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)

Selective hippocampal cell loss and altered neurotransmitter receptor expression have been proposed as pathogenic mechanisms in the development of chronic mesial temporal lobe epilepsy (TLE). Studies in animal models point to metabotropic glutamate receptors (mGluRs) as modulators of hippocampal epileptogenesis. In addition, mGluRs may constitute specific targets for the development of novel anticonvulsive drugs. As mGluR4 represents an inhibitory class III mGluR associated with the reduction of intracellular cyclic AMP levels and calcium influx, we have analyzed the regional and cellular expression of mGluR4 in surgical hippocampal specimens obtained from patients with TLE by using immunohistochemistry and in situ hybridization. Although the hippocampi of control specimens (n = 11) were almost devoid of mGluR4 immunolabeling, all TLE specimens (n = 35) showed a striking up-regulation of mGluR4 immunoreactivity, in particular within the dentate gyrus. Immunoelectron microscopy localized the receptor protein to the periphery of presynaptic and postsynaptic membranes. In situ hybridization revealed increased transcript levels of mGluR4 in dentate granule cells and residual CA4 neurons of TLE specimens compared with controls. Our results suggest a potential role of mGluR4 in counteracting excitatory hippocampal activity and in modulating seizure-associated vulnerability of hippocampal neurons. These data may also provide a basis for pharmacological studies of mGluR4 agonists as potential novel drugs in the treatment of TLE.
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PMID:Up-regulation of the metabotropic glutamate receptor mGluR4 in hippocampal neurons with reduced seizure vulnerability. 1063 98

The cysteine protease caspase-3 may be involved in the mechanism of cell death following seizures. Using a rat model of focally evoked limbic epilepsy with continuous electroencephalography monitoring, we investigated seizure-induced changes in caspase-3 protein expression and processing, enzyme activity, and the in vivo effect of caspase-3 inhibition. Seizures were induced by intraamygdaloid injection of kainic acid (0.1 microg) and were terminated after 45 min by diazepam (30 mg/kg) administration. Animals were killed 0-72 h following diazepam administration. Levels of the 32-kDa proenzyme form of caspase-3 were unaffected by seizures. Levels of the 17-kDa cleaved (active) fragment of caspase-3 were almost undetectable in control brain, but were increased significantly at 4 and 24 h within ipsilateral hippocampus and cortex in seizure animals. Caspase-3-like protease activity was increased within the ipsilateral hippocampus at 8 and 24 h following seizures. Caspase-3 immunoreactivity was increased within the vulnerable ipsilateral CA3/CA4 subfield at 24 and 72 h following seizures and was associated predominantly, but not exclusively, with neurons exhibiting DNA fragmentation. The putatively selective caspase-3 inhibitor N-benzyloxycarbonyl-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-fluoromethyl ketone significantly improved neuronal survival bilaterally within the hippocampal CA3/CA4 subfields following seizures. Collectively, these data suggest that caspase-3 may play a significant role in the mechanism by which neurons die following seizures.
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PMID:Involvement of caspase-3-like protease in the mechanism of cell death following focally evoked limbic seizures. 1069 54

Northern epilepsy is an autosomal recessive childhood onset epilepsy syndrome, clinically characterized by generalized tonic-clonic seizures with onset at 5 to 10 years of age and subsequent slowly progressive mental deterioration. The patients may reach 50 or 60 years of age. A mutation responsible for the disease has recently been identified in a novel gene on chromosome 8p23, encoding a putative membrane protein with an unknown function. The present study, based on three autopsied patients, is the first neuropathological analysis of the disease, and showed intraneuronal accumulation of cytoplasmic autofluorescent granules. The granules were strongly stained by the Luxol fast blue, periodic acid-Schiff, and Sudan black B methods in paraffin sections, and were immunoreactive for subunit c of the mitochondrial ATP synthase and sphingolipid activator proteins A and D. The intraneuronal storage was highly selective: the third layer of the isocortex and the hippocampal CA2, CA3, and CA4 sectors were severely affected, while other layers of the isocortex, the CA1 sector, and the cerebellar cortex were only minimally involved. The membrane-bound storage cytosomes showed a curvilinear ultrastructure with admixture of some granular components. Western blotting and N-terminal sequence analysis of purified storage material identified subunit c as the major component. These findings establish Northern epilepsy as a new form of neuronal ceroid-lipofuscinosis with an exceptionally protracted course.
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PMID:Northern epilepsy: a novel form of neuronal ceroid-lipofuscinosis. 1076 41

