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 expression of the proteins (C-FOS and C-JUN) encoded by the immediate early genes c-fos and c-jun was investigated in the brains of rats undergoing ethanol withdrawal. Both proteins were induced in the cerebral cortex, the piriform cortex, the olfactory bulb, the inferior colliculus, the granular cell layer of the cerebellum and in the brain stem, but only C-JUN was induced in the hippocampus of animals undergoing withdrawal without overt seizures. C-FOS was detected in the hippocampus only in animals with overt seizures. Maximal C-FOS expression occurred 15 hr after withdrawal while C-JUN was maximal at 24 hr. Gel-shift assays indicated the formation of AP-1 binding factors in nuclear extracts of the cerebral cortex, hippocampus and cerebellum 15 and 17 hr after withdrawal. These data reveal a complex pattern of immediate early gene expression during ethanol withdrawal, which may be associated with changes in neuronal plasticity underlying phenomena such as withdrawal kindling.
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PMID:Gene expression during ethanol withdrawal. 897 22

The expression of the constitutive transcription factors activating transcription factor-2 (ATF-2), serum response factor (SRF) and cAMP/Ca response element binding factor (CREB), and the phosphorylation of SRF and CREB were studied in the untreated adult rat nervous system and following seizure activities and neurodegenerative stimuli. In the untreated rat, intense nuclear SRF immunoreactivity was present in the vast majority of neurons in the forebrain, cortex, striatum, amygdala and hippocampus, and in some scattered neurons in the medulla and spinal cord. In contrast, SRF immunoreactivity was absent in the midline areas of the forebrain, e.g., the globus pallidum and septum, and in the hypothalamus, thalamus, mesencephalon and motoneurons. Nuclear ATF-2 was expressed at high levels in apparently all neurons, but not glial cells, throughout the neuraxis except for those neuronal populations which exhibit a high basal level of c-Jun, i.e. dentate gyrus and the motoneurons of cranial and somatosensory neurons. CREB immunoreactivity was present at a rather uniform intensity in all neuronal and glial cells throughout the neuraxis. Two hours, but not 5 h or 24 h, following systemic application of kainic acid, an increase in SRF was detectable by western blot analysis in hippocampal and cortical homogenates whereas the expression of ATF-2 and CREB did not change. Phosphorylation of CREB at serine 133 and of SRF at serine 103 were studied with specific antisera. In untreated rats, intense phosphoCREB and phosphoSRF immunoreactivities labelled many glial cells and/or neurons with the highest levels in the dentate gyrus, the entorhinal cortex and the retrosplenial cortex. Following kainate-induced seizures, phosphoSRF-IR but not phosphoCREB-IR transiently increased between 0.5 h and 2 h. Following transection of peripheral or central nerve fibres such as optic nerve, medial forebrain bundle, vagal and facial nerve fibres, ATF-2 rapidly decreased in the axotomized neurons during that period when c-Jun was rapidly expressed. SRF remained unchanged and CREB disappeared in some axotomized subpopulations. Similar to axotomy, c-Jun increased and ATF-2 decreased in cultured adult dorsal root ganglion neurons following ultraviolet irradiation. The distribution of SRF and ATF-2 suggests that their putative target genes c-fos, junB, krox-24 and c-jun can be independently regulated from SRF and ATF-2. The suppression of ATF-2 and the expression of c-Jun following axotomy and ultraviolet irradiation might be part of a novel neuronal stress response in the brain that strongly resembles the stress response characterized in non-neuronal cells.
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PMID:Expression of activating transcription factor-2, serum response factor and cAMP/Ca response element binding protein in the adult rat brain following generalized seizures, nerve fibre lesion and ultraviolet irradiation. 930 Apr 12

