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)

Recently messenger RNA (mRNA) for glial derived neurotrophic factor (GDNF), a recently discovered member of the TGF-beta superfamily, was shown to increase in the hippocampus after kainic acid-induced seizures. The possibility that exogenous recombinant human (rh) GDNF may have anticonvulsant properties was investigated using a model of temporal lobe epilepsy in the rat. rhGDNF, vehicle or inactive rhGDNF were injected intracerebroventricularly 1 h before peripheral administration of kainic acid. rhGDNF suppressed kainic acid-induced tonic-clonic convulsions when compared to animals treated with vehicle or inactive rhGDNF. The inhibition of kainic acid-induced seizure activity by rhGDNF also prevented the associated neuronal cell loss in hippocampal, thalamic and amygdaloid regions. These results suggest that rhGDNF should be evaluated in other seizure and acute neural disorders that are associated with excitotoxic processes.
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PMID:Potent inhibitory effects of glial derived neurotrophic factor against kainic acid mediated seizures in the rat. 755 52

Glial cell line-derived neurotrophic factor (GDNF) is a novel member of the transforming growth factor-beta superfamily with potent trophic effects on dopamine neurons. Kainate-induced epileptic seizures have been shown to induce gene expression of trophic factors, particularly members of neurotrophin or fibroblast growth factor families, in the hippocampus. In this study, we examined the effects of kainate (12 mg/kg, i.p.)-induced epileptic seizures on the expression of the novel neurotrophic factor GDNF in the hippocampus. While GDNF messenger RNA was not detected during development or in normal adult rats in the hippocampus, kainate-induced epileptic seizures markedly increased GDNF messenger RNA in scattered neurons in the dentate granule layer 3 h after injection. Six hours after kainate almost all dentate granule cells and expressed GDNF messenger RNA. The increase in GDNF messenger RNA in the dentate granule layer returned almost to control levels 24 h after kainate; however, there was still expression of GDNF messenger RNA in the hilus/CA4 and also in pyramidal neurons in areas CA1-CA3. We conclude that GDNF messenger RNA is regulated, in part, via glutamate-mediated excitation and may play a role in long-lasting structural and/or functional reorganization in the hippocampal formation.
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PMID:Neurons of the hippocampal formation express glial cell line-derived neurotrophic factor messenger RNA in response to kainate-induced excitation. 805 21

Glial cell line-derived neurotrophic factor (GDNF) has two receptors, receptor-tyrosine kinase c-ret and glycosylphosphatidylinositol-linked cell surface receptor GDNFRalpha. Kainate-induced seizures, a widely studied model of neuronal plasticity and human epilepsy, have been shown to increase gene expression of several trophic factors, including GDNF, in the rat hippocampus. Here we show that systemic kainate-induced excitation leads to a transient increase of both c-ret and GDNFRalpha messenger RNAs in the rat brain. Northern analysis demonstrated that, in the hippocampus, the maximal 2.5-fold increase of c-ret and four-fold increase of GDNFRalpha messenger RNAs was observed after 12 h of kainate injection, in contrast to GDNF messenger RNA, which reaches its maximum in 4-6 h. The blocking of de novo protein synthesis by cycloheximide inhibited the induction of GDNF receptors by kainate, whereas blocking of the N-methyl-D-aspartate-type glutamate receptors by the antagonist dizocilpine maleate did not significantly alter the response. Thus, GDNF receptor messenger RNA increase by kainate depends on protein synthesis, but is not mediated by the N-methyl-D-aspartate receptor. GDNFRalpha and c-ret show distinct, but partially overlapping, patterns of expression in the brain after kainate treatment. GDNFRalpha messenger RNA was prominently induced in the dentate gyrus of the rat hippocampus, less in the habenular and reticular thalamic nuclei and cerebral cortex as revealed by in situ hybridization. C-ret transcripts were induced in the hilus of the hippocampus, several thalamic and amygdala nuclei and in superficial layers of the piriform cortex. These data suggest that GDNF and its receptors may play a local role in neuronal plasticity and in neuronal protection following epileptic insults.
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PMID:The messenger RNAs for both glial cell line-derived neurotrophic factor receptors, c-ret and GDNFRalpha, are induced in the rat brain in response to kainate-induced excitation. 946 5

