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)

This study evaluated hippocampal inhibitory function and the level of expression of gamma-aminobutyric acid type A (GABAA) receptor mRNA in an in vivo model of epilepsy. Chronic recurrent limbic seizures were induced in rats using injections of pilocarpine. Electrophysiological studies performed on hippocampal slices prepared from control and epileptic animals 1 to 2 months after pilocarpine injections demonstrated a significant hyperexcitability in the epileptic animals. Reduced levels of mRNA expression for the alpha 2 and alpha 5 subunits of the GABAA receptors were evident in the CA1, CA2, and CA3 regions of the hippocampus of epileptic animals. No decrease in mRNA encoding alpha 1, beta 2, or gamma 2 GABAA receptor subunits was observed. In addition, no change in the mRNA levels of alpha CaM kinase II was seen. Selective decreases in mRNA expression did not correlate with neuronal cell loss. The results indicate that selective, long-lasting reduction of GABAA subunit mRNA expression and increased excitability, possibly reflecting loss of GABAergic inhibition, occur in an in vivo model of partial complex epilepsy.
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PMID:Long-lasting reduction of inhibitory function and gamma-aminobutyric acid type A receptor subunit mRNA expression in a model of temporal lobe epilepsy. 879 Mar 88

Exposure of hippocampal slices to Mg2+ free media (0 Mg) has been shown to trigger full production of stimulus-induced seizure activity after restoration of physiological conditions [1]. In the present study employing hippocampal entorhinal cortical slices (HEC), spontaneous epileptiform discharges (SEDs) were induced using 0 Mg treatment following the return of the slices to physiological conditions. To evaluate the effect of sustained epileptiform activity on gene expression in this HEC slice preparation, changes in mRNA levels of the GABAA alpha 1 and alpha 2 and beta CaM Kinase II subunits were measured using in situ hybridization. HEC slices were incubated in oxygenated artificial cerebrospinal fluid (ACSF) in the presence or absence of Mg2+ for 3 h, then placed in oxygenated ACSF containing Mg2+ for up to 3 h. Control slices were maintained in Mg2+ containing ACSF for up to 6 h. Recurrent SEDs were observed in 0 Mg pre-treated slices while no epileptiform discharges were seen in control slices. Following induction of SEDs by 0 Mg pre-treatment, a significant decrease in mRNA encoding GABAA alpha 2 was found in the CA1, CA2, CA3 and dentate gyrus (DG) regions of the hippocampus for up to 3 h after treatment. Levels of mRNA for GABAA alpha 1 and beta CaM Kinase II were not affected. The results document a decrease in GABAA alpha 2 gene expression following the induction of SEDs in the HEC slice preparation and suggest that rapid changes in neuronal gene expression may contribute to long lasting excitability changes associated with the induction of epilepsy.
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PMID:GABAA alpha 2 mRNA levels are decreased following induction of spontaneous epileptiform discharges in hippocampal-entorhinal cortical slices. 879 90

The temporal evolution of irreversible neuronal damage from pilocarpine-induced seizures was studied by light microscopy. Neuronal cell death was judged on a 0-3 scale by estimating the percentage of acidophilic neurons in each of 23 brain regions. In addition, in the dorsal dentate hilus (CA4), quantitative cell counts of normal and acidophilic neurons were also performed. A few dead neurons (grade 0.5 damage) appeared in ventral hippocampal CA1 and CA3 regions after 20-min status epilepticus (SE). Slight-to-mild damage (grades 0.5-1.5) occurred in 14 and 12 brain regions after 40-min and 1-h SE respectively, and slight-to-moderate damage (grades 0.5-2.0) was found in 15 regions after 3-h SE. Twenty-four h and 72 h after 3-h SE, there was slight-to-severe damage (grade 0.5-3.0) in 22 and 21 regions respectively. Three-h SE produced more severe damage to 7 brain regions compared to 1-h SE, and 16 regions had more pronounced neuronal injury 24 h after rather than 0-4 h after 3-h SE. Eight brain regions had less damage 72 h compared to 24 h after SE, probably because of progressive neuronal lysis and dropout, but in mediodorsal and lateroposterior thalamic nuclei damage worsened from 24 to 72 h after SE. Neuronal cell counting revealed 20% acidophilic neurons in dorsal dentate hilus after 40-min SE and no difference between the 1-h and 3-h seizure groups (31% vs. 43% acidophilic neurons respectively). Among the 3 groups of rats with 3-h SE and varying recovery periods, the 24-h and 72-h recovery groups had higher percentages of acidophilic neurons (65% and 54% respectively) than the 0-4-h group (43%). Finally, the hippocampal CA2 region and dentate granule cell layer and the caudate-putamen, considered resistant to seizure-induced cell injury, were all damaged from SE lasting 40 min or more.
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PMID:The temporal evolution of neuronal damage from pilocarpine-induced status epilepticus. 882 81