Excitatory amino acids induce both acute membrane depolarization and latent cellular toxicity, which often leads to apoptosis in many neurological disorders. Recent studies indicate that glutamate toxicity may involve the c-Jun amino-terminal kinase (JNK) group of mitogen-activated protein (MAP) kinases. One member of the JNK family, Jnk3, may be required for stress-induced neuronal apoptosis, as it is selectively expressed in the nervous system. Here we report that disruption of the gene encoding Jnk3 in mice caused the mice to be resistant to the excitotoxic glutamate-receptor agonist kainic acid: they showed a reduction in seizure activity and hippocampal neuron apoptosis was prevented. Although application of kainic acid imposed the same level of noxious stress, the phosphorylation of c-Jun and the transcriptional activity of the AP-1 transcription factor complex were markedly reduced in the mutant mice. These data indicate that the observed neuroprotection is due to the extinction of a Jnk3-mediated signalling pathway, which is an important component in the pathogenesis of glutamate neurotoxicity.
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PMID:Absence of excitotoxicity-induced apoptosis in the hippocampus of mice lacking the Jnk3 gene. 934 20

The expression of c-Fos, c-Jun and Hsp70 was examined in the hippocampus at 6, 12, 24, 48, 72 h, 4, 7 and 42 days following a combination of unilateral common carotid artery ligation and 60 min of systemic hypoxia (8% oxygen, 92% nitrogen) in 25-day-old male rats. While pyknotic cells were not visible in the hippocampus of control animals, pyknosis was evident in the ipsilateral, but not the contralateral hippocampus, of hypoxic-ischemic animals beginning at 24 h post-hypoxia. Immunohistochemical analysis revealed no c-Fos-, c-Jun- or Hsp70-immunoreactivity (IR) in any control animals. However, at 6 h post-hypoxia, Fos- and Jun-IR was evident throughout the injured ipsilateral hippocampus and later appeared throughout the contralateral hippocampus, which never showed signs of pyknosis. In contrast, Hsp70-IR was first observed at 24 h post-hypoxia and was restricted to the injured ipsilateral hippocampus. Hsp70-IR was not, however, limited to dying neurons. H-I/seizure animals did not express these proteins at any time point. These results suggest that, even in irreversibly injured neurons, Fos, Jun and Hsp70 appear to be involved in the aftermath of ischemia but probably do not play a pivotal role in the outcome of H-I compromised cells. Furthermore, compounded injury (H-I/seizure) appears to block the synthesis these proteins.
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PMID:The effects of hypoxia-ischemia on expression of c-Fos, c-Jun and Hsp70 in the young rat hippocampus. 937 54

The expression of inducible transcription factors was studied following repetitive electroconvulsive seizures (ECS), c-Fos, c-Jun, JunB, and JunD immunoreactivities were investigated following a single (1 x ECS) or repetitive ECS evoked once per day for 4, 5, or 10 days (4 x ECS, 5 x ECS, or 10 x ECS). Animals were killed 3 or 12 h following the last ECS. Three hours after 1 x ECS, c-Fos was expressed throughout the cortex and hippocampus. After 5 x ECS and 10 x ECS, c-Fos was reexpressed in the CA4 area, but was completely absent in the other hippocampal areas and cortex. In these areas, c-Fos became only reinducible when the time lag between two ECS stimuli was 5 days. In contrast to c-Fos, intense JunB expression was inducible in the cortex and hippocampus, but not CA4 subfield, after 1 x ECS, 5 x ECS, and 10 x ECS. Repetitive ECS did not effect c-Jun and JunD expression. In a second model of systemic excitation of the brain, repetitive daily injection of kainic acid for 4 days completely failed to express c-Fos, c-Jun, and JunB after the last application whereas injection of kainic acid once per week did not alter the strong expressions compared to a single application of kainic acid. In order to study the maintenance of c-Fos expression during repetitive seizures, brain-derived neurotrophic factor (BDNF) was applied in parallel for 5 or 10 days via miniosmotic pumps and permanent cannula targeted at the hippocampus or the parietal cortex. Infusion of BDNF completely reinduced c-Fos expression during 5 x ECS or 10 x ECS in the cortex ipsilaterally to the cannula and, to a less extent, also increased the expression of c-Jun and JunB when compared to saline-treated controls. BDNF had no effect on the expression patterns in the hippocampus. ECS with or without BDNF infusion did not change the expression patterns of the constitutive transcription factors ATF-2, CREB, and SRF. These data demonstrate that various transcription factors substantially differ in their response to acute and chronic neural stimulation. Repetitive pathophysiological excitation decreases the transcriptional actions of neurons over days in the adult brain, and this decrement can be prevented by BDNF restoring the neuroplasticity at the level of gene transcription.
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PMID:BDNF restores the expression of Jun and Fos inducible transcription factors in the rat brain following repetitive electroconvulsive seizures. 945 25

