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)

The transcription factor KROX-20, unlike many other immediate early genes, is not expressed in the rat hippocampus after bicuculline induced generalized seizures. Since limbic seizures are a more injurious stimulus, the KROX-20 expression profile was investigated in adult rats subjected to kainic acid induced limbic epilepsy at postictal intervals up to 48 h. Immunocytochemistry was performed using a specific polyclonal antiserum. In the hippocampus a sequential induction was observed with peak levels attained in dentate gyrus at 3 h, in CA1 at 8 h and in CA3 between 8 and 24 h, respectively. In contrast, no KROX-20 induction was found in hilus neurons. Prominent neuronal KROX-20 induction was also detected in other areas of the limbic system, in particular in amygdala and piriform cortex, as well as non-limbic regions such as neocortex and striatum. As is the case with KROX-20, heat shock protein (HSP) 70, a reliable marker for reversible neuronal injury, has a high induction threshold. Though not inducible in the hippocampus by generalized seizures, it is expressed after limbic epilepsy. Therefore, co-expression of KROX-20 and HSP70 was studied by a double labeling technique using a monoclonal antibody directed against the inducible form of HSP70. Neuronal subpopulations with perfect co-expression such as hippocampal CA1 neurons contrasted with others demonstrating partial co-induction (cortical neurons) or lack of co-expression (hilus cells), indicating that different stimuli trigger the activation of these two inducible genes.
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PMID:High induction threshold for transcription factor KROX-20 in the rat brain: partial co-expression with heat shock protein 70 following limbic seizures. 809 69

Neuronal storage disorders are fatal neurodegenerative diseases of humans and animals that are caused by inherited deficiencies of lysosomal hydrolase activity. Affected individuals often appear normal at birth but eventually develop progressive neurologic symptoms including sensory and motor deficits, mental retardation, and seizures. We have examined efficacy of bone marrow transplantation as a means of enzyme replacement, using cats with the lysosomal storage disease alpha-mannosidosis. Treated animals showed little or no progression of neurologic signs 1-2 years after transplant, whereas untreated cats became severely impaired and reached endstage disease by 6 months of age. Increased lysosomal alpha-mannosidase activity was found in brain tissue of the treated animals, and electron microscopy revealed no evidence of lysosomal storage within most neurons. Histochemical localization of acidic alpha-D-mannoside mannohydrolase (EC 3.2. 1.24), using 5-bromo-4-chloro-3-indolyl alpha-D-mannopyranoside, showed that functional enzyme was present in neurons, glial cells, and cells associated with blood vessels. This study provides direct evidence that bone marrow transplantation as treatment for a neuronal storage disease can lead to significant levels of a missing lysosomal hydrolase within neurons of the central nervous system and to compensation for the genetic metabolic defect.
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PMID:Bone marrow transplantation corrects the enzyme defect in neurons of the central nervous system in a lysosomal storage disease. 815 89

Repeated kindled seizures induce long-lasting physiological and morphological alterations in the hippocampal formation. In the dentate gyrus (DG), the morphological alterations induced by kindled seizures include loss of polymorphic neurons in the hilus, mossy fiber axon sprouting, and synaptic reorganization of the mossy fiber pathway. In this study, quantitative stereological methods were used to determine the distribution and time course of neuronal loss induced by 3, 30, or 150 kindled generalized tonic-clonic seizures in hippocampal, limbic, and neocortical pathways. Neuronal loss was observed in the hilus of the DG and CA1 after three generalized tonic-clonic seizures, and progressed in these sites to 49% and 44% of controls after 150 seizures. Neuronal loss was also observed in CA3, entorhinal cortex, and the rostral endopyriform nucleus after 30 seizures, and was detected in the granule cell layer and CA2 after 150 seizures. There was no evidence of neuronal loss in the somatosensory cortex after 150 seizures. The time course of the neuronal loss demonstrated selective vulnerability of hippocampal neuronal populations to seizure-induced injury, and suggests that even brief seizures may induce excitotoxic injury in vulnerable neuronal populations. Repeated brief seizures induced neuronal loss in a distribution that resembled hippocampal sclerosis, the most common lesion observed in human epilepsy. The results demonstrated that kindling induces alterations in neural circuitry in a variety of locations in the limbic system, and suggest that hippocampal sclerosis may be acquired in human epilepsy as a consequence of repeated seizures.
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PMID:Neuronal loss induced in limbic pathways by kindling: evidence for induction of hippocampal sclerosis by repeated brief seizures. 818 60