The number of NADPH diaphorase-positive cells in the CA1/CA2 and CA3 regions of Ammon's horn and the subiculum of the hippocampal formation of EL mice, an inbred mutant strain of the ddY mouse susceptible to convulsive seizures, was fewer than that of ddY mice. These findings suggest that smaller numbers of nitric oxide producing cells in the hippocampal formations of EL mice is related to their susceptibility to convulsive seizures.
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PMID:Sparse distribution of NADPH diaphorase neurons in the hippocampal formation of the inbred mutant strain EL mouse. 888 7

The molecular mechanisms that underlie dentate granule cell axon (i.e., mossy fiber) growth during development and following seizure-induced hippocampal injury remain unknown. Part of this process may involve specific factors that support dentate granule cells during differentiation, and molecular cues that allow the appropriate growth of mossy fiber axons toward their targets. To study this process, we developed an in vitro assay system to measure the activity of putative trophic, chemoattractant and chemorepulsive factors. Two-hundred-micrometer-thick transverse hippocampal sections were prepared from neonatal rats and microdissected to isolate the middle one-third of the superior blade of the dentate granule cell layer. These were embedded in a three-dimensional collagen matrix either alone or with microdissected regions of the CA2 pyramidal cell layer. Cultures were maintained in a defined medium and grown for two to three days in a standard culture environment. Results showed that numerous processes grew primarily from the hilar side of explants into the collagen matrix, often in excess of 500 microns in length. These were determined to be axons based on: (i) morphological criteria including size and presence of growth cones, (ii) synaptophysin and growth-associated protein-43 immunoreactivity, (iii) lack of glial fibrillary acidic protein immunoreactivity and (iv) contiguity of biocytin-filled processes with neuronal soma within the explant. Treatment of cultures with brain-derived neurotrophic factor caused a significant increase in axon number and length, and this effect was partially reversed by the addition of a trkB-immunoglobulin fusion protein that blocks the activity of brain-derived neurotrophic factor and neurotrophin-4/5. Basic fibroblast growth factor also caused a marked increase in axon number and length, and caused a migration of neuron-like cells out of the explant into the collagen. These results show that cultured dentate granule cell layer explants are capable of growing mossy fibers into a neutral collagen matrix, and the growth of axons can be modified by the addition of exogenous growth factors. Furthermore, since target tissue and point sources of purified factors can easily be co-cultured with the explants, this new system provides a direct means for testing the molecular cues that influence mossy fiber growth.
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PMID:Dentate granule cell layer collagen explant cultures: spontaneous axonal growth and induction by brain-derived neurotrophic factor or basic fibroblast growth factor. 889 86

Several similarities exist between the alterations observed in the chronic pilocarpine model of recurrent seizures in the rat and those found in human temporal lobe epilepsy. The present studies are focused on changes in the GABA system in this model. Following the initial pilocarpine-induced seizures, a substantial loss of glutamic acid decarboxylase (GAD) mRNA-containing neurons has been found in the hilus of the dentate gyrus (Obenaus et al., J. Neurosci., 13 (1993) 4470-4485), and, recently, a loss of GAD mRNA-labeled neurons has also been found in stratum oriens of CA1. Yet numerous other GABA neurons remain within the hippocampal formation, and there appear to be multiple compensatory changes in these neurons. Labeling for GAD65 mRNA and associated protein is substantially increased in the remaining GABA neurons at 2-4 months after the initial seizure episode. Such increased labeling suggests that the remaining GABA neurons are part of a functional circuit and may be responding to the need for increased activity. Alterations also occur in at least one subunit of the GABA-A receptor. Labeling for the alpha(5) subunit mRNA is substantially decreased in CA1 and CA2 of pilocarpine-treated rats during the chronic, seizure-prone period. These findings emphasize the complexity of changes in the GABA system and indicate a need for evaluating the functional consequences of each of the changes. The initial loss of specific groups of GABA neurons could be a critical first step in the gradual development of epileptiform activity. While many of the subsequent changes in the GABA system may be considered to be compensatory, significant deficits of GABAergic function could remain.
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PMID:Vulnerability and plasticity of the GABA system in the pilocarpine model of spontaneous recurrent seizures. 898 1

Systemic injection of kainic acid (KA) induces limbic seizures in rats, which resemble human temporal lobe epilepsy, the most common form of adult human epilepsy. In this study, we have investigated KA-elicited limbic seizures in the rats by correlating the severity of the seizure attacks with the expression of hippocampal heat shock protein-70 (HSP70) which has been suggested to be a marker for neuronal injury/death in this model of seizures. After a systemic injection of KA, six stages of limbic seizures have been classified, namely, staring (stage 1), wet dog shake (stage 2), hyperactivity (stage 3), rearing (stage 4), rearing and falling (stage 5), and jumping (stage 6). Stages 4, 5 and 6 were further divided into mild and severe sub-stages. HSP70 expression was not detected in animals with stages 1 and 2 seizures. At stage 3 a small amount of HSP70 immunoreactive neurons was detected in the CA3 field and the dentate hilus. From stage 4 to stage 5 the degree of HSP70 immunoreactivity increased in the CA1 field from a few positive cells in stage 4 mild to large numbers of immunoreactive neurons in stage 5 severe. HSP70 became detectable in pyramidal cells in the CA2 field from stage 5 severe and higher. In animals with stage 6 seizures, the majority of HSP70 expression became located in glial cells throughout the whole hippocampus. We concluded that HSP70 expression in the hippocampus positively correlates with the severity of KA-elicited limbic seizures.
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PMID:Gradation of kainic acid-induced rat limbic seizures and expression of hippocampal heat shock protein-70. 915 82