Expression of mRNAs for glial cell line-derived neurotrophic factor (GDNF), neurturin (NTN) and their receptors was studied in adult rat brain using in situ hybridization after 40 kindling-evoked, rapidly recurring seizures or 10 min of global forebrain ischaemia. Following seizures, GDNF and NTN mRNAs were elevated in dentate granule cells, and c-Ret mRNA in hilar neurons and non-pyramidal cells in CA1 and CA3 regions. GFRalpha-1 mRNA levels showed more widespread increases in the dentate granule cell layer and hilus, CA1 and CA3 pyramidal layers, basolateral amygdala and parietal cortex. The expression of GFRalpha-2 mRNA increased in the piriform cortex and decreased in the CA1 region and basolateral amygdala. Forebrain ischaemia induced elevated expression of GDNF mRNA in dentate granule cells, GFRalpha-1 mRNA in the dentate granule cell layer, hilus and CA3 pyramidal layer, and GFRalpha-2 mRNA in the parietal cortex. The gene expression patterns observed here suggest that GDNF and NTN may act as target-derived factors, but also in an autocrine or paracrine manner. GFRalpha-1 can be coexpressed with GFRalpha-2 and c-Ret mRNAs in the same hippocampal or thalamic neurons, but other neurons contain GFRalpha-1 alone or together with c-Ret mRNA. The gene expression changes for the ligands, and the receptor components are region-, cell- and insult-specific, and occur independently of each other, mainly within 24 h after seizures or ischaemia. This dynamic regulation of GDNF and NTN circuits primarily at the receptor level may be important for the effectiveness of neuroprotective responses but could also trigger plastic changes, e.g. those underlying the development of epileptic syndromes.
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PMID:GDNF family ligands and receptors are differentially regulated after brain insults in the rat. 1010 16

We examined the time course of expression of glial cell line-derived neurotrophic factor (GDNF) protein in the granule cells of the dentate gyrus following unilateral intrahippocampal injection of kainic acid (KA). Recurrent behavioral seizures were observed approximately 1 h after KA injection, which lasted for 4-6 h. GDNF immunoreactivity began to increase bilaterally in the granule cells within 3 h after KA injection, continued to increase until post-injection day (PID) 4, and returned to the control level by PID 7. The results suggest that the increase of GDNF protein in the granule cells may be ascribable to seizures induced by the KA injection. The increase of GDNF protein might promote survival of the granule cells after the intrahippocampal KA injection.
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PMID:Time course of transient expression of GDNF protein in rat granule cells of the bilateral dentate gyri after unilateral intrahippocampal kainic acid injection. 1021 94

A putative transcription factor induced in vitro by glial cell line-derived neurotrophic factor (GDNF) and transforming growth factor-beta was recently cloned and characterized [Yajima S. et al. (1997) J. Neurosci. 17, 8657-8666]. The messenger RNA of this protein, termed murine GDNF-inducible transcription factor (mGIF, hereafter referred to as GIF), is localized within cortical and hippocampal regions of brain, suggesting that GIF might be regulated by perturbations of these brain regions. In an effort to learn more about the role of GIF in vivo, we examined GIF messenger RNA in the brains of rats treated with the glutamatergic agonist kainic acid. This treatment is known to induce seizures and alter the messenger RNA expression of several growth factors, including GDNF, in several brain regions. Rats were given intraperitoneal saline (1 ml/kg) or kainic acid (15 mg/kg) and were killed at various time-points for in situ hybridization of brain sections with a GIF messenger RNA riboprobe. In saline-treated rats, GIF messenger RNA was present at low levels in cerebral cortex, hippocampus and hippocampal remnants such as the taenia tecta. Kainic acid treatment induced robust increases in GIF messenger RNA in several brain regions, including cerebral cortex, hippocampus, caudate-putamen, nucleus accumbens, and several nuclei of the amygdala and hypothalamus. Most brain regions showed the greatest increase in GIF messenger RNA 4-6 h after kainic acid administration and a return towards normal levels at 48 h. The CA3 region of hippocampus, however, showed a more rapid increase in GIF messenger RNA that was also evident 48 h after kainic acid administration. These results demonstrate that GIF messenger RNA can be regulated in vivo, and that this novel factor warrants further study as a central mediator of GDNF and perhaps other neurotrophic factors.
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PMID:In vivo regulation of glial cell line-derived neurotrophic factor-inducible transcription factor by kainic acid. 1057 23

Seizure activity regulates gene expression for glial cell line-derived neurotrophic factor (GDNF) and neurturin (NRTN), and their receptor components, the transmembrane c-Ret tyrosine kinase and the glycosylphosphatidylinositol-anchored GDNF family receptor (GFR) alpha 1 and alpha 2 in limbic structures. We demonstrate here that epileptogenesis, as assessed in the hippocampal kindling model, is markedly suppressed in mice lacking GFR alpha 2. Moreover, at 6 to 8 wk after having reached the epileptic state, the hyperexcitability is lower in GFR alpha 2 knock-out mice as compared with wild-type mice. These results provide evidence that signaling through GFR alpha 2 is involved in mechanisms regulating the development and persistence of kindling epilepsy. Our data suggest that GDNF and NRTN may modulate seizure susceptibility by altering the function of hilar neuropeptide Y-containing interneurons and entorhinal cortical afferents at dentate granule cell synapses.
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PMID:Development and persistence of kindling epilepsy are impaired in mice lacking glial cell line-derived neurotrophic factor family receptor alpha 2. 1105 Feb 50

