Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The c-fos immediate early gene is induced by normal stimuli including light, stress, hyperosmolar solutions, and hormones. Ischemia, hypoxia, seizures, cortical injury, nerve section and other pathological stimuli can also induce c-fos. The induction can occur via increases in intracellular calcium that act through a Ca2+/cAMP element on its promoter, or via trophic and other factors that act through a serum response element (SRE) on its promoter. Several studies show that calcium entry via voltage sensitive calcium channels (VSCCs) is important for inducing c-fos. We have shown that calcium entry via the NMDA receptor is important for induction of c-fos mRNA by glutamate and cAMP in cultured cortical neurons. Moreover, the NMDA receptor appears to regulate translation of c-fos mRNA to Fos protein when cells are stimulated with other types of stimuli including vasoactive intestinal peptide, zinc, and fibroblast growth factor. These results suggest that toxins that elevate intracellular calcium will likely induce the c-fos gene in brain. The heat shock or stress genes are induced by a wide variety of stimuli including heavy metals, heat, oxidative and ischemic stress, prolonged seizures, hypoglycemia, calcium ionophores, and certain toxins. It is believed that denatured proteins stimulate heat shock factors to bind to heat shock elements on the promoters of all heat shock genes to induce gene transcription. We and others have shown that global and focal ischemia induce the hsp70 heat shock gene in brain. Mild ischemia induces hsp70 mRNA and HSP70 protein in neurons only.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Alterations in gene expression as an index of neuronal injury: heat shock and the immediate early gene response. 809 Mar 62

The temporospatial expression pattern of four immediate early genes (IEGs) (c-fos, c-jun, junB, NGFI-B) following 30 min of global ischemia was investigated in rat brains by in situ hybridization and immunohistochemistry (c-fos). All examined IEG mRNAs, as well as Fos-like immunoreactivity, increased transiently in vulnerable and resistant brain regions following ischemia, but the induction profiles were distinct. Ischemia caused a post-ischemic early-onset, transient c-fos induction in wide-spread regions, as well as a late-onset induction restricted to vulnerable regions. Late-onset c-fos induction was observed in the CA1 region and the ventral thalamus but not in the striatum or neocortex, where neurons degenerate at a quicker pace. After recirculation, c-jun mRNA appeared to be initially coinduced with c-fos mRNA, but c-jun mRNA levels remained elevated or increased in various regions, including all vulnerable regions, when c-fos mRNA had already declined to near basal levels. Compared to c-fos and c-jun, junB induction was less pronounced and confined largely to the dentate gyrus. NGFI-B mRNA increased moderately and only in brain regions exhibiting the most dramatic c-fos increases and with similar kinetics. The differential activation of the investigated IEGs suggests that rather complex long-term adaptive processes may be initiated at the genomic level after global ischemia. The present findings provide further evidence that the activation of IEGs forms part of the brain's metabolic response to ischemia, but no simple correlation appears to exist between the induction of the investigated IEGs and the phenomenon of selective vulnerability.
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PMID:Differential expression of the immediate early genes c-fos, c-jun, junB, and NGFI-B in the rat brain following transient forebrain ischemia. 811 17

Time-dependent changes in c-fos-like immunoreactivity (c-fos-LI) were studied in the rat during focal cerebral ischemia and reperfusion after middle cerebral artery (MCA) occlusion. In the permanent ischemia model, the levels of c-fos-LI increased for the first 30 min of ischemia in neuronal nuclei in the lesioned hemisphere. They reached a maximum at 60 min. The level in the parietal cortex (PC) diminished considerably after 120 min, and in the cingulate cortex (CC) it gradually decreased to near the control value at 180 min. Regional cerebral blood flow (rCBF) in the PC fell to 32% and that in the CC fell to 64% of pre-ischemic values after MCA occlusion. Reperfusion induced strong expression of c-fos-LI in the PC and CC after 6 h of reperfusion that followed 30 min of ischemia. The c-fos-LI was effectively reduced by preadministration of the N-methyl-D-aspartate (NMDA) receptor antagonist, ketamine (100 mg/kg, IP). These findings suggest that the expression of c-fos after ischemia may be immediately activated through NMDA receptors and may spread to surrounding regions in a manner sensitive to reductions in rCBF. Reperfusion after ischemia also appears to cause activation of expression of c-fos and of intracellular signal transduction.
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PMID:Expression of c-fos in the rat cerebral cortex after focal ischemia and reperfusion. 819 23