We previously demonstrated that 2-iminothiazolidine-4-carboxylic acid (2-ICA), formed by cyanide reacting with cysteine, caused glutamate antagonist-sensitive seizures when injected i.c.v. (intracerebroventricular) in mice and produced hippocampal CA1 damage following i.c.v. infusion in rats. In this study, the ability of either 2-ICA, glutamate, proline or NMDA (N-methyl-D-aspartate) injected i.c.v. to produce hippocampal lesions sensitive to glutamate antagonists was compared in mice. Hippocampal CA1 damage was observed 5-days following either a seizure (3.2 mumol) or subseizure (1.0 mumol) dose of 2-ICA. Glutamate (3.2 mumol) or proline (10 mumol) also produced hippocampal damage; glutamate damage was primarily to the CA1 subfield, whereas proline damaged neurons throughout the entire hippocampal formation. NMDA (3.2 nmol) caused seizure activity in all animals with a 50% lethality. No hippocampal damage was observed in surviving mice. Neither MK-801 (dizocilpine maleate) nor CNQX (6-cyano-7-nitroquinoxaline-2,3-dione) pretreatment prevented hippocampal lesions produced by 2-ICA. In contrast, MK-801 significantly reduced the frequency of mice displaying glutamate hippocampal lesions, but failed to block seizures produced by glutamate. MK-801 also protected neurons in the CA2-3 zone and the dentate gyrus, but not in the CA1 region of proline-injected mice. Finally, pretreatment with the mixed metabotropic glutamate receptor (mGluR)1/mGluR2 antagonist-agonist (S)-4-carboxy-3-hydroxyphenylglycine (CHPG) prevented hippocampal damage produced by the mGluR1 agonist (RS)-3,5-dihydroxyphenylglycine (DHPG), but did not protect against 2-ICA hippocampal lesions. These results show that 2-ICA hippocampal CA1 damage is not mediated through ionotropic or metabotropic glutamate receptors. 2-ICA hippocampal damage may represent a neurotoxicity that is distinct from excitotoxic-mediated cell death.
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PMID:2-Iminothiazolidine-4-carboxylic acid produces hippocampal CA1 lesions independent of seizure excitation and glutamate receptor activation. 921 1

Kainic acid (KA) administration induces an abnormal excitation and spontaneous recurrent seizures. Alterations of granule cell properties may be potential mechanisms. In this study, dynamic alterations of calbindin, a calcium binding protein particularly abundant in the granule cells, have been investigated immunocytochemically in the rat hippocampus after the KA-induced seizures. The calbindin immunoreactivity decreased slightly in the CA1/CA2 fields already after 1 and 3 days, and was lost partly or completely in the pyramidal layer after 10 days. From day 21, the calbindin immunoreactivity decreased in dendrites and soma of the granule cells and mossy fibers. The alterations remained at least to day 90, while no evident neuronal loss occurred in the granule cells. This may reflect a disturbance of calcium homostasis in the granule cells after seizures. The delayed decrease of calbindin has a time course similar to the occurrence of spontaneous recurrent seizures, suggesting a possible correlation between the two events.
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PMID:Delayed decrease of calbindin immunoreactivity in the granule cell-mossy fibers after kainic acid-induced seizures. 925 26

Kainic acid-induced limbic seizures cause lasting increases in neuropeptide Y (NPY) expression in hippocampal granule cells/mossy fibers. The expression of NPY-Y1 receptors in these neurons were investigated, using in situ hybridization for Y1 mRNA and receptor autoradiography with the Y1-specific ligand [125I][Pro34]PYY. Six hours after kainic acid-induced seizures, Y1 receptor mRNA levels decreased by 80% in granule cells and concomitantly increased (by 75%) in CA2 pyramidal neurons. Subsequently, persistent decreases in Y1 mRNA were seen, both in the stratum granulosum and in CA2. Changes in mRNA concentrations were accompanied by a transient, although non-significant, increase in [125I][Pro34]PYY binding in the molecular layer of the dentate gyrus after 4-6 h which was succeeded by a lasting decrease in binding which indicates a persistent down-regulation of Y1 receptors in hippocampal areas in kainic acid-induced epilepsy.
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PMID:Altered expression of NPY-Y1 receptors in kainic acid induced epilepsy in rats. 925 81


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