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)

Overactivation of NMDA-Rs may mediate excitotoxic cell death associated with epileptic seizures, and hypoxic-ischemic conditions. We assessed whether repeated subcutaneous administration of l-glutamate to neonatal rats affects the subunit composition of NMDA-Rs. Accordingly, cortical and hippocampal tissue from 14-day-old rats was analyzed by Western blotting and RT-PCR to quantify the protein and mRNA expression of different NMDA-R subunits. In addition, tissue sections were Nissl stained to assess the cell damage in this tissue. Early exposure of neonatal rats to L-glutamate differentially affects the expression of mRNA transcripts for NMDA-R subunits in the cerebral cortex and hippocampus. In the cerebral cortex, a decrease in NR2B subunit mRNA expression was observed, as well as a loss of NR1 and NR2A protein. By contrast, neonatal L-glutamate administration augmented the transcripts encoding the NR1, NR2B, and NR2C subunits in the hippocampal formation. The expression of mRNA encoding the NR2A subunit was not affected by neonatal L-glutamate administration in either of the brain regions examined. This differential expression of NMDA-R subunits following neonatal exposure to L-glutamate may represent an adaptive response of the glutamate receptors to overactivation in order to reduce the effect of high L-glutamate during the early period of life when the animal is more vulnerable to excitotoxicity.
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PMID:Changes in hippocampal NMDA-R subunit composition induced by exposure of neonatal rats to L-glutamate. 1893 Aug 1

The seizure-induced molecular and functional alterations of glutamatergic transmission in the hippocampus have been investigated. Daily repeated epileptic seizures were induced for 12 days by intraperitoneal administration of 4-aminopyridine (4-AP; 4.5 mg/kg) in adult Wistar rats. The seizure symptoms were evaluated on the Racine's scale. One day after the last injection, the brains were removed for in vitro electrophysiological experiments and immunohistochemical analysis. The glutamate receptor subunits NR1, NR2A, NR2B, GluR1, GluR1(flop), GluR2, and KA-2 were studied using the histoblotting method. The semi-quantitative analysis of subunit immunoreactivities in hippocampal layers was performed with densitometry. In the hippocampus, increase of GluR1, GluR1(flop) and NR2B immunostaining was observed in most of the areas and layers. The significant decrease of GluR2 staining intensity was observed in the CA1 and dentate gyrus. Calcium permeability of hippocampal neurons was tested by a cobalt uptake assay in hippocampal slices. The uptake of cobalt increased in the CA1 area and dentate gyrus, but not in the CA3 region following 4-AP treatment. Effects of AMPA and NMDA (N-methyl-d-aspartate) glutamate receptor antagonists (1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride (GYKI 52466) and D-APV respectively) were measured in hippocampal slices using extracellular recording. Analysis of the population spikes revealed the reduced effectiveness of the AMPA receptor antagonist GYKI 52466, while the effect of the NMDA receptor antagonist d-(2R)-amino-5-phosphonovaleric acid was similar to controls. The results demonstrated that repeated convulsions induced structural and functional changes in AMPA receptor-mediated transmission, while NMDA and kainate receptor systems displayed only alterations in receptor subunit composition.
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PMID:Modification of ionotropic glutamate receptor-mediated processes in the rat hippocampus following repeated, brief seizures. 1915 79

