Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Binding of cyclic AMP to the regulatory subunit of cyclic AMP-dependent protein kinase (PKA) is an essential step in cyclic AMP-mediated intracellular signal transduction. This binding is, however, rapidly inhibited in the acute phase of cerebral ischemia, indicating that the signal transduction via PKA is very vulnerable to ischemia, although this signal pathway is very important for neuronal survival in the brain. Several lines of evidence suggest that the activation of voltage-sensitive Na+ and Ca(2+) channels is an important mediator of acute ischemic brain damage. In the present study, therefore, we examined the effect of a novel Na+ and Ca(2+) channel blocker, NS-7 (4-(4-fluorophenyl)-2-methyl-6-(5-piperidinopentyloxy) pyrimidine hydrochloride), on changes in the binding activity of PKA to cyclic AMP in permanent focal cerebral ischemia, which was induced by occlusion of the middle cerebral artery by the intraluminal suture method for 5 h in the rat. NS-7 (1 mg/kg) or saline was intravenously infused 5 min after occlusion. The binding activity of PKA to cyclic AMP and local cerebral blood flow were assessed by the in vitro [(3)H]cyclic AMP binding and the [(14)C]iodoantipyrine methods, respectively. NS-7 significantly suppressed inhibition of the binding activity of PKA to cyclic AMP in the ischemic regions such as the frontal and parietal cortices and the medial region of the caudate-putamen without affecting cerebral blood flow or arterial blood pressure. Infarct area measured in the brain slices stained with cresyl violet was significantly smaller in animals treated with NS-7 than in those treated with saline. Blockade of voltage-sensitive Na+ and Ca(2+) channels by NS-7 was expected to reduce ischemia-induced depolarization and thus prevent a massive formation of free radicals, which is known to inhibit the binding activity of PKA to cyclic AMP. These data clearly indicate that NS-7 provides very efficient neuroprotection in the acute phase of cerebral ischemia, and sustains the normal function of PKA.
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PMID:A novel voltage-sensitive Na(+) and Ca(2+) channel blocker, NS-7, prevents suppression of cyclic AMP-dependent protein kinase and reduces infarct area in the acute phase of cerebral ischemia in rat. 1174

Urocortin and urocortin II are members of the corticotropin-releasing hormone (CRH) family of neuropeptides that function to regulate stress responses. Two high-affinity G-protein-coupled receptors have been identified that bind CRH and/or urocortin I and II, designated CRHR1 and CRHR2, both of which are present in hippocampal regions of mammalian brain. The hippocampus plays an important role in regulating stress responses and is a brain region in which neurons are vulnerable during disease and stress conditions, including cerebral ischemia, Alzheimer's disease, and anxiety disorders. Here we report that urocortin exerts a potent protective action in cultured rat hippocampal neurons with concentrations in the range of 0.5-5.0 pm, increasing the resistance of the cells to oxidative (amyloid beta-peptide, 4-hydroxynonenal, ferrous sulfate) and excitotoxic (glutamate) insults. We observed that urocortin is 10-fold more potent than CRH in protecting hippocampal neurons from insult, whereas urocortin II is ineffective. RT-PCR and sequencing analyses revealed the presence of both CRHR1 and CRHR2 in the hippocampal cultures, with CRHR1 being expressed at much higher levels than CRHR2. Using subtype-selective CRH receptor antagonists, we provide evidence that the neuroprotective effect of exogenously added urocortin is mediated by CRHR1. Furthermore, we provide evidence that the signaling pathway that mediates the neuroprotective effect of urocortin involves cAMP-dependent protein kinase, protein kinase C, and mitogen-activated protein kinase. This is the first demonstration of a biological activity of urocortin in hippocampal neurons, suggesting a role for the peptide in adaptive responses of hippocampal neurons to potentially lethal oxidative and excitotoxic insults.
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PMID:Urocortin, but not urocortin II, protects cultured hippocampal neurons from oxidative and excitotoxic cell death via corticotropin-releasing hormone receptor type I. 1178 85

Excessive release of glutamate during transient cerebral ischemia initiates a cascade of events that leads to the delayed and selective death of neurons located in the hippocampus. Activity of calcium calmodulin kinase II (CaM kinase), a protein kinase critical to neuronal functioning, disappears following ischemia. The in vivo link between glutamate excitoxicity and alterations in CaM kinase activity has not been extensively studied. Baclofen, a selective gamma-aminobutyric acid (GABA)(B) receptor agonist, has been shown to inhibit glutamate release. The present study evaluated the neuroprotective efficacy of this compound and assessed early changes in hippocampal-dependent behaviors and CaM kinase immunoreactivity following transient cerebral ischemia. Baclofen (50 mg/kg) prevented both the loss of hippocampal CA1 pyramidal cells and the reduction in hippocampal CaM kinase immunoreactivity observed in control animals following ischemic insult. Cerebral ischemia produced a significant increase in working memory errors; however, baclofen failed to attenuate this memory deficit. Results confirm that baclofen is neuroprotective and support a link between glutamate excitotoxicity and reductions in CaM kinase immunoreactivity.
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PMID:Baclofen is neuroprotective and prevents loss of calcium/calmodulin-dependent protein kinase II immunoreactivity in the ischemic gerbil hippocampus. 1189 95

