UMLS:C0022116 - FACTA Search

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Query: UMLS:C0022116 (ischemia)
91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cerebral ischemia in the gerbil results in early hippocampal changes, which include transient activation and/or translocation of protein kinase C (PKC), increased enzymatic activity of ornithine decarboxylase (ODC), and elevated DNA binding ability of activator protein-1 (AP1). The time-course of all three of these postischemic responses was found to be almost parallel, peaking at 3 hr after the ischemic insult. The effectiveness of known modulators of postischemic morphological outcome (MK-801, L-NAME, and gingkolides BN 52020 and BN 52021) in counteracting the induction of PKC, ODC, and AP1 formation was tested. These drugs were administrated as followed: MK-801 (a noncompetitive inhibitor of NMDA channel), 0.8 mg/kg i.p., 30 min before ischemia, and 5 min after the insult; L-NAME (competitive inhibitor of NO synthase), 10 mg/kg i.p., 30 min before ischemia, and 5 mg/kg, 5 min after ischemia; BN52020 and BN52021 (inhibitors of platelet-activating factor: PAF receptors) were administered as a suspension in 5% ethanol in water by oral route, 10 mg/kg for 3 days before ischemia. Three of these drugs, MK-801, L-NAME, and BN52021, significantly reduced ischemia-elevated activity of PKC and ODC, whereas AP1 formation was only partially attenuated. Our observations implicate the existence of different mechanism(s) for postischemic PKC and ODC activation, which in turn is engaged in AP1 induction.
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PMID:Modulation of ischemic signal by antagonists of N-methyl-D-aspartate, nitric oxide synthase, and platelet-activating factor in gerbil hippocampus. 774 16

We studied the chronological changes of protein kinase C (PKC) and muscarinic acetylcholine receptor binding activities of the rat brain which were determined by using [3H]phorbol 12,13-dibutyrate (PDBu) and [3H]quinuclidinyl benzilate (QNB) autoradiographic methods, respectively, after 90 min of right middle cerebral artery (MCA) occlusion and after such occlusion, followed by different periods of recirculation. After the ischemic insult followed by 3 h 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]QNB binding sites was first detected in those ischemic foci. Moreover, 3 days after ischemic insult, both [3H]PDBu and [3H]QNB binding sites were concurrently reduced in the ipsilateral thalamus and 1 week after the ischemia, in the substantia nigra, in which both areas had not been directly affected by the original ischemic insult. These alterations of PKC in the postischemic brain areas developed concurrently with 45Ca accumulation, which was detected in our previous study. These results suggest that postischemic alterations of second-messenger (PKC) and neurotransmitter receptor systems were involved not only in the ischemic foci due to ischemia-induced energy failure, but also in the exo-focal remote areas prior to the histologic changes where neuronal damage might be caused by transsynaptic delayed degeneration.
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PMID:Autoradiographic analysis of second-messenger and neurotransmitter receptor systems in the exo-focal remote areas of postischemic rat brain. 785 Apr 85

Free radical formation and subsequent lipid peroxidation may participate in the pathogenesis of tissue injury, including the brain injury induced by hypoxia or trauma and cardiac injury arising from ischemia and reperfusion. However, the exact cellular mechanisms by which the initial oxidative insult leads to the ultimate tissue damage are not known. A number of reports have indicated that protein kinase C (PKC) may be activated following oxidative stress and that this enzyme may play an important role in the steps leading to cellular damage. In this work, we have examined in a cell model whether PKC is activated following oxidative exposure. UC11MG cells, a human astrocytoma cell line, were treated with H2O2. Incubation with 0.5 mM H2O2 increased malondialdehyde levels by as early as 15 minutes. To assess the effects of H2O2 treatment on PKC activation, we measured phosphorylation of an endogenous PKC substrate, the MARCKS (myristoylated alanine-rich C kinase substrate) protein. Treatment of cells with 0.2-1.0 mM H2O2 resulted in a rapid increase in MARCKS phosphorylation. Phosphorylation was stimulated approximately 2.5-fold following treatment with 0.5 mM H2O2 for ten minutes. Treatment with phorbol 12-myristate 13-acetate, a PKC activator, increased MARCKS phosphorylation approximately 4-fold. The H2O2-induced MARCKS phosphorylation was inhibited by the addition of the kinase inhibitors H-7 and staurosporine. Furthermore, specific down-regulation of PKC by phorbol ester also inhibited H2O2-induced MARCKS phosphorylation. These results indicate that PKC is rapidly activated in cells following an oxidative exposure and that this cell system may be a good model to further investigate the role of PKC in regulating oxidative damage in the cell.
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PMID:Oxidant-induced activation of protein kinase C in UC11MG cells. 788 45