The influence of both acute and chronic electroconvulsive seizure (ECS) or antidepressant drug treatments on expression of mRNAs encoding glial cell line-derived neurotrophic factor (GDNF) and its receptors, GFRalpha-1, GFRalpha-2, and c-Ret proto-oncogene (RET) in the rat hippocampus was examined by in situ hybridization. Two hours after acute ECS, levels of GFRalpha-1 mRNA in the dentate gyrus were significantly increased. This increase peaked to nearly 3-fold at 6 h after acute ECS and returned to basal levels 24 h after treatment. Chronic (once daily for 10 days) ECS significantly increased the expression of GFRalpha-1 mRNA nearly 5-fold after the last treatment. Levels of GFRalpha-2 mRNA in the dentate gyrus were also significantly increased by acute and chronic ECS, although this effect was less than that observed for GFRalpha-1. Maximum induction of GFRalpha-2 was 30% and 70% compared to sham in response to acute or chronic ECS, respectively. Levels of GDNF and RET mRNAs were not significantly changed following either acute or chronic ECS treatment at the time points examined. Chronic (14 days) administration of different classes of antidepressant drugs, including tranylcypromine, desipramine, or fluoxetine, did not significantly affect the GDNF, GFRalpha-1, GFRalpha-2, or RET mRNA levels in CA1, CA3, and dentate gyrus areas of hippocampus. The results demonstrate that acute ECS increases the expression of GFRalpha-1 and GFRalpha-2 and that these effects are enhanced by chronic ECS. The results also imply that regulation of the binding components of GDNF receptor complex may mediate the adaptive responses of the GDNF system to acute and chronic stimulation.
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PMID:Regulation of GFRalpha-1 and GFRalpha-2 mRNAs in rat brain by electroconvulsive seizure. 1107 8

Kindling, a phenomenon in which repeated electrical stimulation of certain forebrain structures leads to an increase in the evoked epileptogenic response, is widely used to investigate the mechanisms of epilepsy. Kindling also results in sprouting of the dentate gyrus mossy fiber pathway and triggers astrocyte hypertrophy and increased volume of the hilus of the dentate gyrus. Our previous studies showed that infusion of the neurotrophin nerve growth factor accelerated the behavioral progression of amygdala kindling and affected kindling-induced structural changes in the brain, whereas intrahilar infusion of another neurotrophin, brain-derived neurotrophic factor, delayed amygdala kindling-induced seizure development and reduced the growth in afterdischarge duration, but had little effect on kindling-induced structural changes. In this paper, we report the effects of infusion of glial cell line-derived neurotrophic factor, a neurotrophic factor of the TGF-beta superfamily having similar central nervous system neuronal targets as brain-derived neurotrophic factor. We show that continuous intraventricular infusion of glial cell line-derived neurotrophic factor inhibits the behavioral progression of perforant path kindling-induced seizures without affecting afterdischarge duration. In addition, we demonstrate that intraventricular administration of glial cell line-derived neurotrophic factor prevents kindling-induced increases in hilar area and blocks mossy fiber sprouting in the CA3 region of the hippocampus. Glial cell line-derived neurotrophic factor did not have a statistically significant effect on the mossy fiber density in the inner molecular layer. Our results raise the possibility that glial cell line-derived neurotrophic factor plays a role in kindling and activation-induced neural growth via mechanisms distinct from those of the neurotrophins.
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PMID:Glial cell line-derived neurotrophic factor modulates kindling and activation-induced sprouting in hippocampus of adult rats. 1246 Jun 7

Recent experimental evidence indicates that neurotrophic factors play a role in the pathophysiology of epilepsy. The objective of this study was to explore whether signaling through one of the glial cell line-derived neurotrophic factor family receptors, GFRalpha2, influences the severity of kindling-evoked, rapidly recurring seizures and the subsequent development of permanent hyperexcitability. We applied the rapid kindling model to adult mice, using 40 threshold stimulations delivered with 5-min interval in the ventral hippocampus. Generalized seizures were fewer and developed later in response to kindling stimulations in mice lacking GFRalpha2. However, GFRalpha2 gene deletion did not influence the acquisition of the permanent abnormal excitability as assessed 4 weeks later. In situ hybridization revealed marked and dynamic changes of GFRalpha2 mRNA levels in several forebrain areas following the stimulus-evoked seizures. Our findings provide evidence that signaling through the GFRalpha2 receptor contributes to seizure generalization in rapid kindling.
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PMID:Generalization of rapidly recurring seizures is suppressed in mice lacking glial cell line-derived neurotrophic factor family receptor alpha2. 1271 Sep 91


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