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)

Chronological changes of protein kinase C (PKC) activity were measured using in vitro [3H]phorbol 12,13-dibutyrate (PDBu) autoradiography to investigate the postischemic alteration of this second messenger system in the rat brain. Transient ischemia was induced by the occlusion of the middle cerebral artery (MCA) for 90 min and such occlusion followed by various recirculation periods of up to 4 weeks. After 90 min of ischemia followed by 3 hours of recirculation, [3H]PDBu binding sites were found to be significantly decreased in the cerebral cortex and lateral segment of the caudate putamen, both supplied by the occluded MCA; thereafter, the binding sites decreased progressively in those ischemic foci. On the contrary, there was no alteration on day 1, but 3 days after ischemic insult, a significant decrease of [3H]PDBu binding sites was first detected in the ipsilateral thalamus and the substantia nigra, which both areas had not been directly affected by the original ischemic insult. This postischemic delayed phenomenon observed in the thalamus and the substantia nigra developed concurrently with 45Ca accumulation, which was detected there in our previous study. These results suggest that alteration of second messenger (PKC) pathways may be involved not only in the ischemic foci, but also in neuronal degeneration of the exo-focal remote areas in relation to the disruption of intracellular calcium homeostasis which plays a key role in the pathogenesis of postischemic neuronal damage and that marked alteration of intracellular signal transduction may precede the neuronal damage in the exo-focal postischemic brain areas.
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PMID:Alteration of protein kinase C activity in the postischemic rat brain areas using in vitro [3H]phorbol 12,13-dibutyrate autoradiography. 836 4

The time course for the ischemia-induced changes in the subcellular distribution of protein kinase C (PKC) (alpha), (beta II), and (gamma) and the activity of PKC were studied in the neocortex of rats subjected to 1, 2, 3, 5, 10, and 15 min of global cerebral ischemia. In the particulate fraction, a 14-fold increase in PKC (gamma) levels was seen at 3 min of ischemia, which further increased at 5-15 min of ischemia. At 15 min of ischemia, PKC (alpha) and (beta II) levels had increased two- and six-fold, respectively. In the cytosolic fraction, a transient early 1.4-fold increase in PKC (beta II) and PKC (gamma) levels was seen, whereas no change in the levels PKC (alpha) was noted. PKC (gamma) levels then progressively declined, reaching 50% at 15 min of ischemia. At 5 min of ischemia, a 43% decrease in PKC activity was seen in the particulate fraction, reaching 50% at 15 min of ischemia concomitant with a 27% decrease in the cytosolic fraction. There was no change in the activator-independent PKC activity. Pretreatment with the ganglioside AGF2 prevented the redistribution of PKC (gamma) in the particulate fraction at 5 min, but not at 10 min of ischemia. The observed time course for the translocation of PKC (gamma) parallels the ischemia-induced release of neurotransmitters and increased levels of diacylglycerols, arachidonate, and increased levels of diacylglycerols, arachidonate, and intracellular calcium and delineates this subspecies as especially ischemia-sensitive. Ganglioside pretreatment delayed the translocation of PKC (gamma), possibly by counter-acting the effects of ischemia-induced factors that favor PKC binding to cell membranes.
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PMID:Time course of the translocation and inhibition of protein kinase C during complete cerebral ischemia in the rat. 837 89

Neurotransmitter receptor-coupled mechanisms have been recently recognized as important determinants of cell damage after central nervous system (CNS) trauma and ischemia. Many of these receptors exert their intracellular effects via second messenger systems. This study used in vitro autoradiographic radioligand binding to measure beta-adrenergic and muscarinic cholinergic receptors and adenylate cyclase and protein kinase C (PKC) binding sites two h after acute subdural hematoma in rats. Both beta-adrenergic and cholinergic receptor binding sites were unchanged in comparison to controls, while adenylate cyclase binding significantly decreased in the ischemic cortex under the hematoma. These changes may constitute a major limiting factor on receptor-linked therapeutic strategies in trauma and ischemia. Protein kinase C activation significantly increased in the ischemic area under the hematoma in these studies. This appears to be a response to calcium flux, which may be in part glutamate mediated.
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PMID:Early changes in second messenger but not receptor binding sites after acute subdural hematoma: an in vitro autoradiographic study. 839 84