The physiological regulation of the intracellular Ca2+ homeostasis and its pathological alteration has been studied in rat and gerbil hippocampal slices using ion-sensitive electrodes and the fluorescence imaging technique. The ischemia-induced intracellular Ca2+ rise, accentuated in the synaptic/dendritic layer of the vulnerable CA1 neurons was observed in vivo and could be replicated at an accelerated time course in the "ischemic" hippocampal slice superfused with unoxygenated, glucose-free medium. The intracellular Ca2+ loading, thought to be instrumental for the generation of postischemic nerve cell damage, seems to result from an increased Ca2+ release out of intracellular stores as well as from an enhanced synaptic Ca2+ influx. The latter is attributed to a depolarization-induced opening of the voltage-dependent Ca2+ channels and to an uncontrolled influx through "upregulated" NMDA receptor-operated channels. Such an ischemia-induced upregulation which is reported to occur physiologically by the activation of PKC, is reflected by the selective loss of the depressive control of the synaptic NMDA Ca2+ influx by adenosine. Ischemia also leads to a hypertrophy of astrocytes which may go along with an impairment of their physiological function to take up glutamate adding to the extracellular rise of the excitotoxic amino acids. A pathological activation of microglial cells and their transformation into macrophages, known to release oxygen radicals, may further add to neuronal damage. The observed neuroprotection by adenosine can be primarily ascribed to its limiting effect on a pathological membrane depolarization and its deleterious consequences. The more powerful neuroprotection by propentofylline, thought to act analogue to adenosine, seems to be achieved by additional mechanisms. This pharmacon depresses the ischemia-induced neuronal Ca2+ loading in vivo and in vitro, prevents the activation of astrocytes and interferes with the transformation as well as with the free radical formation of microglia-derived macrophages as demonstrated in complementary studies with fluorescence techniques on cell cultures.
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PMID:The use of ion-sensitive electrodes and fluorescence imaging in hippocampal slices for studying pathological changes of intracellular Ca2+ regulation. 789 1

Northern blot analysis was performed to investigate the long-term changes in mRNA expression of protein kinase C (PKC) in the gerbil brain following transient cerebral ischemia. We have previously demonstrated an increase in mRNA levels of certain Ca(2+)-independent forms of PKC in early recirculation periods i.e., 6 h and 24 h postischemia (PI). But, since neuronal death in susceptible regions usually occurs 2-3 days following ischemia, this study examined the mRNA levels of PKC after prolonged periods of reperfusion following ischemia. The mRNA expression was also examined at an early recirculation period, i.e., 1 h, to determine how early the alterations begin to occur. Global forebrain ischemia was produced in gerbils by 10 min of bilateral carotid artery occlusion. RNA was prepared from forebrains of nonischemic controls and PI animals following 1 h, 3 d, and 7 d of recirculation (n = 3 to 4 in each group) and hybridized with synthetic oligonucleotide probes for PKC, delta, epsilon, and zeta based on cDNA sequences in rat and labelled with 32P. The autoradiographs were recorded and quantified by a sensitive system, Phosphor Imager, followed by conventional x-ray film exposure. The mRNA levels of all 3 PKC isozymes examined were found to be elevated as early as 1 h recirculation following ischemia. The increases in mRNA levels of both delta PKC following 6 h and 24 h of recirculation as well as that of zeta PKC following 24 h of recirculation, as reported earlier, return to control levels by 3 d PI and remain at that level 7 d PI.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Post-ischemic changes in protein kinase C RNA in the gerbil brain following prolonged periods of recirculation: a phosphorimaging study. 789 99

