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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of one and five electroshock seizures on [3H]flunitrazepam binding, diazepam-insensitive (DIS) [3H]Ro 15-4513 binding, and levels of mRNA for GABA(A) receptor alpha1, alpha4, beta3 and gamma2 subunits were examined in rats. No changes in any parameter were observed in the CA1 region of hippocampus or in parietal cortex. However, a single seizure produced a rapid and transient increase of alpha4 mRNA in the dentate gyrus, without altering the expression of the other subunits. The putative alpha4 protein, as measured by DIS [3H]Ro 15-4513 binding, was also elevated in the dentate gyrus by a single shock. Repeated electroshock (48-h intervals) resulted in an enhanced response of the alpha4 subunit to the seizure. Neither one nor five seizures altered [3H]flunitrazepam binding.
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PMID:Sensitivity of the rat hippocampal GABA(A) receptor alpha 4 subunit to electroshock seizures. 969 55

Deficits of GABAergic transmission have been reported to occur in tissue surrounding ischemic cortical lesions between a few days and several weeks after the insult. In the present experiments, we used immunohistochemistry with antibodies against parvalbumin and two major subunits of the GABA(A) receptor (alpha1, alpha2) to characterize the events that underlie these changes at different levels of circuit organization. Neocortical infarcts (2 mm diameter) consistently affecting medial parts of the primary somatosensory cortex were induced photochemically in adult male Wistar rats; animals were allowed to recover for one week before perfusion-fixation. When compared to controls the pattern of immunoreactivity had changed for the al subunit of the GABA(A) receptor seven days after the insult. Ipsilateral to the ischemic lesions, we found a decrease in staining intensity reaching up to 4 mm laterally, resulting in a partial or complete absence of the normal laminar staining pattern. No consistent changes were observed for the alpha2 subunit. Parvalbumin staining revealed pathological alterations in a rim of tissue surrounding the infarct, measuring up to 1 mm from the border of the infarcts. Parvalbumin-positive interneurons in this region showed signs of degeneration; both a reduction of the number of dendrites and, to a lesser extent and only immediately adjacent to the ischemic lesions, a reduction of the number of parvalbumin-positive neurons was readily apparent. The results provide evidence for both a differential regulation of two GABA(A) receptor subunits and degenerative changes of parvalbumin-containing interneurons ipsilateral to cortical infarcts. The relevance of these findings for mechanisms underlying long-term recovery, transient functional deficits and postinfarct seizures warrants further investigation.
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PMID:Immunohistochemical evidence for dysregulation of the GABAergic system ipsilateral to photochemically induced cortical infarcts in rats. 975 75

The GABA(A) receptor is a ligand gated chloride channel consisting of five membrane spanning proteins for which 13 different genes have been identified in the mammalian brain. The present review summarizes recent work from our laboratory on the characterization of the immunocytochemical distribution of these GABA(A) receptor subunits in the rat brain and changes in immunoreactivity and mRNA expression after kainic acid-induced status epilepticus. A heterogeneous distribution of immunoreactive GABA(A) receptor subunits was observed. The most abundant ones were: alpha1, alpha2, alpha4, alpha5, beta2, beta3, gamma2, and delta. Alpha1, beta2, and gamma2 were about equally distributed in all subfields of the hippocampus; alpha4- and delta-subunits were preferentially found in the dentate molecular layer and in CA1; alpha2 was localized to the dentate molecular layer and CA3; alpha5 was found in the dendritic areas of CA1 to CA3; and beta1 was preferentially seen in CA2. Alpha1, beta2, gamma2 and delta were highly concentrated in interneurons. Kainic acid-induced seizures caused acute and chronic changes in the expression of mRNAs and immunoreactive proteins. Acute changes included decreases in alpha2, alpha5, beta1, beta3, gamma2 and delta mRNA levels (by about 25-50%), accompanied by increases (by about 50%) in alpha1, alpha4, and beta2 messages in granule cells (after 6-12 h). Chronic changes, characterized by losses in mRNA and immunoreactive proteins in CA1 and CA3, are undoubtedly due to seizure-related cell damage. However, compensatory expression of alpha2 and beta3 subunits, especially in CA3b/c, was observed. Furthermore, increases in mRNAs and immunoreactive proteins were seen for alpha1, alpha2 alpha4, beta1, beta2, beta3 and gamma2 in granule cells and in the molecular layer of the dentate gyrus at 7-30 days after kainic acid injection. The changes in the expression of GABA(A) receptor subunits, observed in practically all hippocampal subfields, may reflect altered GABA-ergic transmission during development of the epileptic syndrome. Increased expression of GABA(A) receptor subunits in the dendritic field of granule cells and CA3 suggest that GABA-ergic inhibition may be augmented at these levels. However, the lasting preservation of alpha1-, beta2-, and gamma2-subunits in interneurons could provide a basis for augmented inhibition of GABA-ergic interneurons, leading to net disinhibition.
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PMID:Expression of GABA(A) receptor subunits in the hippocampus of the rat after kainic acid-induced seizures. 976 15

