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)

Kainic acid (KA) induces status epilepticus in both adult and young rats but with different consequences on pathology and gene expression. In adults, GluR2(B) AMPA subunit expression is markedly reduced in CA3 neurons before neurodegeneration. In pups, the GluR2(B) subunit is sustained, possibly contributing to neuronal survival. Mechanisms underlying the reduced vulnerability of developing neurons to seizures was investigated by examining the effects of unilateral microinfusions of GluR2(B) antisense oligodeoxynucleotides (AS-ODNs) into the hippocampus of young rats in the presence or absence of a subconvulsive dose of KA. GluR2(B) AS-ODN infusions resulted in spontaneous seizure-like behavior, high stimulus intensity population spikes in the absence of long-term potentiation, and neurodegeneration of CA3 neurons lateral to the infusion site. Electroencephalography revealed paroxysmal activity and high-frequency high-amplitude discharges associated with vigorous and continuous scratching, wild running, or bilateral jerking movements. Pups lacking phenotypic behavior exhibited high-rhythmic oscillations and status epilepticus by the dose of KA used. Radiolabeled AS-ODNs accumulated throughout the ipsilateral dorsal hippocampus. GluR2(B) but not GluR1(A) receptor protein was markedly reduced after GluR2(B) knockdown. In contrast, GluR1(A) knockdown reduced GluR1(A) but not GluR2(B) protein without change in behavior or morphology. Therefore, unilateral downregulation of hippocampal GluR2(B) but not GluR1(A) protein reduces the seizure threshold and survival of CA3 neurons in the immature hippocampus, possibly providing a novel partial seizure model in the developing rat.
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PMID:Unilateral GluR2(B) hippocampal knockdown: a novel partial seizure model in the developing rat. 1053 45

The excitatory amino acid glutamate has been implicated in the neurodegeneration associated with several different central nervous system diseases. Treatment with kainic acid (KA), a glutamate analog known to activate the AMPA/KA subtype of glutamate receptor, has been widely used as a model of epilepsy. Long term temporal studies of its neuropathological effects, however, are lacking. In this study, two techniques were used to directly visualize and characterize the neuropathology that occurred over a 2-month period following KA-induced status epilepticus in adult female Sprague-Dawley rats. Post-injection survival was 2, 4, 8 h, 2 days, 2 weeks, or 2 months. Labeling with Fluoro-Jade B (FJB), a fluorescent green dye that labels the cell body, dendrites, axons and axon terminals of degenerating neurons, was observed within the cortex, hippocampus, thalamus, basal ganglia, and amygdala by 4 h post-treatment. The highest level of labeling was seen in the piriform cortex, hippocampus, and thalamus. Myelin changes in the rat forebrain following KA treatment were also examined using the myelin-specific Black-Gold (BG) stain. Varicose myelinated fibers were observed in the same regions as FJB positive neurons, although these changes were evident by the 2-h survival time-point. Both stains showed a temporal progression of brain damage throughout the affected areas. By 2 months post-treatment, few degenerating neurons could be detected and abnormal myelin was absent in most regions. As myelin changes can be seen prior to neuronal degeneration, and oligodendrocytes express functional AMPA/kainate-type glutamate receptors, the neurodegeneration and myelin pathologies may occur as independent events. Thus, researchers should consider the temporal and multiple effects of kainic acid to optimize conditions for their endpoint of interest when designing experiments.
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PMID:Temporal progression of kainic acid induced neuronal and myelin degeneration in the rat forebrain. 1079 88

Systemic administration of kainic acid (KA) induces status epilepticus (SE) that causes neurodegeneration and may subsequently lead to spontaneous recurrent seizures. We investigated the effects of KA-induced SE on tyrosine phosphorylation and solubility properties of the NMDA receptor. Following 1 h of SE, total protein tyrosine phosphorylation was elevated in both the hippocampus and frontal cortex relative to controls. Tyrosine phosphorylation of the NMDA receptor subunits NR2A and NR2B was also enhanced following SE. Animals that received KA but did not develop SE, did not exhibit increased tyrosine phosphorylation. SE resulted in a decrease in the solubility of NMDA receptor subunits and of PSD-95 in 1% deoxycholate. In contrast, the detergent solubility of AMPA and kainate receptors was not affected. These findings demonstrate that SE alters tyrosine phosphorylation of the NMDA receptor, and indicate that the interaction of the NMDA receptor with other components of the NMDA receptor complex are altered as a consequence of seizure activity.
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PMID:Seizure activity results in increased tyrosine phosphorylation of the N-methyl-D-aspartate receptor in the hippocampus. 1168 75