Loss of function mutations in the gene encoding the cysteine protease inhibitor, cystatin B (CSTB), are responsible for the primary defect in human progressive myoclonus epilepsy (EPM1). CSTB inhibits the cathepsins B, H, L and S by tight reversible binding, but little is known regarding its localization and physiological function in the brain and the relation between the depletion of the CSTB protein and the clinical symptoms in EPM1. We have analysed the expression of mRNA and protein for CSTB in the adult rat brain using in situ hybridization and immunocytochemistry. In the control brains, the CSTB gene was differentially expressed with the highest levels in the hippocampal formation and reticular thalamic nucleus, and moderate levels in amygdala, thalamus, hypothalamus and cortical areas. Detectable levels of CSTB were found in virtually all forebrain neurons but not in glial cells. Following 40 rapidly recurring seizures evoked by hippocampal kindling stimulations, CSTB mRNA expression showed marked bilateral increases in the dentate granule cell layer, CA1 and CA4 pyramidal layers, amygdala, and piriform and parietal cortices. Maximum levels were detected at 6 or 24 h, and expression had reached control values at 1 week post-seizures. The changes of mRNA expression were accompanied by transient elevations (at 6-24 h) of CSTB protein in the same brain areas. These findings demonstrate that seizure activity leads to rapid and widespread increases of the synthesis of CSTB in forebrain neurons. We propose that the upregulation of CSTB following seizures may counteract apoptosis by binding cysteine proteases.
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PMID:Seizures induce widespread upregulation of cystatin B, the gene mutated in progressive myoclonus epilepsy, in rat forebrain neurons. 1079 46

In the CNS there is a differential distribution of the metabotropic glutamate receptor 5 (mGluR5) in neurons and glia. Hippocampal nerve cells contain large amounts of the receptor transcript and protein that are expressed at very low levels in astrocytes. This is unexpected, as mGluR-induced phosphoinositide hydrolysis is substantial in cultured astrocytes and is mediated only by mGluR5 in these cells. In order to detect mGluR5 in astrocytes in vivo, we destroyed in a circumscribed part of the hippocampus nerve cells that have high level of receptor expression. Unilateral injection of kainate into the right amygdala produced epileptic seizures, as well as selective degeneration of nerve cells restricted to the ipsilateral CA3 and CA4 regions of the hippocampus, followed by the development of gliosis. In the affected fields only, mGluR5 immunoreactivity was severely reduced 3 days after kainate injection, followed by a progressive reappearance and lasting presence of the receptor protein. Receptor mRNA virtually disappeared from the pyramidal cell layer of the lesioned CA3/4 region. On the other hand, the message level increased persistently in the CA3 stratum lucidum and radiatum, the site of massive astrogliosis. In these sites, mGluR5 mRNA became detectable in double labeling studies in glial fibrillary acidic protein-positive astrocytes. We showed previously that growth factors induce a pronounced elevation of mGluR5 expression in cultured astrocytes (Miller et al. J Neurosci 15:-6109, 1995). The well-documented increase in the level of growth factors in the damaged brain may underlie the induction of the receptor expression in astrocytes in vivo, which may also be involved in repair processes in the injured nervous tissue.
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PMID:Expression of metabotropic glutamate receptor 5 is increased in astrocytes after kainate-induced epileptic seizures. 1079 15