Although specific patterns of cellular vulnerability have been identified in experimental models of cerebral ischemia, there is little data on the occurrence of similar abnormalities in human ischemia. We therefore used a variety of histochemical methods to define changes affecting specific classes of cells in post-mortem specimens from seven patients with hippocampal and neocortical ischemic lesions. In acute lesions, staining with SMI-32, an antibody directed against nonphosphorylated neurofilaments that labels pyramidal projection neurons, was prominently depleted even when conventional Nissl staining revealed only mild pyknosis. In contrast, staining for other markers such as microtubule-associated protein 2 (MAP-2), another cytoskeletal protein, or parvalbumin, a calcium-binding protein found in gamma-aminobutyric acid (GABA)-ergic interneurons, were relatively preserved. SMI-32 antibody also labeled dystrophic axons and axonal retraction balls in and around acute ischemic lesions. The pattern of differential changes in immunoreactivity was essentially the same in all acute ischemic injuries, including both diffuse lesions in the CA1 field (Sommer's sector) and discrete infarcts in CA1 and neocortex. In addition, immunoreactivity for the immediate early gene product c-fos was enhanced in and around the acute ischemic lesions that we studied. In some very acute lesions, immunoreactivity for glial fibrillary acidic protein (GFAP) was depleted in areas of severe ischemia and necrosis, but, as expected, GFAP immunoreactivity was increased in lesions more than a few days old. In contrast, the loss of SMI-32 immunoreactivity persisted in chronic lesions. These findings are consistent with those of experimental ischemia in animals and confirm the relevance of these studies for human cerebral ischemia. The pattern of selective changes also resembles that of injuries induced directly by excitatory amino acids, which may play a significant role in the pathogenesis of ischemic damage.
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PMID:Immunohistochemical patterns of selective cellular vulnerability in human cerebral ischemia. 827 38

Induction of hsp70 mRNA and protein appear to provide useful markers for delineating stages in the progression of neuronal pathophysiology after ischemia. Detection of hsp70 encoded by the induced mRNA is dependent on complex interactions between the time course of mRNA expression and recovery of protein synthesis in a given neuron population, and perhaps other factors relating to specific aspects of hsp70 physiology, during recirculation intervals of hours to days. Transient mRNA expression and subsequent detection of immunoreactive hsp70 protein appear to identify neurons more likely to survive ischemia and other insults, while prolonged expression of hsp70 mRNA is associated with more severe neuronal injury. Fos and Jun immunoreactivities are also increased after ischemia, and provide indexes of functional gene expression during earlier recirculation periods. The accumulation of Fos immunoreactivity in particular designates neurons in which rapid recovery of protein synthesis during 1-3 h recirculation has allowed translation of the very transiently expressed c-fos mRNA. Jun-like immunoreactivity allows an evaluation of events at later recirculation intervals, and provides a clear demonstration of synthesis and accumulation of induced protein in CA1 neurons at 6 h following 2 min ischemia. Detailed understanding of the significance of such interactions between transcriptional and translational events will continue to evolve as information accumulates regarding the expression of additional mRNAs and proteins after ischemia. The present demonstration that Jun-like immunoreactivity accumulates in CA1 neurons after brief ischemia indicates that widespread changes in gene expression, expected as a consequence of such primary effects on transcription factor activity, are likely to contribute to the phenomenon of induced ischemic tolerance and to other persistent changes in the brain following diverse insults.
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PMID:Stress protein and proto-oncogene expression as indicators of neuronal pathophysiology after ischemia. 833 41