Excitatory amino acid-induced death of central neurons may be mediated by at least two receptor types, the so-called NMDA (N-methyl-d-aspartate) and AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionate) receptors. We have studied the neurodegenerative mechanisms set in motion by AMPA receptor activation using incubated slices of 8-day-old rat cerebellum and hippocampus. In both preparations, AMPA induced a pattern of degeneration that differed markedly from the one previously shown to be elicited by NMDA. In cerebellar slices, AMPA induced the degeneration of most Purkinje cells together with a population of Golgi cells; in hippocampal slices the neurons were affected in the order CA3 > CA1 > dentate granule cells. Three mechanisms could be discerned: an acute one in which neurons (e.g. cerebellar Golgi cells) underwent a rapid degeneration; a delayed one in which the neurons (Purkinje cells and hippocampal neurons) appeared to be only mildly affected immediately after a 30 min exposure but then underwent a protracted degeneration during the postincubation period (1.5 - 3 h); and finally a slow toxicity, which took place during long (2 h) exposures to AMPA (3 - 30 microM). Although Purkinje cells were vulnerable in both cases, the efficacy of AMPA was higher for the delayed mechanism than for the slow one. The pathology displayed by the acutely destroyed Golgi neurons was a classical oedematous necrosis, whereas most neurons vulnerable to the delayed and slow mechanisms displayed a 'dark cell degeneration', whose cytological features bore a close resemblance to those of neurons irreversibly damaged by ischaemia, hypoglycaemia or status epilepticus in vivo.
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PMID:AMPA Neurotoxicity in Rat Cerebellar and Hippocampal Slices: Histological Evidence for Three Mechanisms. 1210 58

Topiramate, an antiepileptic drug with a number of mechanisms of action including inhibition of glutamate activity at the AMPA and KA receptors, was assessed as a neuroprotective agent following seizures. We administered topiramate, 80 mg/kg, or saline for 4 weeks following a series of 25 neonatal seizures or status epilepticus (SE) induced by lithium-pilocarpine in postnatal day 20 rats. Age-matched control rats without a history of seizures were administered topiramate or saline. Following completion of the topiramate injections, animals were tested in the water maze for spatial learning and the brains examined for cell loss and sprouting of mossy fibers. While there was a trend for improved visual-spatial performance in the water maze following topiramate therapy in rats with neonatal seizures, no differences were found in the histological examination of the hippocampus. Neonatal rats exposed to 4 weeks of topiramate did not differ from non-treated controls in water maze performance or histological examination. In weanling rats subjected to SE, topiramate provided a moderate degree of neuroprotection, with topiramate-treated rats performing better in the water maze than rats receiving saline. However, no differences in cell loss or mossy fiber sprouting were found in the histological examination of the brains. These findings demonstrate that chronic treatment with topiramate following SE improves cognitive function. In addition, long-term administration of high-dose topiramate in the normal developing rat brain does not appear to impair cognitive performance.
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PMID:Effect of topiramate following recurrent and prolonged seizures during early development. 1239 72