Repeated ethanol withdrawal experience has been shown to result in exacerbated seizures associated with future withdrawal episodes. This sensitization of the withdrawal response has been postulated to represent a "kindling" phenomenon. The present study employed an established model of repeated ethanol withdrawals to examine the potential role of GABA(A), and NMDA and non-NMDA glutamate receptor systems in mediating enhanced seizure activity, as assessed by sensitivity to seizures induced by pentylenetetrazol (PTZ), NMDA, and kainic acid (KA) i.v. infusions, respectively. Adult C3H mice were chronically exposed to ethanol vapor in inhalation chambers. A multiple withdrawal (MW) group received four cycles of 16-h ethanol vapor exposure interrupted by 8-h periods of abstinence; a single withdrawal (SW) group was tested after a single 16-h bout of ethanol intoxication; and the third group was ethanol-naive, serving as controls (C). Results indicated that the MW group evidenced significantly lower PTZ and NMDA seizure thresholds compared to SW and C groups at 8 and 24 h post-withdrawal. In contrast, MW and SW groups exhibited reduced sensitivity (higher seizure threshold) to KA in comparison to controls, and this effect only emerged at 24 h post-withdrawal. Further, MW mice required significantly less additional PTZ or NMDA to induce more severe convulsions once initial signs of seizures were elicited. Conversely, latency and amount of KA required to transition from initial seizure signs to more severe end-stage convulsions was significantly greater for MW and SW groups compared to controls. Taken together, these results suggest that repeated ethanol withdrawal experience does not result in a global non-specific lowering of threshold to convulsive stimuli, but rather, selective changes in CNS mechanisms associated with neural excitability may underlie potentiated withdrawal responses. Thus, reduced GABA(A) receptor function and increased NMDA receptor activity may become exaggerated as a consequence of repeated withdrawal experience, while reduced sensitivity to KA induced seizures may represent a compensatory response to withdrawal-related CNS hyperexcitability.
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PMID:Repeated ethanol withdrawal experience selectively alters sensitivity to different chemoconvulsant drugs in mice. 976 52

Ganaxolone (3alpha-hydroxy-3beta-methyl-5alpha-pregnan-20-one) is a novel neurosteroid which has anticonvulsant properties in a number of seizure models as well as the ability to enhance function of the gamma-aminobutyric acid-A (GABA(A)) receptor complex via a neurosteroid binding site. The object of these experiments was to ascertain the efficacy of ganaxolone against absence seizures. Ganaxolone was assessed in the low-dose pentylenetetrazol (PTZ) and the gamma-hydroxybutyric acid (GHB) model of absence seizures in rats. Ganaxolone pretreatment resulted in a significant prolongation of absence seizure in both the PTZ and GHB models. Further, ganaxolone in doses above 20 mg/kg alone produced bilaterally synchronous spike wave discharges (SWDs) associated with behavioral arrest. These data suggest that augmentation of GABA(A) receptor complex function by neurosteroids has the potential to result in or exacerbate absence seizures.
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PMID:Ganaxolone, a selective, high-affinity steroid modulator of the gamma-aminobutyric acid-A receptor, exacerbates seizures in animal models of absence. 977 70

1. Imidazole 4-acetic acid (IMA) is a naturally occurring metabolite in brain, although it is unclear what biochemical pathways are involved in its biosynthesis and breakdown. Some evidence, however, suggests that IMA is an oxidation product of histamine. 2. The compound has pronounced neuropharmacological properties, many of which are consistent with an activation of GABA(A) receptors. Indeed, IMA is able to displace [3H]GABA from GABA(A) sites in a potent manner. 3. IMA displays definite partial agonist characteristics as an enhancer of benzodiazepine binding to the GABA(A) receptor complex in membrane preparations. In addition, it has an affinity for GABA(C) receptors, where it seems to act as an antagonist, and perhaps as a weak partial agonist. A third recognition site for IMA in brain is the I1-imidazoline receptor. 4. Parenteral administration to experimental animals leads to a sleep-like state which can often be accompanied by seizures. In addition, central application of IMA has been associated with a dose-related reduction in arterial pressure and sympathetic nervous discharge. 5. No specific receptor site or uptake system for IMA has yet been discovered, adding uncertainty to its role in central nervous system function. Yet the possibility cannot be overlooked that IMA plays a role in regulating blood pressure.
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PMID:Pharmacology and function of imidazole 4-acetic acid in brain. 979 7