Lysophosphatidylcholine (LPC) increases extracellularly during ischemia in vivo in both animals and man as judged by measurements from venous effluents, but more recent studies have shown little or no increase in buffer-perfused, isolated heart preparations. The appearance of LPC in blood and lymph in animals and in venous effluents in man in response to ischemia suggests a vascular site for the production of LPC. The present study was performed to assess whether thrombin could stimulate phospholipase A2 in endothelial cells and whether this would evoke an increase in and release of LPC. Endothelial cells were disassociated from canine aortas by incubating with 0.1% collagenase for 20 min. Cells were plated and allowed to grow to confluence. Measurement of LPC was performed using Bligh and Dyer extraction of lipids, high performance liquid chromatography separation, and quantification of LPC using a recently developed radiometric assay employing [3H]acetic anhydride. Incubation of endothelial cells with thrombin (0.05 unit/ml) resulted in a 2.5-fold increase in LPC to 2.3 +/- 0.1 nmol/mg of protein at 2 min (p < 0.01) and returned to control levels within 20 min. The increase in LPC induced by thrombin exhibited a concentration-dependent response with an ED50 = 0.04 unit/ml. A concentration-dependent increase in LPC was also elicited by stimulation with the peptide portion of the thrombin receptor's tethered ligand SFLLRNPNDKYEPF with an ED50 = 8 microM. The LPC produced was rapidly and completely released into the surrounding media. Hirudin completely blocked the thrombin-induced increase in LPC. Dansylarginine N-(3-ethyl-1,5-pentanediyl)amide (0.1 microM), which rapidly inactivates thrombin's proteolytic activity in situ without impairing binding, or phenyl-prolyl-arginyl-chloromethyl ketone (PPACK, 5 nM), which inactivates thrombin due to chemical alteration of the proteolytic site, each prevented the increase in LPC in response to thrombin. Stimulation of protein kinase C with phorbol 12-myristate-13-acetate (PMA, 1 microM) enhanced the response to thrombin. In contrast, staurosporine (100 nM), H7 (15 microM), or chronic treatment with PMA for 20 h to down-regulate protein kinase C completely prevented the increase in LPC in response to thrombin. Thus, thrombin stimulation of endothelial cells in vivo during ischemia may be a primary mechanism contributing to the marked increase in LPC extracellularly during ischemia.
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PMID:Thrombin-induced release of lysophosphatidylcholine from endothelial cells. 839 49

We have established an in vitro model of ischemia incorporating the combination of anoxia with glucose deprivation, which is toxic to PC12 cells. In this model, nerve growth factor (NGF), basic fibroblast growth factor (bFGF), and epidermal growth factor (EGF) improve PC12 cell survival. K252a, a specific inhibitor of NGF-induced trk p140 autophosphorylation, did not alter the neuroprotection provided by EGF or bFGF, yet it completely abolished the protection provided by NGF. Activation of protein kinase A (PKA) with dibutyryl-cAMP also protected during ischemia, although it was not additive with the effect provided by growth factors. Furthermore, growth factors protected a PKA-deficient mutant as effectively as the parental cell line; thus, activation of PKA is protective against ischemia but is not necessary for the action of peptide growth factors. Neither the stimulation of protein kinase C (PKC) with acute phorbol ester treatment nor the downregulation of PKC with chronic high-dose phorbol ester treatment resulted in an altered response to growth factors in either the PC12 wild type or PKA-deficient mutant. Thus, protection by peptide growth factors depends on neither PKA nor PKC. Furthermore, downregulation of PKC alone was protective, indicating that PKC may contribute to toxicity. Interestingly, treatment with the kinase inhibitor H-7 was neuroprotective and may have enhanced the neuroprotective effect of NGF. In contrast, staurosporine, a broadly acting kinase inhibitor, inhibited the neuroprotective effect of NGF, but not of EGF or FGF.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Growth factors protect PC12 cells against ischemia by a mechanism that is independent of PKA, PKC, and protein synthesis. 841 Jan 84

We produced an improved microembolism model of cerebral focal ischemia by injection of 1000-2000 microspheres (50 +/- 5 microns diameter) via a tube retrogradely inserted into the right external carotid artery in freely moving rats. The group injected with 2000 spheres showed a much more severe mortality rate as well as neurological signs than did the 1000-sphere group. Brain water content of the 2000-sphere group was examined and found to show an increase from 4 to 24 h after embolization in the right hemisphere, indicating serious brain edema. Severe neurological signs and individual deaths by embolization were most likely related to the extent of development of brain edema. Examination of learning behavior by shuttle-box avoidance revealed partial but significant impairment of learning in the 1000-sphere group. Autoradiographic studies for muscarinic acetylcholine receptors and protein kinase C binding sites were conducted. Both these binding sites decreased in number, but protein kinase C seems to be more susceptible to ischemic injury than muscarinic acetylcholine receptors. The observation was considered to be closely related with an impairment of learning. The present study suggests that our microembolism model in freely moving rats is useful for investigations of the early phase and late phase of cerebral ischemia.
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PMID:A cerebral ischemia model produced by injection of microspheres via the external carotid artery in freely moving rats. 841 14