The substantia nigra pars reticulata (SNpr) has been proposed to play an important role in the control of the propagation and/or the generation of epileptic seizures. Earlier studies have shown differential effects of the lesion of the SNpr on seizure genesis that demonstrated a regional difference in the anterior and posterior parts of the SNpr in preconvulsive behavior induced by unilateral reticulata injection of dopamine (DA). This study was aimed to investigate some of the underlying mechanisms of the preconvulsive behavior elicited by unilateral SNpr DA injection by the study of changes in the gene expression of glutamate receptor subunits (GluR1, GluR2 and NMDAR1) and of changes in animal behavior following coinfusion of DA and a DA D1 antagonist SCH 23390 into the SNpr. Unilateral injection of exogenous DA into the anterior region of the SNpr induced rapid and short lasting preconvulsive behavior up to wet dog shakes stage and a significant reduction of gene expression for GluR1, GluR2 and NMDAR1 subunits in rat hippocampal subfields including CA1 through CA4 and dentate gyrus (DG) at 1 day after nigral DA injection. The effect was long lasting and persisted for at least 3 weeks. Both preconvulsive behavior and downregulation of glutamate receptor subunit genes were completely blocked by simultaneous coinfusion of DA and SCH 23390. The results suggest, for the first time, that DA D1 receptor in the SNpr may mediate the nigral-involved seizure development. Glutamate desensitization, and/or selective early neuronal damage might be responsible for the downregulation of glutamate receptor subunits by transient preconvulsive activity.
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PMID:Substantia nigra pars reticulata lesion induces preconvulsive behavior and changes in glutamate receptor gene expression in the rat brain. 1083 96

Studies with animal seizure models have indicated that changes in temporal and spatial expression of voltage-gated sodium channels may be important in the pathology of epilepsy. Here, by using in situ hybridisation with previously characterised subtype-selective oligonucleotide probes [Whitaker et al. (2000) J. Comp. Neurol. 422, 123-139], we have compared the cellular expression of all four brain alpha-subunit sodium channel mRNAs in "normal" and epileptic hippocampi from humans. Neuronal cell loss was observed in all regions of the hippocampus of diseased patients, indicating that sclerosis had occurred. Losses of up to 40% compared to post-mortem controls were observed which were statistically significant in all regions studied (dentate gyrus, hilus, and CA1-3). To assess mRNA levels of the different alpha-subtypes in specific subregions, control and diseased tissue sections were hybridised to subtype-specific probes. To quantify any changes in expression while allowing for cell loss, the sections were processed for liquid emulsion autoradiography and grain counts were performed on populations of individual neurones in different subregions. No significant differences were found in the expression of type I and VI mRNAs. In contrast, a significant down-regulation of type II mRNA was observed in the epileptic tissue in the remaining pyramidal cells of CA3 (71+/-7% of control, P<0.01), CA2 (81+/-8% of control, P<0.05) and CA1 (72+/-6% of control, P<0.05) compared with control tissue. Additionally, a significant up-regulation in type III mRNA in epileptic CA4 pyramidal cells (145+/-7% of control, P<0.05) was observed. It is not clear whether these changes play a causal role in human epilepsy or whether they are secondary to seizures or drug treatment; further studies are necessary to investigate these alternatives. However, it is likely that such changes would affect the intrinsic excitability of hippocampal neurones.
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PMID:Changes in the mRNAs encoding voltage-gated sodium channel types II and III in human epileptic hippocampus. 1156

Changes of emotional behavior and neuronal cell loss in the hippocampus were investigated after pentylenetetrazol (PTZ) induced kindling in rats. Behavioral and morphological changes were studied in partially and fully kindled rats and after different postkindling periods comparing to the controls. The resident-intruder test indicated a diminished offensive behavior in partially and fully kindled animals. The open-field and the cat-odor exposition tests reveal changes in defensive behavioral pattern only in fully kindled rats. A decrease of exploratory locomotion and an increase in freezing were assessed in the open-field and the cat-odor exposition test, respectively, up to 10 weeks after the end of kindling. The first damaged neurons (CA4 region) were observed in the partially kindled group (PK), correlating with an increase in the glial fibrillary acidic protein (GFAP)-immunoreactivity (GFAP-IR) and hypertrophy of astrocytes. The most significant increase in the number of damaged neurons was detected 24 h after completion of kindling (selective vulnerability: CA4/CA1>DG>CA2+CA3). The neuronal loss went on for 10 weeks postkindling. A low correlation between the number of Stage 4 kindling seizures and the number of damaged hippocampal neurons was found 24 h after the end of kindling in individual rats. The present results demonstrate that PTZ kindling goes along with long-lasting changes in emotional behavior. The alterations of the defensive behavior after the termination of kindling can be interpreted as depression-like and are obviously associated with a characteristic pattern of neuronal loss in various hippocampal regions.
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PMID:Morphological alterations of neurons and astrocytes and changes in emotional behavior in pentylenetetrazol-kindled rats. 1170 Dec