The present study has investigated the congruence of mRNA induction and protein expression of inducible transcription factors (ITFs). The patterns of c-jun, junB, c-fos, fra-1 and fra-2 mRNAs were studied by radioactive and non-radioactive in situ hybridization in the adult rat brain following kainate-induced seizure activity and axotomy. In the same animals, the expression of c-Jun, JunB and c-Fos proteins was compared with the respective mRNA signals. Using radioactive labeled probes all investigated mRNAs showed an onset within 1 h after systemic kainate application and the maximal levels were generally reached after 3 h. Each mRNA displayed a specific temporo-spatial expression pattern. Whereas fra-1 and fra-2 were restricted to the hippocampus, c-jun, junB and c-fos were additionally induced in the cortex, amygdala and thalamus. The areas with maximal labeling were the dentate gyrus and the hippocampal CA1 and CA3 subfields. The expression patterns between c-jun, junB and c-fos mRNA were virtually congruent with the respective protein. Labeling of the junB and fra-2 probes with digoxigenin yielded similar results. Twenty-four hours, 3 and 10 days following transection of the medial forebrain bundle and the mamillo-thalamic tract, high levels of c-jun mRNA (either digoxigenin or radioactive labeled probes) and protein were seen in the axotomized neurons of the substantia nigra pars compacta and mamillary body whereas the other mRNAs studied and the JunB or c-Fos proteins could not be detected. These findings demonstrate that mRNAs encoding for ITFs are translated into the respective proteins following excitotoxic seizures and axotomy, and that the antisera used for immunocytochemistry yield specific expression patterns of homologous proteins.
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PMID:Expression of c-jun, junB, c-fos, fra-1 and fra-2 mRNA in the rat brain following seizure activity and axotomy. 962 45

Transcription factor c-Jun is proposed to control neuronal cell death and survival, but its activation by N-terminal phosphorylation and the underlying activity of the c-Jun N-terminal kinases (JNKs) remain to be elucidated in the adult mammalian brain. We generated a polyclonal antiserum that specifically recognizes c-Jun phosphorylated at its serine 73 (S73) residue after UV irradiation of 3T3 cells. Disruption of the c-jun locus in 3T3 cells abolished this reaction, and retransfection of the human c-jun at the c-jun-/- background restored it. The phospho-c-Jun antiserum was used to visualize N-terminally phosphorylated c-Jun in the adult rat brain with cellular resolution. Prolonged c-Jun S73 phosphorylation was detected in affected neurons up to 5 d after transient occlusion of medial cerebral artery or up to 50 d after transection of central nerve fiber tracts. After cerebral ischemia-reperfusion, phosphorylation of c-Jun was linked with induced expression of Fas-ligand (APO-1, CD95-ligand), whose gene is a putative c-Jun/AP-1 target, and with terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL) reactivity, a marker for apoptosis. After nerve fiber transection, however, lasting c-Jun phosphorylation occurred in axotomized neurons negative for Fas-ligand or TUNEL and regardless of degeneration or survival. In contrast to these lasting phosphorylation patterns, transient seizure activity by pentylenetetrazole provoked only a brief c-Jun phosphorylation and JNK activation. In extracts from ischemic or axotomized brain compartments, c-Jun phosphorylation correlated with enhanced long-term JNK activity, and in-gel kinase assays visualized proteins with sizes corresponding to JNK isoforms as the only c-Jun N-terminally phosphorylating enzymes. These results demonstrate that lasting c-Jun S73 phosphorylation and JNK activity are part of neuronal stress response after neurodegenerative disorders in the adult mammalian brain with Fas-ligand as a putative apoptotic effector.
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PMID:Lasting N-terminal phosphorylation of c-Jun and activation of c-Jun N-terminal kinases after neuronal injury. 965 Nov 96