Excitotoxic activation of glutamate receptors is thought to be a key event for the molecular pathogenesis of postischemic delayed neuronal death of CA-1 neurons in the gerbil hippocampus. Glutamate receptor stimulation also causes induction of transcription factors that belong to the class of immediate early genes. We examined the expression of six different immediate early genes in the gerbil hippocampus after transient global ischemia. Comparative analysis of c-fos and Krox-24 expression was carried out in the same animals at the transcriptional and translational level by in situ hybridization and immunocytochemistry. Postischemic synthesis of four additional immediate early gene (IEG)-encoded proteins (FOS-B, c-JUN, JUN-B, and JUN-D) was investigated by immunocytochemistry at recirculation intervals between 1 and 48 h. After 5 min of ischemia, transcription of c-fos and Krox-24 mRNA was induced in all hippocampal subpopulations with peak expression at 1 h after recirculation. In vulnerable CA-1 neurons, increased transcription of c-fos and Krox-24 was not followed by translation into protein. Induction of immediate early gene-encoded proteins was restricted to neuronal populations less vulnerable to brief ischemia and identified neurons that are targets of glutamate receptor-mediated neurotoxicity but that are destined to survive. Our data indicate an asynchronous synthesis and persistence of individual IEG-encoded proteins in these neurons. The staggered induction implies that combinatorial changes of transcription factors allow a differential postischemic regulation of target gene expression both spatially and over time.
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PMID:Differential transcription and translation of immediate early genes in the gerbil hippocampus after transient global ischemia. 840 17

Transient global forebrain ischemia induces in rat brain a large increase of expression of the immediate early genes c-fos and c-jun and of the mRNAs for the 70-kDa heat-shock protein and for the form of the amyloid beta-protein precursor including the Kunitz-type protease-inhibitor domain. At 24 hr after ischemia, this increased expression is particularly observed in regions that are vulnerable to the deleterious effects of ischemia, such as pyramidal cells of the CA1 field in the hippocampus. In an attempt to find conditions which prevent the deleterious effects of ischemia, representatives of three different classes of K+ channel openers, (-)-cromakalim, nicorandil, and pinacidil, were administered both before ischemia and during the reperfusion period. This treatment totally blocked the ischemia-induced expression of the different genes. In addition it markedly protected neuronal cells against degeneration. The mechanism of the neuroprotective effects involves the opening of ATP-sensitive K+ channels since glipizide, a specific blocker of that type of channel, abolished the beneficial effects of K+ channel openers. The various classes of K+ channel openers seem to deserve attention as potential drugs for cerebral ischemia.
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PMID:K+ channel openers prevent global ischemia-induced expression of c-fos, c-jun, heat shock protein, and amyloid beta-protein precursor genes and neuronal death in rat hippocampus. 841 18

A short period of cerebral ischemia leads to necrosis of the hippocampal CA1 pyramidal cells. Until recently no mechanisms contributing to this selective vulnerability were known. During the last decade an increasing amount of research has been concentrated on identifying signs of disturbed signal transduction in these neurons after ischemia. The present thesis is a review of these studies with some emphasis on my own contributions to the field. Gerbil and rat models of transient global ischemia are the most frequently employed. In order to produce the selective necrosis the main arteries to the brain are occluded for 5-20 minutes. In the rat it is often also necessary to lower the blood pressure. It takes 2-7 days of recirculation before the CA1 pyramidal cells become necrotic. The studies show that the necrosis can be attenuated or aggravated by drugs acting as inhibitors or enhancers of signal transduction--also if administered shortly after ischemia. The necrosis can be similarly influenced by lesions of excitatory or inhibitory afferent neurons. The protective effect of the lesion however, can be due to the lesion-induced decrease in metabolism. During ischemia there is an increase in the extracellular concentration of several excitatory and inhibitory neurotransmitters as well as in intracellular second messengers. Some of the latter also show an increase during recirculation. In vitro autoradiographic studies of receptor proteins show either unchanged or diffusely distributed downregulation of the ligand binding to the various extra- and intracellular receptor proteins following ischemia and early recirculation. A second decrease is seen in the CA1 at the time of and probably secondary to the necrosis. The IP3 receptor decrease appears during the first minutes of recirculation and lasts for up to 14 days. The protective lesion of the excitatory afferents from CA3 also leads to a decrease in IP3 binding. The changes in receptor regulation are not accompanied by increased postischemic electrophysiological activity in the CA1. In vivo autoradiographic mapping of the regional cerebral metabolic rate of glucose show increased metabolism in the CA1 during the first hour of recirculation compared to the rest of the brain were it is depressed. This relative hypermetabolism is not seen if the CA1 has been deprived of its primary source of excitatory afferents. A later secondary increase seen in the more or less necrotic CA1 pyramidal cell layer is probably due to macrophage activity. In situ hybridization and immunohistochemical studies on the expression of c-fos mRNA and protein respectively has been used to depict neurons with increased activity.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The role of signal transduction in the delayed necrosis of the hippocampal CA1 pyramidal cells following transient ischemia. 847