In patients suffering from temporal lobe epilepsy (TLE), increased extracellular glutamate levels in the epileptogenic hippocampus both during and after clinical seizures have been reported. These increased glutamate levels could be the result of malfunctioning and/or downregulation of glutamate transporters (also known as EAATs; excitatory amino acid transporters). In this study, the distribution of protein and mRNA of EAAT subtypes was examined in the hippocampus of TLE patients with hippocampal sclerosis (HS group) and without hippocampal sclerosis (non-HS group), and in autopsy controls without neurological disorders. EAAT protein localization was studied by immunohistochemistry on paraffin sections using specific poly- and monoclonal antibodies against the glial glutamate transporters EAAT1 and EAAT2 and the neuronal glutamate transporter EAAT3. Antibody specificity was shown by immunoblotting. In the HS group, a small decrease in EAAT1-immunoreactivity (IR) was observed in CA4 and in the polymorphic and supragranular layer of the dentate gyrus, compared with the control group. The strongest changes were found for EAAT2 levels. In the non-HS group, increased EAAT2-IR was detected in the CA1 and CA2 field, compared with non-epileptic controls. EAAT2-IR was decreased in the HS compared with the non-HS group. Fewer EAAT3-positive cells were found in the HS group than in the non-HS and control group. In both TLE groups, increased EAAT3 levels were observed in individual neurones. In the HS group, the percentage of EAAT3-IR neurones was increased in CA2 and in the granule cell layer of the dentate gyrus. Radioactive in situ hybridization for EAAT1-3 confirmed our immunohistochemical results. Non-radioactive in situ hybridization showed that not only astrocytes, but also neurones express EAAT2 mRNA. Taken together, differences in both mRNA and protein levels of glutamate transporter subtypes were found in specific regions in the TLE hippocampus, with most severe changes found for EAAT2 and EAAT3 levels. The results indicate an upregulation of EAAT2 protein expression in CA1 and CA2 in neurones in the non-HS group. This is in line with decreased EAAT2 protein levels in the HS group, since these hippocampi are characterized by severe neuronal cell loss. The functional consequences (glutamate transport capacity) of the reported changes in EAAT2 and EAAT3 remain to be determined.
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PMID:Distribution of glutamate transporters in the hippocampus of patients with pharmaco-resistant temporal lobe epilepsy. 1183 91

Many experimental studies suggest that NFkappaB, a transcription factor involved in acute inflammation, and cytokines participate in neuronal excitability and/or glial scar formation in epilepsy. In this report, we looked for the expression of NFkappaB in hippocampi surgically removed in patients with medial temporal lobe epilepsy (MTLE) and hippocampal sclerosis (HS) who had an history of febrile convulsions. We analyzed 18 hippocampi from epileptic patients with MTLE and HS, and we used as control specimens three hippocampi from non-epileptic patients and four hippocampi from patients with cryptogenic MTLE without HS. We used antibodies raised against the NFkappaB-p65 subunit and we identified glial cells with specific antibodies. Hippocampi from patients with MTLE and HS displayed severe neuronal loss surrounded by gliosis in CA1 area and more or less in CA3/CA4 areas. Double immunolabeling showed that reactive astrocytes of lesioned areas over-expressed NFkappaB-p65 (significantly when compared to control specimens). Moreover, some surviving pyramidal neurons in these areas and numerous dentate granule cells were strongly positive for NFkappaB-p65 in cytoplasm and nucleus, whereas control hippocampi showed a faint basal cytoplasmic staining in neurons. These results suggest that in epileptic hippocampi with typical sclerosis, inflammatory processes are chronically active or transiently re-induced by recurrent seizures. Whether NFkappaB over-expression reflects protective or deleterious mechanisms in the epileptic focus remains to be elucidated.
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PMID:Inflammatory reactions in human medial temporal lobe epilepsy with hippocampal sclerosis. 1237 76


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