Certain naturally-occurring steroid metabolites and their synthetic analogs (neuroactive steroids) allosterically enhance GABA(A) receptor function and possess potent anticonvulsant properties. In the present study, the effect of two synthetic neuroactive steroids, alphaxalone (5alpha-pregnane 3alpha-ol-11, 20-dione) and tetrahydrodeoxycorticosterone was studied in a rat model of generalized absence seizures induced by gamma-hydroxybutyric acid. Both steroids dose-dependently exacerbated gamma-hydroxybutyric acid-induced absence seizures upon systemic administration and after focal administration into thalamic ventrobasal nucleus. However, alphaxalone and tetrahydrodeoxycorticosterone failed to potentiate gamma-hydroxybutyric acid-induced absence seizures when injected into thalamic reticular nucleus. In all the doses of steroids tested in thalamic reticular nucleus, the duration of gamma-hydroxybutyric acid-seizures was neither prolonged nor shortened. This nonresponsiveness of thalamic reticular nucleus to neuroactive steroids in modulating absence seizures may have arisen due to the molecular heterogeneity of GABA(A) receptor subunits within the thalamus.
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PMID:Neuroactive steroids exacerbate gamma-hydroxybutyric acid-induced absence seizures in rats. 983 Dec 91

The effects of ethanol on the development of pentylenetetrazol (PTZ)-kindling as well as on fully PTZ-kindled convulsions in rats were investigated. Ethanol (0.5, 1.0 and 1.5 g/kg i.p.) administered 15 min prior to each PTZ-injection (35 mg/kg i.p.; 3 times/week) significantly inhibited the progressive seizure development compared to saline-treated controls. For the higher doses of ethanol the kindling process was restricted to seizure stages of 1 or 2. Tolerance to this antiepileptogenic action did not occur even after 20 PTZ-stimulations. In a second series of experiments, 0.5 g/kg ethanol administered 10h before each PTZ-injection facilitated the rate of kindling development after 7 to 10 PTZ-injections, while the higher doses of ethanol did not modulate or even slightly reduced the seizure development. In a third test, intermittent administration of a high dose of ethanol (2 g/kg p.o.; twice daily for 6 days) before the kindling procedure (0.5 g/kg i.p. ethanol 10h prior to each PTZ-injection), significantly intensified the kindling development. In addition, studies with fully PTZ-kindled rats demonstrated that ethanol (0.1 to 1.5 g/kg i.p.), given 15 min prior or 2 min after PTZ, reduced the seizure severity in a dose-dependent manner. In conclusion, the present findings provide evidence for pronounced antiepileptogenic and anticonvulsant effects of ethanol after acute application, whereas repeated administration of high doses with longer withdrawal periods leads to proconvulsant actions, possible mediated via neuroadaptive changes in NMDA and/or GABA(A) receptor-related mechanisms.
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PMID:Influence of ethanol on the pentylenetetrazol-induced kindling in rats. 992 83

Effects of i.p. administration of the neurosteroids, allopregnanolone and pregnenolone sulfate, were studied in WAG/Rij rats, a genetic model for generalized absence epilepsy. EEG recordings showed that allopregnanolone, a positive modulator of the GABA(A) receptor, in doses ranging from 5 to 20 mg/kg, increased dose-dependently the number- and total duration of spike-wave discharges. Pregnenolone sulfate, a positive modulator of NMDA receptors, also increased those parameters, though only at the highest dose used (100 mg/kg). Significant changes in spike-wave discharges occurred during the first hour post-injection and were not accompanied with behavioral alterations. The obtained data indicate that both these neurosteroids aggravate the spike-wave activity. This finding contrasts with the anti-convulsant effects of some neurosteroids and they point to a different pharmacological profile of epilepsy with convulsive or non-convulsive seizures.
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PMID:Effects of neurosteroids on spike-wave discharges in the genetic epileptic WAG/Rij rat. 1002 63

Effects of some neurosteroids on the binding of [3H]-glutamate, [3H]-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and [3H]-MK-801, as well as on the [3H]-glutamate uptake were examined in rat hippocampus. The following compounds were evaluated: (a) positive modulators of the GABA(A) receptor: 5alpha-pregnan-3alpha-ol-20-one (allopregnanolone), 5alpha-pregnane-3alpha,21-diol-20-one (allotetrahydrodeoxycorticosterone), 5alpha-pregnan-3alpha-ol-11,20-dione (alphaxalone) and 5alpha-androstan-3alpha-ol-17-one (androsterone); (b) compounds showing GABA(A)-antagonistic and/or N-methyl-D-aspartic acid (NMDA)-agonistic properties: dehydroepiandrosterone sulfate and pregnenolone sulfate; (c) a substance which, apart from its GABA(A)-agonistic potency, has a NMDA-antagonistic action: 5beta-pregnan-3alpha-ol-20-one. None of those neurosteroids tested at concentrations of 0.001-100 microM affected the binding of [3H]-glutamate, [3H]-AMPA and [3H]-MK-801 or the glutamate uptake. The present study suggests that the previously reported inhibitory effects of neurosteroids on excitatory amino acid-induced seizures and neurotoxicity can be linked neither to the direct interaction of these compounds with the above binding sites on glutamate receptor complexes, nor to the glutamate uptake mechanism.
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PMID:Effect of neurosteroids on glutamate binding sites and glutamate uptake in rat hippocampus. 1009 21


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