Systemic administration of kainic acid in C57BL/6 and FVB/N mice induces a comparable level of seizure induction yet results in differential susceptibility to seizure-induced cell death. While kainate administration causes severe hippocampal damage in mice of the FVB/N strain, C57BL/6 mice display no demonstrable cell loss or damage. At present, while the cellular mechanisms underlying strain-dependent differences in susceptibility remain unclear, some of this variation is assumed to have a genetic basis. As glutamate receptors are thought to participate in seizure induction and the subsequent neuronal degeneration that ensues, previous studies have proposed that variation in the precise subunit composition of glutamate receptors may result in differential susceptibility to excitotoxic cell death. Thus, we chose to examine the relationship between the cellular distribution and expression of glutamate receptor subunit proteins and cell loss within the hippocampus in mouse strains resistant and susceptible to kainate-induced excitotoxicity. Using semi-quantitative Western blot techniques and immunohistochemistry with the use of antibodies that recognize subunits of the KA (GluR5,6,7), AMPA (GluR1, GluR2, and GluR4), and NMDA (NMDAR1 and NMDAR2A/2B) receptors, we found no significant strain-dependent differences in the expression or distribution of these glutamate receptor subunits in the intact hippocampus. Following kainate administration, expression changes in ionotropic glutamate receptor subunits paralleled the development of susceptibility to cell death in the FVB/N strain only. Strain differences in hippocampal vulnerability to kainate-induced status epilepticus are not due to glutamate receptor protein expression.
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PMID:Differences in ionotropic glutamate receptor subunit expression are not responsible for strain-dependent susceptibility to excitotoxin-induced injury. 1267 Jul 4

Ca2+ currents are thought to enhance glutamate excitotoxicity. To investigate whether reduced expression of the Ca2+ limiting GluR2(B) subunit enhances seizure-induced vulnerability to either CA1 or CA3 neurons, we delivered GluR2(B) oligodeoxynucleotides (AS-ODNs) to the dorsal hippocampus of adult rats before inducing kainate (KA) seizures. After knockdown, no changes in behavior, electrographic activity, or histology were observed. In contrast, GluR2(B) knockdown and KA-induced status epilepticus produced accelerated histological injury to the ipsilateral CA3a-b and hilar subregions. At 8 to 12 h, the CA3a was preferentially labeled by both silver and TUNEL methods. TUNEL staining revealed 2 types of nuclei. They were round with uniform label, features of necrosis, or had DNA clumping or speckled chromatin deposits within surrounding cytosol, features of apoptosis. At 16 to 24 h, many CA3a-c neurons were shrunken, eosinophilic, argyrophilic, or completely absent. Immunohistochemistry revealed marked decreases in GluR2(B) subunits throughout the hippocampus, NR1 immunoreactivity was also reduced but to a lesser extent. In contrast, GluR1 and NR2A/B immunohistochemistry was relatively uniform except in regions of cell loss or within close proximity to the CA1 infusion site. At 144 h, the CA3 was still preferentially injured although bilateral CA1 injury was also observed in some AS-ODN-, S-ODN-, and KA-only-treated animals. Glutamate receptor antibodies revealed generalized decreases in the CA3 with all probes tested at this delayed time. In contrast, GluR2(B) expression was increased within CA1 irregularly shaped, injured neurons. Therefore, hippocampal deprivation of GluR2(B) subunits is insufficient to induce cell death in mature animals but may accelerate the already known CA3/hilar lesion, possibly by triggering apoptosis within CA3 neurons. CA1 and DG survive the first week despite their loss of GluR2(B) subunits, suggesting that other intrinsic properties such as increased Na+ conductance and reduced ability of the GluR2(B) subunit to interact with certain cytoplasmic proteins may be responsible for the augmented cell death rather than changes in AMPA receptor-mediated Ca2+ permeability. Alternatively, changes in allosteric interactions that affect other receptor classes of high density at the mossy fiber synapse (e.g. KA receptors) may augment KA neurotoxicity. Latent GluR2(B) increases in CA1 injured neurons support a role for AMPA receptor subunit alterations in seizure-induced tolerance.
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PMID:GluR2(B) knockdown accelerates CA3 injury after kainate seizures. 1290