Ischemic preconditioning in the rabbit is initiated by adenosine A1-receptor stimulation, which activates protein kinase C (PKC). Additionally, alpha 1-adrenergic agonists can similarly protect ischemic myocardium, but there has been confusion about the role adenosine receptors play in this protection. To characterize the interaction between adrenergic and adenosine receptors and to study the possible role of PKC in this protection, we used isolated rabbit hearts perfused with oxygenated Krebs' buffer. All hearts were subjected to 30 minutes of regional myocardial ischemia and 2 hours of reperfusion. Infarct size was determined by triphenyltetrazolium staining. Pharmacologic preconditioning in hearts with a 5-minute phenylephrine (PE) infusion 10 minutes before the prolonged regional ischemia resulted in significantly smaller infarcts (9.7 +/- 1.3% of risk area) than in control hearts (31.0 +/- 2.6%, P < .05). This protection could be effectively blocked by administration of the alpha-adrenergic blocker phenoxybenzamine. Methoxamine, an alpha 1a-selective agonist, failed to protect, whereas the alpha 1b-selective antagonist chloroethylclonidine aborted the protective effect of PE. Polymyxin B, an inhibitor of PKC, also blocked the protective effect of PE, implying that PKC has an important role in preconditioning. The adenosine receptor blocker 8-(p-sulfophenyl)theophylline (SPT) given at the same time as the PE infusion did not affect the protection, implying that an alpha 1-agonist could initiate protection independent of adenosine, presumably by direct coupling to PKC. However, the protective effect of PE could be blocked if SPT were administered during the 30-minute regional ischemia. This observation suggested that adenosine receptor occupancy is necessary during long ischemia to reactivate PKC and mediate the protection. However, the addition of a second PE infusion beginning 5 minutes before and continuing throughout the long ischemic period restored the protective effect of PE despite the presence of SPT. Thus, as long as at least one of the receptors (alpha 1-adrenegic or adenosine A1) is activated during long ischemia, protection will be realized. These data indicate that alpha 1 receptors do not precondition through an adenosine intermediate but that alpha 1-adrenergic and adenosine receptors activate parallel pathways within the myocyte that can trigger and mediate protection.
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PMID:alpha 1-adrenergic agonists precondition rabbit ischemic myocardium independent of adenosine by direct activation of protein kinase C. 791 39

This study describes immunocytochemical distribution of the protein kinase C (PKC) subspecies: alpha, beta and gamma in the CAI sector of gerbil hippocampus. Immunolabelling was performed with 10 nm gold-antibody complexes against each of the PKC subspecies. The subspecies of PKC were expressed specifically in different populations of hippocampal cells. An enhanced PKC immunoreactivity was noted in the animals after ischemia. We propose that this phenomenon reflects an activation of PKC in the early phase of brain ischemia.
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PMID:Protein kinase C-like immunoreactivity in gerbil hippocampus after a transient cerebral ischemia. 795 73