Asphyxia triggers a cascade of cellular biochemical events that lead to temporary alterations in cellular function and/or cell death. Tissue hypoxia and ischemia lead to depolarization of neuronal membranes, alteration in cellular ion homeostasis and changes in energy metabolism. The changes are accompanied by enhanced release and diminished re-uptake of neurotransmitters, including the excitatory amino acid glutamate. Abnormal accumulation of calcium in neurons is produced by several factors, including opening of voltage-sensitive calcium channels, activation of excitatory amino acid-mediated ion channels, diminished pumping of calcium out of neurons, and increased release of free calcium from the endoplasmic reticulum. Elevated intracellular calcium levels appear to kill cells by activation of proteases, lipases, protein kinase C, and generation of free radicals. These factors act synergistically over minutes to hours to produce cellular necrosis. Current research is directed at defining the relative contribution of these steps to cell death and to devising therapeutic strategies to salvage brain tissue.
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PMID:Cellular alterations associated with perinatal asphyxia. 851 12

The correlation between regional phorbol ester binding and cerebral blood flow (CBF) was evaluated in the gerbil brain after 2-hour unilateral common carotid artery occlusion. [3H]phorbol 12,13-dibutyrate (PDBu) was used as a specific ligand for estimating the translocation of protein kinase C (PKC), and CBF was determined by the [14C]iodoantipyrine method. A quantitative autoradiographic method permitted concurrent measurement of these two parameters in the same brain. In the ischemia group of the animals, statistically significant, inverse correlations were noted between the CBF and PDBu binding in the hippocampus (CA1 and CA3 regions and dentate gyrus), the caudate-putamen and lateral nuclei of the thalamus. In these regions, the PDBu binding increased progressively as CBF fell below 35-40 ml/100 g/min. On the other hand, the PDBu binding in the cerebral cortices did not show any significant changes even when CBF was decreased to below 35 ml/100 g/min. The above data suggest that (1) the translocation of PKC to the cell membrane may be regionally specific in response to ischemia, and may remain in the regions particularly vulnerable to ischemia such as the hippocampus, caudate-putamen and lateral nuclei of the thalamus in the early ischemic phase; (2) the threshold of CBF below which PKC begins to translocate to the cell membrane in the above regions, may be 35-40 ml/100 g/min in 2-hour ischemia.
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PMID:Flow threshold for enhanced phorbol ester binding in the ischemic gerbil brain. 857 3

When the heart is subjected to a transient non-lethal period of ischemia, it quickly adapts itself to become resistant to infarction from a subsequent ischemic insult. This adaptation, termed preconditioning, occurs in all species studied, including man. The protection has been shown to be mediated by stimulation of adenosine and probably bradykinin receptors. Recent studies reveal that these receptors may protect by activating protein kinase C in cardiomyocytes. In this review the evidence supporting the protein kinase C hypothesis and therapeutic possibilities for employing the preconditioning phenomenon in clinical situations are discussed.
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PMID:Signal transduction in ischemic preconditioning. 858 77

The effect of incubation with the protein kinase C activator, 4 beta-phorbol 12,13-dibutyrate (beta-PDBu) on the electrophysiological responses to hypoxia and combined hypoxia and hypoglycemia was investigated in the rat hippocampal slice. Preincubation with beta-PDBu prevents adenosine-mediated inhibition of synaptic transmission under normoxic, normoglycemic conditions. beta-PDBu preincubation also reduces the adenosine-mediated hypoxia-induced depression of synaptic transmission revealing a substantial adenosine-independent hypoxia-induced depression of synaptic transmission. During combined hypoxia and hypoglycemia, slices preincubated in beta-PDBu display a significant shortening of the time of anoxic depolarization, an effect of beta-PDBu that is not mimicked by application of the adenosine antagonist cyclopentyltheophylline (8-CPT). It is concluded that the state of PKC activation may influence the electrophysiological responses to hypoxia and ischemia.
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PMID:Phorbol ester alters the electrophysiological responses to hypoxia and ischemic-like conditions in the rat hippocampal slice. 858 22


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