Within the area tempestas (AT) in the anterior piriform cortex, unilateral microinfusions of GABA receptor antagonists and glutamate receptor agonists trigger brief episodic limbic seizures. In the present study, we document a synergistic effect of coinfusing bicuculline (GABAA receptor antagonist) with either carbachol (muscarinic receptor agonist) or cyclothiazide (inhibitor of AMPA receptor desensitization) but not with glutamate receptor agonists (AMPA, NMDA or kainate) in the rat AT. In particular, coadministration of bicuculline (118 pmol) with either carbachol (328 pmol) or cyclothiazide (1.2 nmol) triggered continuous self-sustaining seizures (status epilepticus; SE). Cyclothiazide alone did not evoke seizures. Although blockade of NMDA receptors with AP-7 (100 or 500 pmol) prevented episodic seizures evoked by carbachol or bicuculline alone, it was without effect on the continuous seizures evoked by combined treatments. NMDA-insensitive self-sustaining seizures were also evoked by the combination of AMPA and cyclothiazide. Regardless of the mechanism by which SE was evoked, it was prevented only by an AMPA receptor antagonist, NBQX, thus reinforcing the crucial role of AMPA receptors in the transition to SE. Further evidence for AMPA receptor regulation of seizure severity came from the overexpression of the GluR1 AMPA receptor subunit in AT. This resulted in substantially increased severity of bicuculline-evoked seizures that was reversed by focal application of NBQX. Thus, desensitization of AMPA receptors appears to limit the duration and severity of seizure activity, and a failure of this mechanism, or an overabundance of slowly desensitizing AMPA receptors, predisposes to severe and prolonged seizures.
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PMID:AMPA receptor desensitization as a determinant of vulnerability to focally evoked status epilepticus. 1567 44

The perforant path provides the main excitatory input into the hippocampus and has been proposed to play a critical role in the generation of temporal lobe seizures. It has been hypothesized that changes in glutamatergic transmission in this pathway promote the epileptogenic process and seizure generation. We therefore asked whether epileptogenesis is associated with enhanced glutamatergic transmission from the perforant path to dentate granule cells. We used a rat model of temporal lobe epilepsy in which spontaneous seizures occur after an episode of pilocarpine-induced status epilepticus. Whole cell patch-clamp recordings were obtained from dentate granule cells in hippocampal slices from control and epileptic animals 3 wk after pilocarpine-induced status epilepticus. The paired pulse ratio of perforant path-evoked AMPA receptor-mediated excitatory postsynaptic currents (EPSCs) was reduced in tissue obtained from epileptic rats. This is consistent with an increase in release probability. N-methyl-d-aspartate (NMDA) receptor-mediated EPSCs were also prolonged. This prolongation could not be accounted for by decreased activity of glutamate transporters or by a change in NMDA receptor subunit composition in dentate granule cells, implying a change in NMDA receptor kinetics. This change in NMDA receptor kinetics was associated with the emergence of significant synaptic cross-talk, detected as a use-dependent block of receptors activated by medial perforant path synapses after lateral perforant path stimulation in MK-801. Enhanced glutamatergic transmission and the emergence of cross-talk among perforant path-dentate granule cell synapses may contribute to lowering seizure threshold.
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PMID:Epileptogenesis is associated with enhanced glutamatergic transmission in the perforant path. 1628 3

Recurrent mossy fiber synapses in the dentate gyrus of epileptic brain facilitate the synchronous firing of granule cells and may promote seizure propagation. Mossy fiber terminals contain and release zinc. Released zinc inhibits the activation of NMDA receptors and may therefore oppose the development of granule cell epileptiform activity. Hippocampal slices from rats that had experienced pilocarpine-induced status epilepticus and developed a recurrent mossy fiber pathway were used to investigate this possibility. Actions of released zinc were inferred from the effects of chelation with 1 mM calcium disodium EDTA (CaEDTA). When granule cell population bursts were evoked by mossy fiber stimulation in the presence of 6 mM K(+) and 30 microM bicuculline, CaEDTA slowed the rate at which evoked bursting developed, but did not change the magnitude of the bursts once they had developed fully. The effects of CaEDTA were then studied on the pharmacologically isolated NMDA receptor- and AMPA/kainate receptor-mediated components of the fully developed bursts. CaEDTA increased the magnitude of NMDA receptor-mediated bursts and reduced the magnitude of AMPA/kainate receptor-mediated bursts. CaEDTA did not affect the granule cell bursts evoked in slices from untreated rats by stimulating the perforant path in the presence of bicuculline and 6 mM K(+). These results suggest that zinc released from the recurrent mossy fibers serves mainly to facilitate the recruitment of dentate granule cells into population bursts.
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PMID:Facilitation of granule cell epileptiform activity by mossy fiber-released zinc in the pilocarpine model of temporal lobe epilepsy. 1649 Jan 81


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