Tumor necrosis factor (TNF)-alpha is a proinflammatory cytokine acting on two distinct receptor subtypes, namely p55 and p75 receptors. TNF-alpha p55 and p75 receptor knockout mice were previously shown to display a decreased or enhanced susceptibility to seizures, respectively, suggesting intrinsic modifications in neuronal excitability. We investigated whether alterations in glutamate system function occur in these naive knockout mice with perturbed cytokine signaling that could explain their different propensity to develop seizures. Using Western blot analysis of hippocampal homogenates, we found that p55(-/-) mice have decreased levels of membrane GluR3 and NR1 glutamate receptor subunits while GluR1, GluR2, GluR6/7 and NR2A/B were unchanged as compared to wild-type mice. In p75(-/-) mice, GluR2, GluR3, GluR6/7 and NR2A/B glutamate receptor subunits were increased in the hippocampus while GluR1 and NR1 did not change. Extracellular single-cell recordings of the electrical activity of hippocampal neurons were carried out in anesthetized mice by standard electrophysiological techniques. Microiontophoretic application of glutamate increased the basal firing rate of hippocampal neurons in p75(-/-) mice versus wild-type mice, and this effect was blocked by 2-amino-5-phosphopentanoic acid and 6-nitro-7-sulfamoyl-benzo(f)quinoxaline-2,3-dione denoting the involvement of N-methyl-D-aspartic acid and AMPA receptors. In p55(-/-) mice, hippocampal neurons responses to glutamate were similar to wild-type mice. Spontaneous glutamate release measured by in vivo hippocampal microdialysis was significantly decreased only in p55(-/-) mice. No changes were observed in KCl-induced glutamate release in both receptor knockout mice strains versus wild-type mice. These findings highlight specific molecular and functional interactions between p55 and p75 receptor-mediated signaling and the glutamate system. These interactions may be relevant for controlling neuronal excitability in physiological and pathological conditions.
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PMID:Molecular and functional interactions between tumor necrosis factor-alpha receptors and the glutamatergic system in the mouse hippocampus: implications for seizure susceptibility. 1928 15

Systemic administration of the potassium channel blocker 4-aminopyridine (4-AP) elicits acute convulsions. Synchronized tonic-clonic activity develops during the first hour after the treatment. However, subsequent chronic spontaneous seizures do not appear which suggests changes in neuronal excitability. The aim of our present work was to evaluate alterations in the glutamatergic transmission in the somatosensory cortex of rats following daily, brief convulsions elicited by 4-AP treatment. Changes in general neuronal excitability and pharmacological sensitivity of glutamate receptors were tested in ex vivo electrophysiological experiments on brain slices. In parallel studies quantitative changes in subunit composition of glutamate receptors were determined with immunohistoblot technique, together with the analysis of kainate induced Co2+ uptake. The results of our coordinated electrophysiological, receptor-pharmacological and histoblot studies demonstrated that repeated, daily, short convulsions resulted in a significant decrease of the general excitability of the somatosensory cortex together with changes in ionotropic glutamate receptor subunits. The relative inhibitory effect of the AMPA receptor antagonist, however, did not change. The NMDA receptor antagonist exerted somewhat stronger effect in the slices from convulsing animals. 4-AP pretreatment resulted in the attenuation of kainate induced Co2+ uptake, which suggests either reduction in non-NMDA receptors numbers or reduction in their Ca2+ permeability. Repeated seizures decreased GluR1-4 AMPA receptor subunit levels in all cortical layers with a relaitve increase in GluR1 subunits. While the principle NR1 NMDA receptor subunit showed no significant change, the staining density of NR2A subunit increased. These changes in ionotropic glutamate receptors are consistent with reduced excitability at glutamatergic synapses following repeated 4-AP induced seizures.
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PMID:Repeated 4-aminopyridine induced seizures diminish the efficacy of glutamatergic transmission in the neocortex. 1944 32

