UMLS:C0022116 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Target Concepts:

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

Major mitochondrial phospholipids were examined in rat brain after 30 minutes of reperfusion following 30- or 60-minute periods of ischemia to examine their changes and explore their relationship to mitochondrial dysfunction during postischemic reperfusion. The amount of phospholipids and the percentage of polyunsaturated fatty acid chains, which tended to decrease during 30 minutes of ischemia, recovered after reperfusion. However, after ischemia lasting for 60 minutes, these parameters did not recover but decreased further, suggesting progressive disruption of phospholipids by phospholipase A2 after reperfusion. These changes were particularly notable in cardiolipin, which is contained specifically in mitochondria. The changes were also closely associated with mitochondrial respiration and respiratory enzyme (cytochrome c oxidase and F0F1-adenosine triphosphatase) activities, which have been known to correlate with the amount of cardiolipin. These results suggest that phospholipid metabolism in mitochondrial membranes is an important factor bearing on the integrity of energy metabolism during postischemic reperfusion.
...
PMID:Changes in major phospholipids of mitochondria during postischemic reperfusion in rat brain. 130 64

The effects of cellular mediators that contribute to ischemia-induced neuronal degeneration on gamma-aminobutyric acid (GABAA)-receptor function were studied. In vitro, phospholipase A2 (PLA2) inhibited muscimol-induced 36Cl- uptake in cerebral cortical synaptoneurosomes. The major hydrolysis product of PLA2 activity, arachidonic acid, also inhibited GABA-mediated 36Cl- uptake. The unsaturated nature of arachidonic acid makes it (and its metabolites) highly susceptible to peroxidation by oxygen radicals. Incubation of synaptoneurosomes with the superoxide radical-generating system, xanthine and xanthine oxidase, decreased muscimol-induced 36Cl- uptake, suggesting that the peroxidation of arachidonic acid and/or its metabolites interferes with GABAA-receptor function. Another factor involved in ischemia-induced neuronal degeneration is an increase in intracellular Ca2+. Calcium also inhibited GABA-mediated 36Cl- flux, consistent with its ability to activate PLA2. In contrast, Mg2+, which blocks Ca2+ channels, enhanced muscimol-induced 36Cl- uptake, consistent with its neuroprotective effects. Each of these cellular processes is activated during cerebral ischemia and can lead to neuronal degeneration. We used a model of transient forebrain ischemia in gerbils to determine if GABAA-receptor regulation is altered in vivo at a time when CA1 hippocampal cells have degenerated. Four days after a 5 minute bilateral carotid artery occlusion, receptor autoradiography was performed to measure the binding of [35S]t-butylbicyclophosphorothionate (TBPS) to the GABA-gated chloride channel. Significant decreases in TBPS binding were observed only in the dendritic layers (stratum oriens and lacunosem moleculare) of the CA1 hippocampus. The results suggest that ischemia-induced cellular processes that contribute to cell death can decrease GABA-gated chloride channels on dendrites of CA1 pyramidal cells, and that GABAA receptors may also reside on neurons afferent to or intrinsic to the dendritic layers of CA1 hippocampus.
...
PMID:Cellular regulation of the benzodiazepine/GABA receptor: arachidonic acid, calcium, and cerebral ischemia. 131 67

Recent studies have indicated two major mechanisms for the release of arachidonic acid (20:4) from membrane phospholipids: 1) activation of phospholipase A2 and 2) stimulated hydrolysis of poly-phosphoinositides (PI) and diacylglycerols (DG) through phospholipase C and diacylglycerol lipase, respectively. In mammalian brain both mechanisms seem to be operable, although the relative contributions by these two pathways have not been carefully assessed. In this study three experimental protocols were used to examine 20:4 release in brain due to ischemia and agonist stimulation, as well as the metabolic relationship between this release and the increase in diacylglycerols, lysophospholipids, and inositol phosphates. The preferential release of arachidonic acid during the initial phase after decapitation was attributed mainly to the sequential hydrolysis of poly-PI to DG. During the second phase, the release of 20:4 along with other free fatty acids (FFA) correlated well with the increase in labeled lysophospholipids, suggesting the involvement of phospholipase A2. Diacylglycerols in brain are enriched in 18:0 and 20:4. Decapitation induced a rapid increase in the level of DG, which remained elevated during the 30 min period under study. Between 5 sec and 5 min, the increase in FFA lagged behind that of DG. The parallel increases in 18:0 and 20:4 in the FFA pool further support the notion that, during the early phase, 20:4 could be derived from the sequential hydrolysis of poly-PI and DG. Decapitation also induced a sequential appearance of Ins(1,4,5)P3, Ins(1,4)P2, and Ins(4)P, which peaked at 30 sec, 1 min, and 2 min, respectively. The level of 20:4 in brain was also examined with respect to poly-PI turnover due to stimulation by cholinergic agonists. Administration of pilocarpine to lithium-treated mice resulted in increased accumulation of labeled inositol monophosphate (IP1) compared to the amount in controls receiving lithium alone, as well as a less obvious increase in 20:4. Both pilocarpine-mediated increases (IP1 and 20:4) could be blocked by atropine. These results point to the presence of an active mechanism for poly-PI turnover and for the recycling of 20:4 in brain.
...
PMID:Contributions to arachidonic acid release in mouse cerebrum by the phosphoinositide-phospholipase C and phospholipase A2 pathways. 132 24