Axon sprouting in dentate granule cells is an important model of structural plasticity in the hippocampus. Although the process can be triggered by deafferentation, intense activation of glutamate receptors, and other convulsant stimuli, the specific molecular steps required to initiate and sustain mossy fiber (MF) reorganization are unknown. The cellular immediate early genes (IEGs) c-fos, c-jun, and zif/268 are major candidates for the initial steps of this plasticity, because they encode transcription factors that may trigger cascades of activity-dependent neuronal gene expression and are strongly induced in all experimental models of MF sprouting. The mutant mouse stargazer offers an important opportunity to test the specific role of IEGs, because it displays generalized nonconvulsive epilepsy and intense MF sprouting in the absence of regional cell injury. Here we report that stargazer mice show no detectable elevations in c-Fos, c-Jun, or Zif/268 immediate early gene proteins (IEGPs) before or during MF growth. Experimental results in stargazer, including (1) a strong IEGP response to kainate-induced convulsive seizures, (2) no IEGP response after prolongation of spike-wave synchronization, (3) no IEGP increase at the developmental onset of seizures or after prolonged seizure suppression, and (4) unaltered levels of the intracellular Ca2+-buffering proteins calbindin-D28k or parvalbumin, exclude the possibility that absence of an IEGP response in stargazer is either gene-linked or suppressed by known refractory mechanisms. These data demonstrate that increased levels of these IEGPs are not an obligatory step in MF-reactive sprouting and differentiate the early downstream molecular cascades of two major seizure types.
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PMID:Nonobligate role of early or sustained expression of immediate-early gene proteins c-fos, c-jun, and Zif/268 in hippocampal mossy fiber sprouting. 980 64

This article reviews findings up to the end of 1997 about the inducible transcription factors (ITFs) c-Jun, JunB, JunD, c-Fos, FosB, Fra-1, Fra-2, Krox-20 (Egr-2) and Krox-24 (NGFI-A, Egr-1, Zif268); and the constitutive transcription factors (CTFs) CREB, CREM, ATF-2 and SRF as they pertain to gene expression in the mammalian nervous system. In the first part we consider basic facts about the expression and activity of these transcription factors: the organization of the encoding genes and their promoters, the second messenger cascades converging on their regulatory promoter sites, the control of their transcription, the binding to dimeric partners and to specific DNA sequences, their trans-activation potential, and their posttranslational modifications. In the second part we describe the expression and possible roles of these transcription factors in neural tissue: in the quiescent brain, during pre- and postnatal development, following sensory stimulation, nerve transection (axotomy), neurodegeneration and apoptosis, hypoxia-ischemia, generalized and limbic seizures, long-term potentiation and learning, drug dependence and withdrawal, and following stimulation by neurotransmitters, hormones and neurotrophins. We also describe their expression and possible roles in glial cells. Finally, we discuss the relevance of their expression for nervous system functioning under normal and patho-physiological conditions.
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PMID:Inducible and constitutive transcription factors in the mammalian nervous system: control of gene expression by Jun, Fos and Krox, and CREB/ATF proteins. 985 69

Absence seizures are characterised by a well-defined disturbance of thalamocortical function, and there is no spread to other systems. In this study, we continue our examination of the mechanisms underlying the increased nuclear cyclic AMP responsive element (CRE)- and activator protein 1 (AP-1) DNA-binding activities in a gamma-butyrolactone (GBL)-induced mouse model of absence seizure. The administration of GBL increased CRE- and AP-1 DNA-binding activities in the cerebral cortex and thalamus, but not in other regions such as the hippocampus, cerebellum or pons + medulla oblongata, at doses which induced absence seizures. Not only the absence-seizure behavior but also the increased CRE- and AP-1 DNA-binding activities in the thalamocortical regions were reversibly inhibited by ethosuximide, a typical anti-absence drug, and the GABAB antagonists CGP 35348 and CGP 46381. A gel-supershift assay revealed that the GBL-induced CRE-binding activity was supershifted by an anti-CRE-binding protein (CREB) antibody, and that AP-1 DNA-binding activity was blocked by anti-c-Jun and anti-c-Fos antibodies. These results suggest that increased CRE- and AP-1 DNA-binding activities in the cerebral cortex and thalamus are related to the pathogenesis of generalized absence seizures and that these increases in DNA-binding activity are related to ethosuximide- and GABAB antagonist-sensitive abnormal neuronal activity in the thalamocortical circuit.
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PMID:Pharmacological profiles of absence seizure-induced increases in CRE- and AP-1 DNA-binding activities in gamma-butyrolactone-treated mice. 986 26


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