Neuronal activity results in long term cellular changes that underlie normal brain development and synaptic plasticity. To examine the molecular basis of activity-dependent plasticity, we have used differential cloning techniques to identify genes that are rapidly induced in brain neurons by synaptic activity. Here we describe an inducible novel member of the Ras family of small GTP-binding proteins we have termed Rheb. rheb mRNA is rapidly and transiently induced in hippocampal granule cells by seizures and by NMDA-dependent synaptic activity in the long term potentiation paradigm. The predicted amino acid sequence of Rheb is most closely homologous to yeast Ras1 and human Rap2. The putative GTP binding regions are highly conserved. A bacterial fusion protein of Rheb binds GTP and exhibits intrinsic GTPase activity. Like Ha-Ras, the carboxylterminal sequence encodes a CAAX box that is predicted to signal post-translational farnesylation and to target Rheb to specific membranes. rheb mRNA is expressed at comparatively high levels in normal adult cortex as well as a number of peripheral tissues, including lung and intestine. In the developing brain, rheb mRNA is expressed at relatively high levels in embryonic day 19 cortical plate, and expression remains at stable levels throughout the remainder of prenatal and postnatal development. Its close homology with ras and its rapid inducibility by receptor-dependent synaptic activity suggest that rheb may play an important role in long term activity-dependent neuronal responses.
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PMID:rheb, a growth factor- and synaptic activity-regulated gene, encodes a novel Ras-related protein. 820 40

Microinjections of the neuroexcitotoxin, domoic acid (DOM), in the ipsilateral rat hippocampal CA-3 region, induced generalized electrical seizure discharge activity, characterized by spikes and waves, followed by intermittent burst discharges. Computerized EEG analysis exhibited relative dominance of delta and theta and reductions in alpha and beta activities during domoic acid epileptogenesis. Seizure discharge activity was attenuated by the microinjection of the 5-HT1A agonist, 8-hydroxy-2-(di-N-propylamino)tetralin(8-(OH)-DPAT) and augmented by the specific 5-HT1A antagonist, spiroxatrine in the contralateral hippocampal CA-3 region. Neuronal recovery following 8-(OH)-DPAT was associated with significant reductions in the relative dominance of delta and theta and increases in the alpha and beta activities. The results suggest that activation of serotonergic 5-HT1A receptor in the hippocampus has a neuroprotective action.
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PMID:Suppression of domoic acid induced seizures by 8-(OH)-DPAT. 821 55

Neuronal Ca2+ channels have been shown to be involved in both alcohol drinking behavior in rats and nonhuman primates and in the manifestation of alcohol withdrawal symptoms in rodents. Experiments were performed to determine the effect of a single injection of levemopamil, a novel Ca2+ channel antagonist with antiserotonergic [5-hydroxytryptamine2 (5-HT2)] properties, on alcohol preference and alcohol withdrawal symptoms in alcohol-preferring (P) and Wistar rats, respectively. P rats were individually housed and provided free access to food, water, and a solution of 10% (v/v) ethanol. Ethanol, food, and water intakes were measured daily. After establishing a stable baseline, P rats were injected with levemopamil (0, 3.3, 10, 15, and 20 mg/kg) and their food, water, and alcohol intakes measured 24 h later. In a separate experiment, the ability of acute and chronic (12 consecutive days) administrations of levemopamil to suppress alcohol withdrawal symptoms in chronically alcohol-treated rats was studied. In addition, the effects of levemopamil on the level of monoamines in different areas of the brain, as well as its action in alcohol metabolism, were examined. Our findings showed that a single administration of levemopamil (10, 15, and 20 mg/kg) significantly and dose-dependently attenuated alcohol intake and increased water intake in P rats. Both acute and chronic treatment with levemopamil reduced the alcohol withdrawal symptoms, overall seizure scores, and proportion of rats seizing. A single injection of levemopamil produced a clear, but not significant, trend to increase the 5-HT turnover rate in certain brain areas. This drug did not influence the pharmacokinetics of alcohol.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Reduction of spontaneous alcohol drinking and physical withdrawal by levemopamil, a novel Ca2+ channel antagonist, in rats. 826 91