Intracerebral administration of [3H]arachidonic acid ([3H]ArA) into 19-20-day-old rat embryos, resulted in a rapid incorporation of label into brain lipids. One hour after injection, 55.6 +/- 8.2, 18.0 +/- 3.4, and 13.7 +/- 1.3% of the total radioactivity was associated with phosphatidylcholine, phosphatidylinositol, and phosphatidylethanolamine, respectively. Approximately 10% of radioactivity was found acylated in neutral lipids of which free ArA comprised only 1.5 +/- 0.2% of the total radioactivity. Complete restriction of the maternal-fetal circulation for < or = 40 min did not affect the rate of [3H]ArA incorporation (t1/2 = 2 min) into fetal brain lipids, suggesting an effective acylation mechanism that proceeds irrespective of the impaired blood flow. After a short restriction period (5 min), the radioactivity in diacylglycerol was elevated by 50%. After a longer restriction period (20 min), the radioactivity in the free fatty acid and diacylglycerol fractions increased to values of 130 and 87%, respectively. Polyphosphoinositides prelabeled with either [3H]ArA or 32P were rapidly degraded after 5 min of ischemia. After 20 min, the decrease in phosphatidylinositol-4-phosphate and phosphatidylinositol-4,5-bisphosphate radioactivity was 47 and 70%, respectively. Double labeling of phospholipids with [14C]palmitic acid and [3H]ArA indicated a preferential loss of [3H]ArA within the polyphosphoinositide species after 20 min, but not after 5 min of ischemia. The specific activity of [14C]palmitate remained unchanged. The current data suggest phospholipase C-mediated diacylglycerol formation at the beginning of the insult followed by a phospholipase A2-mediated ArA liberation at a later time, both enzymes presumably acting preferentially on polyphosphoinositide species.
...
PMID:Generation of arachidonic acid and diacylglycerol second messengers from polyphosphoinositides in ischemic fetal brain. 132 30

The N-methyl-D-aspartate (NMDA)-sensitive subtype of glutamate receptor, which gates Ca(2+)-permeable ion channels, is known for its role in learning and memory formation, in the induction of long-term potentiation, and also in seizure activity and neurotoxicity. In primary cultures of cerebellar neurons, agonists of NMDA receptors induce a dose-dependent release of [3H]arachidonic acid ([3H]AA), which is potentiated by activation of the glycine-positive modulatory site and inhibited by NMDA receptor antagonists. NMDA receptor-induced [3H]AA release is inhibited by quinacrine and partially depends on the presence of extracellular calcium. The [3H]AA release is not sensitive, however, to pretreatment with pertussis or cholera toxin, which suggests a Ca(2+)-dependent activation of phospholipase A2 not employing G proteins. Pretreatment of cultures with the natural and semisynthetic sphingolipids GT1b and PKS 3, respectively, inhibits NMDA receptor-mediated [3H]AA release. We also demonstrated glutamate-evoked [3H]AA release from rat hippocampal slices, which is NMDA receptor mediated, calcium dependent and sensitive to quinacrine. Arachidonic acid and its metabolites have been shown to play a role as second messengers and to modulate neuronal activity. Moreover, they are thought to act as transsynaptic modulators in the mechanism of NMDA receptor-induced long-term potentiation in the hippocampus. Their role in ischemic brain pathology has also been postulated. Our experiments on cultured cerebellar granule cells, incubated in a Mg(2+)-free medium deprived of glucose and oxygen, demonstrated a time-dependent stimulation of [3H]AA release. This release was inhibited by antagonists of NMDA receptors and by quinacrine. Stimulation of NMDA-sensitive glutamate receptors and the subsequent calcium-mediated activation of phospholipase A2 may play a role in the in vivo release of arachidonic acid during brain ischemia. This hypothesis is supported by the observation that the enhanced level of thromboxane B2 in the gerbil brain after 5 min of global ischemia is reduced by the systemic application of either the NMDA antagonist MK-801 or the ganglioside GM1.
...
PMID:NMDA receptor-mediated arachidonic acid release in neurons: role in signal transduction and pathological aspects. 138 78