Tosyl-polyamine derivatives such as N-{4-[4-(guanidinobutylamino)-butylamino]butyl}-4-methylbenzenesulfonamide trihydrochroride (TsHSPMG) have been found to strongly inhibit macroscopic currents through heteromeric N-methyl-D-aspartate (NMDA) receptors (NR1/NR2A, NR1/NR2B) and Ca(2+)-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (homomeric glutamate receptor 1) receptors expressed in Xenopus laevis oocytes on voltage-clamp recording. In the present study, it was found that the inhibition of NMDA receptor activity induced by tosyl-polyamine derivatives was voltage-dependent. Some mutations located in the intracellular region of the channel pore, such as NR1 E621Q and NR2B W607L, reduced the inhibition by tosyl-polyamine derivatives, suggesting that tosyl-polyamine derivatives penetrate deeply into the channel pore of NMDA receptors. The neuroprotective effects of tosyl-polyamine derivatives against cell injury caused by NMDA were investigated in cultured rat hippocampal neurons. Addition of 1 microM TsHSPMG to medium ablated the neurotoxicity induced by NMDA, and a similar effect was observed with 30 microM memantine. The neuroprotective effects of tosyl-polyamine derivatives on NMDA-induced seizures in mice were also assayed. Intracerebroventricular or intravenous injection of TsHSPMG (0.1 or 0.5 mg/kg) decreased the seizures induced by intraperitoneal injection of NMDA in mice. These findings indicate that tosyl-polyamine derivatives exhibit neuroprotective effects not only in primary cultured neurons but also in mice.
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PMID:Neuroprotection by tosyl-polyamine derivatives through the inhibition of ionotropic glutamate receptors. 1964 42

Viral infections of the CNS and their accompanying inflammation can cause long-term neurological effects, including increased risk for seizures. To examine the effects of CNS inflammation, we infused polyinosinic:polycytidylic acid, intracerebroventricularly to mimic a viral CNS infection in 14 day-old rats. This caused fever and an increase in the pro-inflammatory cytokine, interleukin (IL)-1beta in the brain. As young adults, these animals were more susceptible to lithium-pilocarpine and pentylenetetrazol-induced seizures and showed memory deficits in fear conditioning. Whereas there was no alteration in adult hippocampal cytokine levels, we found a marked increase in NMDA (NR2A and C) and AMPA (GluR1) glutamate receptor subunit mRNA expression. The increase in seizure susceptibility, glutamate receptor subunits, and hippocampal IL-1beta levels were suppressed by neonatal systemic minocycline. Thus, a novel model of viral CNS inflammation reveals pathophysiological relationships between brain cytokines, glutamate receptors, behaviour and seizures, which can be attenuated by anti-inflammatory agents like minocycline.
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PMID:Viral-like brain inflammation during development causes increased seizure susceptibility in adult rats. 1966 May 46

Seizures early in life cause long-term behavioral modifications, namely long-term memory deficits in experimental animals. Since caffeine and adenosine A(2A) receptor (A(2A)R) antagonists prevent memory deficits in adult animals, we now investigated if they also prevented the long-term memory deficits caused by a convulsive period early in life. Administration of kainate (KA, 2 mg/kg) to 7-days-old (P7) rats caused a single period of self-extinguishable convulsions which lead to a poorer memory performance in the Y-maze only when rats were older than 90 days, without modification of locomotion or anxiety-like behavior in the elevated-plus maze. In accordance with the relationship between synaptotoxicity and memory dysfunction, the hippocampus of these adult rats treated with kainate at P7 displayed a lower density of synaptic proteins such as SNAP-25 and syntaxin (but not synaptophysin), as well as vesicular glutamate transporters type 1 (but not vesicular GABA transporters), with no changes in PSD-95, NMDA receptor subunits (NR1, NR2A, NR2B) or alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor subunits (GluR1, GluR2) compared with controls. Caffeine (1 g/L) or the A(2A)R antagonist, KW6002 (3 mg/kg) applied in the drinking water from P21 onwards, prevented these memory deficits in P90 rats treated with KA at P7, as well as the accompanying synaptotoxicity. These results show that a single convulsive episode in early life causes a delayed memory deficit in adulthood accompanied by a glutamatergic synaptotoxicity that was prevented by caffeine or adenosine A(2A)R antagonists.
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PMID:Caffeine and an adenosine A(2A) receptor antagonist prevent memory impairment and synaptotoxicity in adult rats triggered by a convulsive episode in early life. 1987 34