Neuronal excitation by experimentally induced seizures elicits the rapid induction of a set of genes called immediate early genes (IEGs). The gene products of fos, jun and Krox, multimember gene families that belong to the class of IEGs, participate in a fundamental biological control mechanism, the regulation of gene transcription. IEG encoded proteins act as third messengers in an intracellular signal transduction cascade between neural cell surface receptors, cytoplasmic second messenger systems and specific target genes in the nucleus, a process for which the term 'stimulus transcription coupling' has been given. Almost all types of seizures cause dynamic alterations of IEG expression in neurons of the limbic system, but also in non-limbic areas, such as the cortex, striatum and thalamus. IEG encoded transcription factors are thought to up- or down-regulate effector genes with preferential expression in the central nervous system, including genes for neurotransmitters, growth factors, receptors, synaptic and axonal proteins. If the concept holds true that IEGs act as molecular switches converting epileptic short-term excitation of neurons into alterations of the molecular phenotype, future research may help to explain hitherto unexplained phenomena in epileptogenesis including changes of synaptic efficacy, kindling and sprouting.
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PMID:Immediate early gene expression in experimental epilepsy. 829 94

Prostaglandins play important and diverse roles in the CNS. The first step in prostaglandin synthesis involves enzymatic oxidation of arachidonic acid, which is catalyzed by prostaglandin H(PGH) synthase, also referred to as cyclooxygenase. We have cloned an inducible form of this enzyme from rat brain that is nearly identical to a murine, mitogen-inducible cyclooxygenase identified from fibroblasts. Our studies indicate that this gene, here termed COX-2, is expressed throughout the forebrain in discrete populations of neurons and is enriched in the cortex and hippocampus. Neuronal expression is rapidly and transiently induced by seizures or NMDA-dependent synaptic activity. No expression is detected in glia or vascular endothelial cells. Basal expression of COX-2 appears to be regulated by natural synaptic activity in the developing and adult brain. Both basal and induced expression of COX-2 are inhibited by glucocorticoids, consistent with COX-2 regulation in peripheral tissues. Our studies indicate that COX-2 expression may be important in regulating prostaglandin signaling in brain. The marked inducibility in neurons by synaptic stimuli suggests a role in activity-dependent plasticity.
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PMID:Expression of a mitogen-inducible cyclooxygenase in brain neurons: regulation by synaptic activity and glucocorticoids. 835 45

In an effort to validate methods to be used in a screen for drugs effective as anticonvulsants for soman-induced convulsions, scopolamine (0.2 mg/kg) or diazepam (1 mg/kg) were given (i.m.) to male guinea pigs as a pretreatment 30 min before a convulsant dose of soman. Pyridostigmine, atropine and pralidoxime chloride also were given to counteract the lethality of soman. All animals challenged with soman and which did not receive either diazepam or scopolamine exhibited convulsive status epilepticus (SE), identified by continuous electrographic seizure activity (EGSA) and continuous motor convulsions. Despite the presence of continuous motor convulsions in all animals pretreated with diazepam and challenged with soman, EGSA was not observed in five of the seven animals. Continuous motor convulsions developed in four of seven animals pretreated with scopolamine and challenged with soman, but EGSA was not observed in any scopolamine-pretreated guinea pig. Neuronal necrosis was observed in the hippocampus, thalamus, amygdala, and cerebral and pyriform cortices in each animal with EGSA, but not brain damage was found in subjects without EGSA. Thus, although convulsions, EGSA and brain damage normally occur together in animals exposed to soman, the convulsions can be pharmacologically dissociated from the EGSA and brain damage, demonstrating that the clinically manifested convulsions are not dependent on EGSA recorded from the cortex or on abnormal activity which leads to neuronal necrosis in the forebrain.
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PMID:Pharmacological dissociation of the motor and electrical aspects of convulsive status epilepticus induced by the cholinesterase inhibitor soman. 845 54

The effects of sustained epileptic activity induced by pentylenetetrazol on morphology of buccal ganglia of Helix pomatia were investigated. Neuronal somata and processes as well as glial cells were evaluated after 5 hours of epileptic activity and after 5 hours under control conditions. After epileptic activity neurons showed signs of degeneration consisting of condensation of nuclear chromatin, decreased activity of Golgi apparatus, increased numbers of lamellar bodies and multivesicular bodies, clusters of vesicles and vacuoles, loss of microtubuli, and scattered lamellar bodies. Neuronal somata and large neuronal processes appeared less affected than the smaller processes. Glial cells showed signs of phagocytotic activity as increased cell size, numerous degenerating neuronal processes within the cytoplasm as well as lysosome like bodies and vacuoles. The changes developing along with epileptic activity were interpreted to indicate degeneration and subsequent phagocytotic activity of neuronal processes in synaptic regions of the ganglia. Thus, evidence is presented for synaptically induced degenerative processes in an intact nervous tissue that is not affected by seizure-induced alterations of respiration or systemic circulation.
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PMID:Epileptic discharges induced by pentylenetetrazol: ultrastructural alterations in identified neurons and glial cells (Helix pomatia). 856 64


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