileptic tissue fragments are taken into consideration in combination with the low GAD levels, then it can be estimated that 60 to 70% of the present patient population had deficient GABAergic transmission in epileptic foci as compared to nonepileptic brain tissue from the same patients. It follows that the GABA hypothesis of human epilepsy is not an exclusive or unitary hypothesis, and some patients appear to have normally functioning GABA synapses (as assessed biochemically) in epileptogenic areas. Thus, other neurotransmitter and neurohumoral systems certainly play a role in the epileptic process.
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PMID:Alterations of GABA-mediated synaptic transmission in human epilepsy. 301 Jun 75

Several previous studies have suggested a strong GABA-mimetic action of the endogenous brain imino acid, L-pipecolic acid (L-PA). In the present study, these observations were evaluated using electrophysiological and neurochemical methods. In contrast to published data our electrophysiological studies on rat cortical neurones in situ showed only a weak, but bicuculline-sensitive depressant action of L-PA on cortical neurones. Furthermore, L-PA proved to have no affinity for any of the three components of the GABA-benzodiazepine-chloride channel receptor complex. However, using a modification of published methods a weak affinity for the GABA-B receptor site was demonstrated (IC50 = 1.8 X 10(-3) M). L-PA showed no anticonvulsive activity in several tests; in particular, it did not protect mice from seizures induced by inhibition of L-glutamate-1-decarboxylase (EC 4.1.1.15: GAD). L-PA had a very weak action on brain GABA levels of mice, and did not modify the rate of GABA synthesis. In conclusion, these results are not compatible with a strong in vivo interaction between L-PA and GABA-mediated inhibitory transmission.
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PMID:Dose pipecolic acid interact with the central GABA-ergic system? 302 50

The effect of mannitol treatment on the behavioural, morphological and neurochemical brain damage induced after subcutaneously applied kainic acid (10 mg/kg) was studied in the rat. Mannitol at a dose of 1.5 g/kg was injected intravenously 10 min, 1.5 h and 3 h respectively after kainic acid administration. A protective effect of mannitol was observed only when mannitol was given 1.5 h after kainic acid application, i.e. within the early phase of kainic acid-induced brain oedema development. At this time period, mannitol prevented the development of kainic acid-induced seizures as well as irreversible brain lesions and neurochemical changes, the latter being reduction of noradrenaline levels in amygdala/pyriform cortex measured 3 h, and reduction of glutamate decarboxylase and choline acetyltransferase activities measured 3 days after kainic acid treatment. Similarly loss of glutamate decarboxylase activity in dorsal hippocampus induced by kainic acid was prevented by mannitol treatment. It is concluded that by washing out brain oedema, mannitol treatment may prevent propagation of seizures and brain damage in the kainic acid model of epilepsy.
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PMID:Effect of mannitol treatment on brain neurotransmitter markers in kainic acid-induced epilepsy. 311 66

The brains of seizure-sensitive (SS) and seizure-resistant (SR) gerbils were studied with an immunocytochemical method to localize glutamic acid decarboxylase (GAD) to determine whether a defect existed in the inhibitory GABAergic system similar to that which has been reported in animal models of focal epilepsy in which GABAergic cell bodies and terminals are decreased in number. A major difference between the two strains of gerbils was found in the number of GABAergic neurons in the hippocampal formation. Specifically, a paradoxical increase occurred in the number of glutamate decarboxylase GAD-immunoreactive neurons: there were approximately 65% more GABAergic cells within the dentate gyrus and the CA3 region of the hippocampus in the SS gerbils. Furthermore, the density of GAD-immunoreactive puncta, the light microscopic correlates of synaptic boutons, was greater in the SS animals. Other histological methods were used to determine if the difference between SS and SR gerbils was specific for the GABAergic system. Nissl-stained preparations showed that the number of granule cells in the dentate gyrus was 20% greater in SS gerbils than in SR gerbils. An examination of some hippocampal afferents, efferents, and intrinsic connections with acetylcholinesterase histochemistry and the Timm's stain for heavy metals demonstrated no differences between the two strains. In addition, Golgi-stained preparations of the dentate gyrus indicated that the morphology of basket cells did not differ between the two strains nor between the gerbil and the rat. Several brain regions in addition to the hippocampus were studied to determine whether or not the increased number of GAD-immunoreactive neurons was specific for the hippocampal formation. These regions included the substantia nigra, motor cortex, and nucleus reticularis thalami and were selected because they contain large populations of GABAergic neurons and have been implicated in seizure activity. No differences between the two strains were detected in any of these regions. Therefore, a major morphological difference between the brains of SS and SR gerbils exists in the hippocampal formation of SS gerbils in which an increase occurs in the number of GABAergic neurons and granule cells. If these additional inhibitory neurons act mainly to inhibit other inhibitory neurons, the net effect would be increased disinhibition of the principal excitatory neurons of the hippocampal formation. This could lead to seizure activity within the hippocampal formation and at distant sites through multiple synaptic connections.
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PMID:Hippocampus of the seizure-sensitive gerbil is a specific site for anatomical changes in the GABAergic system. 361 18


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