In this study, the release of lysophospholipids (to depict phospholipase A2 activity) and diacylglycerols (DG) (to depict stimulated hydrolysis of polyphosphoinositides) was related to the decapitation-induced release of free fatty acid (FFA) in the mouse brain. To assay for lysophospholipids, Balb/c mice were injected intracerebrally with either [3H]choline or [3H]inositol for 16 h in order to label their respective phospholipids. These lipids were examined at various times (30 s to 30.5 min) after decapitation. Between 30 s and 1.5 min after decapitation, the rate of FFA release (3 micrograms FA/mg FA in phospholipids/min) was three times more rapid than that between 10 and 15 min (0.8 microgram FA/mg FA in phospholipids/min). FFA released during the initial phase were enriched in 20:4 and 18:0 whereas those released during the latter phase were nonspecific. The DG fatty acids are enriched in 18:0 and 20:4. Ischemia induced a rapid release of DG as measured by its fatty acid content (3.2 micrograms FA/mg FA in phospholipids/min). Unlike FFA, the level of DG reached a plateau after 1.5 min and remained elevated for the entire 30.5 min. In agreement with previous notions indicating the involvement of phospholipase A2 in ischemic insult, steady increases in radioactivity of both lysophosphatidylcholines and lysophosphatidylinositols were observed with time after decapitation. Based on the preferential increase in both 18:0 and 20:4 during the initial time period, the results suggest that poly-PI hydrolysis coupled to DG-lipase may contribute to the initial release of FFA, whereas the FFA released subsequent to the initial phase may be mainly a result of activation of phospholipase A2 acting on phosphatidylcholines and phosphatidylinositols.
...
PMID:Decapitation ischemia-induced release of free fatty acids in mouse brain. Relationship with diacylglycerols and lysophospholipids. 138 50

The effects of L-ascorbic acid 2-[3,4-dihydro-2,5,7,8-tetramethyl-2- (4,8,12-trimethyltridecyl)-2H-1-benzopyran-6yl-hydrogen phosphate] potassium salt (EPC-K1, CAS 127061-56-7), a new compound for ischemia-reperfusion injuries, on lipid peroxidation and phospholipase A2 activity were studied in vitro using rat brain homogenates and human plasma. EPC-K1 inhibited phospholipase A2 activity in human plasma in a concentration-dependent manner (IC50 = 7.3 x 10(-4) mol/l), whereas a mixture of alpha-tocopherol and ascorbic acid did not exhibit this effect. In rat brain homogenates, EPC-K1 also inhibited lipid peroxidation in a concentration-dependent manner (IC50 = 2.3 x 10(-6) mol/l). alpha-Tocopherol was less active than EPC-K1. These properties of EPC-K1 suggest that EPC-K1 may prove useful in the treatment of ischemia-reperfusion injuries.
...
PMID:In vitro studies on the influence of L-ascorbic acid 2-[3,4-dihydro- 2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2H-1-benzopyran-6yl-hy drogen phosphate] potassium salt on lipid peroxidation and phospholipase A2 activity. 144 71

The levels of brain free fatty acids rapidly increase after the onset of ischemia. The purpose of this study was to investigate the action of phospholipases A2 and C during complete ischemia based on the effects of a phospholipase C inhibitor (phenylmethylsulfonyl fluoride) and the N-methyl-D-aspartate antagonist MK-801 on the release of free fatty acids in rat neocortex. Complete brain ischemia was induced in rats with cardiac arrest by intracardiac injection of KCl. Free fatty acid levels in the neocortex were measured 0, 2, 4, and 8 minutes after cardiac arrest. Phenylmethylsulfonyl fluoride inhibited the release of free fatty acids primarily from phosphatidylinositol during the first 2 minutes of ischemia and from phosphatidylcholine and phosphatidylethanolamine at 4 to 8 minutes of ischemia. Conversely, MK-801 inhibited free fatty acid release mainly from phosphatidylcholine and phosphatidylethanolamine at 2 to 4 minutes of ischemia. These results indicate that the release of free fatty acids during the first 2 minutes of ischemia can be attributed mostly to the action of phospholipase C, and that the activation of phospholipase C further influences the activation of phospholipase A2 in the subsequent course, while phospholipase A2 predominantly acts after 2 minutes of ischemia.
...
PMID:Action of phospholipases A2 and C on free fatty acid release during complete ischemia in rat neocortex. Effect of phospholipase C inhibitor and N-methyl-D-aspartate antagonist. 153 28