In order to study the possible role of C kinase (PKC) on sodium pump of cerebral vessels, we used diacylglycerol (diC8: sn-1,2-dioctanoylglycerol) and phorbol esters (PMA: phorbol 12-myristate 13-acetate; PDA: phorbol 12,13-diacetate; 4 alpha-P: 4-alpha phorbol) as PKC activators, and examined their effects on Na,K-ATPase activity in rat brain microvessels (MVs). Rats were divided into non-treated (control; n = 9), four-vessel occlusion (4VO; 30-30 minutes ischemia and recirculation, n = 5), and middle cerebral artery occlusion (MCAO, n = 3) groups. MVs were passed through nylon meshes and were obtained by ultracentrifuge at 58000 g. Na,K-ATPase activity in MVs was determined by the phosphomolybdate method. DiC8 enhanced Na,K-ATPase activity at 10(-4) M in the control group, the 4VO group and the contralateral hemispheres of the MCAO group (139% +/- 0.06, 135% +/- 0.2, 133% +/- 0.18, mean +/- SE, p < 0.05, p < 0.01, Wilcoxon rank sum) respectively, but had no effects on MVs in the ipsilateral hemispheres of MCAO group (74% +/- 0.04). This activation by diC8 was inhibited by PKC inhibitors, staurosporine (3 x 10(8) M) and H7 (10(-6) M) in the control MVs. By contrast, PMA suppressed Na, K-ATPase at 10(-5) M in the control group (-25% +/- 0.07), but it tended to activate Na,K-ATPase activity in the ipsilateral hemispheres of the MCAO groups (33% +/- 0.09). PDA and 4 alpha-P did not have any consistent effects at the concentration examined. The cause of difference between the effects of diC8 and PMA is unclear at present, but it may stem from the mode of lipid-membrane interaction in these agents and the difference in the condition of cells as well.
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PMID:Effects of protein kinase C activators on Na, K-ATPase activity in rat brain microvessels. 797 18

Catecholamines have been implicated in the phenomenon of ischemic preconditioning. We have previously demonstrated that ischemic preconditioning against postischemic mechanical dysfunction in the isolated rat heart is mediated by the alpha 1-adrenergic receptor. The purpose of this study was to delineate the signal transduction of preconditioning distal to the alpha 1-adrenergic receptor. Our results suggest that (1) transient ischemia and alpha 1-adrenergic receptor-induced preconditioning is inhibited by protein kinase C (PKC) antagonists, (2) functional protection against global ischemia/reperfusion injury can be induced by infusion of diacylglycerol, the second messenger of the alpha 1-adrenergic pathway, and (3) transient ischemia and alpha 1-adrenergic preconditioning are both characterized by similar translocation of PKC-delta to the sarcolemma of myocardium. These findings suggest that PKC is an effector of preconditioning in the isolated rat heart.
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PMID:Preconditioning of isolated rat heart is mediated by protein kinase C. 800 Dec 80

It is well established that ischemia-induced release of glutamate and the subsequent activation of post-synaptic glutamate receptors are important processes involved in the development of ischemic neuronal damage. Moderate intraischemic hypothermia attenuates glutamate release and confers protection from ischemic damage, whereas mild intraischemic hyperthermia increases glutamate release and augments ischemic pathology. As protein kinase C (PKC) is implicated in neurotransmitter release and glutamate receptor-mediated events, we evaluated the relationship between intraischemic brain temperature and PKC activity in brain regions known to be vulnerable or nonvulnerable to transient global ischemia. Twenty minutes of bilateral carotid artery occlusion plus hypotension were induced in rats in which intraischemic brain temperature was maintained at 30 degrees C, 37 degrees C, or 39 degrees C. Prior to and following ischemia, brain temperature was 37 degrees C in all groups. Cytosolic, membrane-bound, and total PKC activities were determined in hippocampal, striatal, cortical, and thalamic homogenates at the end of ischemia and at 0.25-24 h of recirculation. PKC activity of control rats varied by region and were affected by altered brain temperature. For both membrane-bound and cytosolic PKC, there was a significant temperature effect, and for membrane-bound PKC there was also a significant effect of region. Rats with normothermic ischemia (37 degrees C) showed extensive depressions of all PKC fractions. Hippocampus and striatum were noteworthy for depressions in PKC activity extending from the earliest (15 min) to the latest (24 h) recirculation times studied, whereas cortex showed PKC depressions chiefly during the first hour of recirculation, and the thalamic pattern was inconsistent.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regional alterations of protein kinase C activity following transient cerebral ischemia: effects of intraischemic brain temperature modulation. 805 50

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