It has been reported that N-methyl-D-aspartate receptor (NMDAR)-triggered neurotoxicity is related to excessive Ca(2+) loading and an increase in nitric oxide (NO) concentration. However, the molecular mechanisms that underlie these events are not completely understood. NMDARs and neuronal NO synthase each binds to the scaffolding protein postsynaptic density (PSD)-93 through its PDZ domains. In this study, we determined whether PSD-93 plays a critical role in NMDAR/Ca(2+)/NO-mediated neurotoxicity. We found that the targeted disruption of the PSD-93 gene attenuated the neurotoxicity triggered by NMDAR activation, but not by non-NMDAR activation, in cultured mouse cortical neurons. PSD-93 deficiency reduced the amount of NMDAR subunits NR2A and NR2B in synaptosomal fractions from the cortical neurons and significantly prevented NMDA-stimulated increases in cyclic guanosine 3',5'-monophosphate and Ca(2+) loading in the cortical neurons. These findings indicate that PSD-93 deficiency could block NMDAR-triggered neurotoxicity by disrupting the NMDAR-Ca(2+)-NO signaling pathway and reducing expression of synaptic NR2A and NR2B. Since NMDARs, Ca(2+), and NO play a critical role during the development of brain trauma, seizures, and ischemia, the present work suggests that PSD-93 might contribute to molecular mechanisms of neuronal damage in these brain disorders.
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PMID:Postsynaptic density-93 deficiency protects cultured cortical neurons from N-methyl-D-aspartate receptor-triggered neurotoxicity. 2009 70

The developing brain undergoes major reorganization in response to early environmental changes. The elevated excitation that allows the neonatal brain to develop quickly also makes it highly vulnerable to age-specific seizures that can cause lifelong cognitive and neurological disability. However, it is not yet clear how seizures interfere with the developmental program and how epileptogenesis actualize. Here, by using an in vitro model, we report a global abnormal status of cortical cells after epileptiform activity was induced: more NR2B is targeted on the neuronal surface with less NR2A. Dendrotoxicity including dendritic beading, distortion and simplification of dendritic branching patterns were observed. Early-life seizure-like insults also exert effects on the excitatory synaptic size and interactions between PSD-95 and NR2A or NR2B receptor subunits. Our findings support an abnormal development or, worse, cellular degeneration that resembles immature cells, which may enlighten better understanding of the pathological mechanism of early-life seizures and its related injury.
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PMID:Characterization of developing rat cortical neurons after epileptiform discharges. 2060 Jul 87

Inhibitory mechanism of cerebellum epileptic activity can be involved depending on the intensity and frequency of seizure convulsions. N-methyl-D-aspartate receptors (NMDARs) play key roles in excitatory synaptic transmission and have been implicated in neurological disorders: in cerebellum, they have specific characteristics. NMDARs are heteromeric complexes, and the expression of functional receptors in mammalian cells requires the subunit NR1 (essential) and one NR2 subtype of the four isoforms: NR2A-NR2D. In mature Purkinje cells, the combination of NR1 with NR2B subunits forms functional NMDARs; NR2B subunit may be altered in exocitotoxic events. Cyclopentyladenosine (CPA), an adenosine analogue, administered to rats, for one or more days, increases seizure threshold induced by the convulsant drug 3-mercaptopropionic acid (MP). In this study, we focused on the expression of NR2B in cerebellum after repetitive seizures induced by MP and the effect of adenosine analogue CPA administered alone or previous to MP (CPA + MP). A significant decrease in NR2B in the whole cerebellum was observed after MP and CPA administration with a tendency to recover to normal values in the combined treatment of CPA administered 30 min before MP by Western blot assay. In immunohistochemical studies, NR2B expression was observed and analysed in Purkinje cells. NR2B expression was decreased after MP (55%) and CPA (12%) administration, and CPA injected 30 min before MP led to 28% reduction in Purkinje cells. These results could be related to Purkinje cell damage or alternatively to avoid the excitotoxic effect. Results recorded after CPA + MP treatment seemed involved in decreasing the convulsant MP effect.
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PMID:3-mercaptopropionic acid-induced seizures decrease NR2B expression in Purkinje cells: cyclopentyladenosine effect. 2062 10


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