The effects of treatment with rolipram, a specific phosphodiesterase IV inhibitor, on learning and memory function and on the cyclic AMP/PKA/CREB signal transduction system were examined in rats with microsphere embolism (ME)-induced cerebral ischaemia. Sustained cerebral ischaemia was induced by the injection of 900 microspheres (48 microm in diameter) into the right hemisphere of the rat brain. The animals were treated once daily with 3 mg kg(-1) rolipram i.p. from 6 h after the onset of the operation for consecutive 10 days. Microsphere-embolized rats showed prolongation of the escape latency in the water maze task starting from day 7 after the operation and lasting for 3 consecutive days. Treatment with rolipram reduced the escape latency. ME decreased the cyclic AMP content, cytosolic PKA Cbeta level, and nuclear PKA Calpha and Cbeta levels, as well as reduced the pCREB level and the DNA-binding activity of CREB in the cerebral cortex and hippocampus on day 10 after the operation. These alterations were attenuated by treatment with rolipram. These results suggest that ME-induced failure in learning and memory function may be mediated by dysfunction of the cyclic AMP/PKA/CREB signal transduction system, that rolipram may ameliorate ME-induced impairment of learning and memory function, and that the drug effect may be partly attributed to activation of the cyclic AMP/PKA/CREB signal transduction system.
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PMID:Effects of a phosphodiesterase IV inhibitor rolipram on microsphere embolism-induced defects in memory function and cerebral cyclic AMP signal transduction system in rats. 1193 20

The transcription factor cAMP-responsive element binding protein (CREB) has been implicated in synaptic plasticity and memory. The purpose of the present study was to characterize alterations in the cAMP/protein kinase A (PKA)/CREB system after sustained cerebral ischemia. Sustained cerebral ischemia was induced by injection of 900 microspheres (48 microm in diameter) into the right (ipsilateral) hemisphere of rats. Alterations in the CREB, PKA, and cAMP levels in the cerebral cortex and hippocampus were examined up to 7 days after microsphere embolism. Immunoblotting analysis showed a decrease in the immunoreactivity of phosphorylated CREB (pCREB) in the ipsilateral hemisphere on the third day after microsphere embolism, whereas that of the total CREB was not altered. An electrophoretic gel mobility shift assay showed a decrease in the cAMP response element (CRE)-DNA binding activity of CREB in the ischemic region on the third day after the microsphere embolism. Cytosolic PKA C beta in the ipsilateral hemisphere was selectively decreased on the first day after the microsphere embolism, whereas the levels of another catalytic subunit, C alpha, and a regulatory subunit, RII alpha, were not altered. Immunoreactivity of the PKA catalytic subunit C alpha in the nucleus of the ipsilateral hemisphere was decreased on the third day after the embolism. The decreases in the pCREB, CRE-DNA binding activity, and PKA C alpha and C beta levels lasted at least up to 7 days after the operation. A decrease in the cAMP content was also seen in the ipsilateral hemisphere throughout the experiment. Furthermore, microsphere embolized rats showed prolongation of the escape latency in the water maze task determined on the seventh to ninth day after the operation. Our results suggest that sustained cerebral ischemia may impair the phosphorylation and CRE-DNA binding activity of CREB and that these effects may be one of the possible causes for learning and memory dysfunction.
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PMID:Impairment of cerebral cAMP-mediated signal transduction system and of spatial memory function after microsphere embolism in rats. 1215 Jul 72

We investigated the expression, activation and autophosphorylation of apoptosis signal-regulating kinase 1 (ASK1) in rat hippocampus after cerebral ischemia. The in vitro kinase assay showed that ASK1 activity gradually increased while the autophosphorylation of ASK1 gradually reduced during 5, 15 and 30 min of cerebral ischemia. At various time points of reperfusion, the activation and autophosphorylation of ASK1 reached a high point at 30 min and reduced to basal level at 6 h and then slightly increased at 3 d compared with sham operation. Both of the increases of ASK1 activation and autophosphorylation were suppressed by N-acetylcysteine, a well-known antioxidant, which was administered to the Sprague-Dawley rat 20 min before cerebral ischemia. Immunoprecipitation and Western blotting assay showed that there was no obvious change in the amount of ASK1 at each time point compared with sham control. Our results suggest that ASK1 protein which is known as an upstream mediator of JNK/p38 mitogen-actived protein kinase (MAPK) activation may play an important role in signal transduction in response to ischemic stress, given the fact that activation of JNK/p38 MAPK and subsequent phosphorylation of c-Jun are involved in the apoptotic pathway in cerebral ischemia.
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PMID:Activation and autophosphorylation of apoptosis signal-regulating kinase 1 (ASK1) following cerebral ischemia in rat hippocampus. 1216 19