Using a unilateral, focal, cortical, ischemia-reperfusion rat model, c-fos mRNA and Fos immunoreactivity in the brain were investigated. The study was divided into a series of reperfusion intervals which were carried out for a period of up to 7 days. The c-fos mRNA peaked in the ischemic cortex (about 15-fold) after 30 minutes of ischemia followed by 1 hour of reperfusion and dropped to baseline level after 1 day of reperfusion. Increased expression switched to the bilateral retrosplenial and frontal cortex, as well as the left (nonischemic) parietal cortex, at 3- or 5-days of reperfusion (about three- to fourfold). Fos immunohistochemical staining correlated positively with the surge of c-fos mRNA. Nuclear run-off transcription assays further indicated that the increase in c-fos mRNA was regulated at the transcriptional level not only in the ischemic cortex (30 min of ischemia, followed by 1 h of reperfusion) but also in the contralateral counterpart (30 min of ischemia, followed by 3 d of reperfusion). A link between altered gene expression and diaschisis is suggested. The distant/delayed c-fos expression is probably caused by loss of inhibition from the ischemic cortex through a polysynaptic transneural pathway.
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PMID:Delayed transhemispheric c-fos gene expression after focal cerebral ischemia-reperfusion in rats. 852 70

The response of the kidney to ischemic injury includes increased DNA synthesis, which is preceded by rapid and brief expression of the c-fos proto-oncogene. While the timing of these two events would suggest that c-Fos participates in an immediate-early gene program leading to proliferation, no direct test of this hypothesis exists. The purpose of these studies was (1) to determine whether c-fos is expressed as part of a typical immediate-early (IE) gene response, which would require co-expression of c-jun and sensitivity to cycloheximide, and (2) to determine whether the cells expressing c-Fos are the same as those undergoing DNA synthesis. Northern analysis was performed on renal mRNA at different times following release of a 50 minute period of renal hilar clamping. c-jun and c-fos mRNA were rapidly and briefly expressed following renal ischemia and their expression was superinduced by cycloheximide in a manner typical of an immediate-early gene response. 3H-thymidine autoradiography performed on semi-thin sections from intravascularly perfusion fixed kidneys 24 hours following induction of ischemia showed labeled nuclei in cells lining the damaged proximal tubules of the outer stripe of the outer medulla, as well as proximal tubules in the cortex and interstitial cells throughout the kidney. However, immunohistochemical localization of c-Fos and c-Jun protein occurred predominantly in nuclei of the thick ascending limb, distal tubule and collecting duct cells. The studies demonstrate that c-fos and c-jun are expressed following renal ischemia as a typical immediate-early gene response, but they are expressed in cells that do not enter the cell cycle. The failure of the cells to enter the cell cycle may depend on the co-expression of jun-B and jun-D, which suppress the mitogenic activity of c-Jun in other cells. The data suggest that the IE response following renal ischemia is part of the stress response, which is antiproliferative rather than proliferative. The role of the stress response during renal ischemia and the fate of the cells undergoing it are unknown.
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PMID:DNA synthesis is dissociated from the immediate-early gene response in the post-ischemic kidney. 854 1


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