Phospholipid metabolism is altered during ischemia and post-ischemic reperfusion. Past studies demonstrating elevated myocardial free fatty acid and lysophospholipid content infer accelerated phospholipid degradation involving phospholipase A activity. Recently, ischemic and post-ischemic reperfusion (reperfusion) have been shown to affect levels of phosphoinositide (PPI) degradation products. Considering the role of PPI turnover in regulation of cellular calcium homeostasis, our laboratory and others have suggested that alteration in the metabolism of the inositol phospholipids could play a role in the development of ischemia-induced calcium overload injury. Using an isolated rat heart model (Langendorff perfusion), this study examines the effect of global ischemia and reperfusion on ventricular phosphoinositide-specific phospholipase C (PLC) activity and PLA2 activity. The primary purpose was to determine if ischemia and reperfusion-induced changes in PLC activity could explain previously observed changes in PPI degradation products, and whether PLC and PLA2 activities were similarly or differentially altered by ischemia and reperfusion. PLC and PLA2 activities were measured in cytosolic and total membrane fractions from control (perfused), ischemic (5, 10, 30, and 60 min), and post-ischemic reperfused ventricular tissue. Phospholipase activity was determined under optimal in vitro conditions using exogenous radiolabeled substrates. Alterations in membrane-associated PPI-PLC activity correlated with reported ischemia and reperfusion-induced changes in ventricular content of PPI metabolites. Membrane PLC activity increased slightly at 5 min of ischemia, decreased significantly at 10 min of ischemia, and continued to decrease with longer duration of ischemia (73% of control after 60 min). Cytosolic PPI-PLC activity was decreased at 5 min, and then significantly increased by longer durations of ischemia, while cytosolic PLA2 activity was reduced at all time points. Pretreatment with muscarinic, alpha 1-adrenergic, beta-adrenergic, and adenosine receptor blockers did not alter ischemia-elicited changes in PLC activity. Reperfusion caused a 140% to 200% rise in the activities of all phospholipases in all fractions after 40 min of ischemia, but not after 10 min of ischemia. Results suggest 1) ischemia and reperfusion-elicited alterations in membrane-associated PPI-PLC activity can explain previously observed changes in phosphoinositide turnover metabolites, 2) cytosolic and membrane-associated PPI-PLC and PLA2 activities are not uniformly affected by ischemia, 3) reperfusion following ischemia of sufficient duration initiates uniform activation of PIP2-PLC and PLA2, and 4) because ischemia and reperfusion-induced changes in phospholipase activity can be detected under optimal in vitro assay conditions (removed from the in vivo ischemic microenvironment), it is likely that the enzymes themselves have been altered.
...
PMID:Changes in phosphoinositide-specific phospholipase C and phospholipase A2 activity in ischemic and reperfused rat heart. 159 Jul 34

Oxygen deprivation following cessation of blood flow to vital organs such as brain, heart, and kidney is a ubiquitous human disease, invariably leading to devastating consequences. Studies in experimental models support the contention that membrane permeability is altered, ion fluxes impaired, and energy stores depleted under these circumstances. Certain lipids such as diglycerides (DG) and arachidonic acid (AA), both of which are important cellular second messengers, appear to increase during ischemia. At this point, the contribution of these and other lipids to cell deregulation, loss of function, and ultimate death has not been clarified because no precise link between lipid alterations as detected in ischemia and subsequent cellular processes has been made. In this report we examine the origin of lipid-derived second messengers in fetal rat brain prelabeled with [3H]AA and study the fate of various lipids upon obstruction of the fetal-maternal circulation. The data support the possibility of a phospholipase A2-mediated deacylation of poly-phosphoinositides (poly-PI) to form free AA and a phospholipase C-mediated hydrolysis of PC to form DG during ischemia.
...
PMID:Regulation of arachidonic acid metabolism in the perinatal brain during development and under ischemic stress. 163

1 2 3 4 5 6 7 8 9 10 Next >>