Death-associated protein kinase (DAPK) is a pro-apoptotic, calmodulin (CaM)-regulated protein kinase whose mRNA levels increase following cerebral ischemia. However, the relationship between DAPK catalytic activity and cerebral ischemia is not known. This knowledge is critical as DAPK function is dependent on the catalytic activity of its kinase domain. Consequently, we examined DAPK catalytic activity in a rat model of neonatal cerebral hypoxia-ischemia (HI). An increase in DAPK specific activity was found in homogenates of the hippocampus from the injured right hemisphere, compared to the uninjured left hemisphere, 7 days after injury. The results raised the possibility that an upregulation of DAPK activity might be associated with the recovery phase of HI, during which neuronal repair and differentiation are initiated. Therefore, we examined the change of DAPK in an experimentally tractable cell culture model of neuronal differentiation. We found that DAPK catalytic activity and protein levels increase after nerve growth factor (NGF)-induced differentiation of rat PC12 cells. These results suggest that DAPK may have a previously unappreciated role in neuronal development or recovery from injury, and that potential future therapies targeting DAPK should consider a restricted time window.
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PMID:DAPK catalytic activity in the hippocampus increases during the recovery phase in an animal model of brain hypoxic-ischemic injury. 1244 68

Many cellular responses to corticosteroids involve the transcriptional modulation of target genes by the glucocorticoid receptor (GR). A rapid, non-nuclear effect of GR was found to mediate neuroprotection. High-dose corticosteroids (20 mg/kg intraperitoneally), given within 2 hours of transient cerebral ischemia, acutely increased endothelial nitric oxide synthase (eNOS) activity, augmented regional cerebral blood flow (CBF) by 40% to 50%, and reduced cerebral infarct size by 32%. These neuroprotective effects of corticosteroids were abolished by the GR antagonist RU486 and by inhibition of phosphatidylinositol 3-kinase (PI3K), and were absent in eNOS(-/-) mice. To determine the mechanism by which GR activated eNOS, we measured the effect of corticosteroids on PI3K and the protein kinase Akt. In a ligand-dependent manner, GR activated PI3K and Akt in vitro and in vivo caused NO-dependent vasodilation, which was blocked by cotreatment with RU486 or the PI3K inhibitor LY294002 but not by transcriptional inhibitors. Indeed, a mutant GR, which cannot dimerize and bind to DNA, still activated PI3K and Akt in response to corticosteroids. These findings indicate that non-nuclear GR rapidly activates eNOS through the PI3K/Akt pathway and suggest that this mechanism mediates the acute neuroprotective effects of corticosteroids through augmentation of CBF.
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PMID:Rapid nontranscriptional activation of endothelial nitric oxide synthase mediates increased cerebral blood flow and stroke protection by corticosteroids. 1246 78

The present study was aimed at determining whether nefiracetam might have a persistent cognition-enhancing effect in animals with sustained cerebral ischemia. Sustained cerebral ischemia was induced by injecting 700 microspheres into the right internal carotid artery of rats [microsphere-embolized (ME) rats]. The ME and sham-operated rats were treated with 10 mg/kg/day nefiracetam p.o. from the first to the 9th day after the operation. The escape latency of the ME rat in the water maze test, when performed on days 7 to 9 after the operation, was lengthened. This effect was attenuated by the delayed treatment with nefiracetam. The nefiracetam-treated ME rat showed a shortened escape latency in the retention test on day 17 as well as in the contraposition test on day 18. These results indicate that a persistent improvement of the spatial memory function impaired by sustained cerebral ischemia was achieved even after cessation of treatment with nefiracetam. The functional damage to learning and memory was associated with decreases in the membranous adenylyl cyclase I and cytosolic protein kinase A (PKA) catalytic subunit and regulatory subunit proteins in the right hippocampus and cerebral cortex. The delayed treatment with nefiracetam appreciably prevented the decreases in these proteins. The present study suggests that nefiracetam may have an ability to cause persistent improvement of learning and memory function, possibly through protection against the ischemia-induced impairment to the adenylyl cyclase/cAMP/PKA signal transduction pathway.
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PMID:Persistent effects of delayed treatment with nefiracetam on the water maze task in rats with sustained cerebral ischemia. 1253 2

The acid-sensing ion channel-1 (ASIC1) contributes to synaptic plasticity and may influence the response to cerebral ischemia and acidosis. We found that cAMP-dependent protein kinase phosphorylated heterologously expressed ASIC1 and endogenous ASIC1 in brain slices. ASIC1 also showed significant phosphorylation under basal conditions. Previous studies showed that the extreme C-terminal residues of ASIC1 bind the PDZ domain of the protein interacting with C-kinase-1 (PICK1). We found that protein kinase A phosphorylation of Ser-479 in the ASIC1 C terminus interfered with PICK1 binding. In contrast, minimizing phosphorylation or mutating Ser-479 to Ala enhanced PICK1 binding. Phosphorylation-dependent disruption of PICK1 binding reduced the cellular colocalization of ASIC1 and PICK1. Thus, the ASIC1 C terminus contains two sites that influence its binding to PICK1. Regulation of this interaction by phosphorylation provides a mechanism to control the cellular localization of ASIC1.
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PMID:cAMP-dependent protein kinase phosphorylation of the acid-sensing ion channel-1 regulates its binding to the protein interacting with C-kinase-1. 1257 70


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