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)

It is becoming clear that PAF plays an important role in a variety of life-threatening pathologies including shock, asthma, graft rejection and ischemia-induced damage. Pierre Braquet and colleagues analyse recent reports on PAF and ischemia and propose a hypothesis based on the catastrophe theory to explain why PAF antagonists are effective in countering ischemic injury and many other disorders. PAF antagonists, perhaps in combination with other agents, may consequently prove to have extensive therapeutic potential.
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PMID:Is there a case for PAF antagonists in the treatment of ischemic states? 268 13

Cerebral ischemia and ischemia-reperfusion induced cerebral injury results in the accumulation of free fatty acids and diacylglycerols as a result of increased activity of phospholipases A and C. We have evaluated the incorporation of 14C arachidonic acid into the whole brain and synaptoneurosomes, the effect of cerebral ischemia on 14C incorporation, and the effect of a PAF antagonist (BN 52021) on cerebral blood flow, free fatty acids, diacylglycerols, and polyphosphoinositides. Peak incorporation of 14C arachidonic acid into the whole brain and synaptoneurosomal fractions occurred 30 minutes following intraventricular injection. Peak incorporation into cerebellar synaptoneurosomal fractions was at 60 minutes following intraventricular injection. Turnover in phospholipid pools was similar in the whole brain and synaptoneurosomes (PI greater than PC greater than PE). Considering phosphatidylinositol content in the gerbil brain, the specific activity of 14C arachidonic acid was 22 times greater in PI than PC. Five minutes of bilateral carotid artery ligation resulted in decreased phosphatidylinositol and polyphosphoinositols. Bilateral carotid artery ligation resulted in systemic arterial hypertension, complete forebrain ischemia (CBF less than 7 ml/100 gm/min) and a 20% to 50% reduction in midbrain CBF. Reperfusion resulted in cerebral reactive hyperemia and systemic hypotension. BN 52021 inhibited the maturation of ischemia-reperfusion induced cerebral injury. Cerebral blood flow was improved. Free fatty acids were decreased, suggesting inhibition of phospholipase A activity. Decreased DAG pools with increased PIP2 pools suggest a possible coinhibition of phospholipase C.
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PMID:Arachidonic acid metabolism and cerebral blood flow in the normal, ischemic, and reperfused gerbil brain. Inhibition of ischemia-reperfusion-induced cerebral injury by a platelet-activating factor antagonist (BN 52021). 277 4

We have investigated the effects of the specific platelet-activating factor (PAF; 1-alkyl-2-acetyl-glycerophosphocholine) antagonist BN52021 on free fatty acid (FFA) and diacylglycerol (DG) accumulation and on the loss of fatty acids from phosphatidylinositol-4,5-bisphosphate (PIP2) in mouse brain. Mice were pretreated with BN52021 (10 mg/kg, i.p.) 30 min before electroconvulsive shock (ECS) or postdecapitation ischemia. These procedures cause rapid breakdown of PIP2 and accumulation of FFA and DG. Lipid extracts were prepared from microwave-fixed cerebrum and fractionated by TLC, and the fatty acid methyl esters were prepared by methanolysis and quantified by capillary GLC. In saline or vehicle (dimethyl sulfoxide)-treated mice, ECS caused marked accumulation of FFA and DG and loss of mainly stearic (18:0) and arachidonic (20:4) acids from PIP2. BN52021 pretreatment of ECS-treated mice decreased the accumulation of free palmitic (16:0), 18:0, 20:4, and docosahexaenoic (22:6) acids with no effect on the fatty acids in DG or the loss of PIP2. BN52021 had no effect on basal levels of FFA, DG, or PIP2. One minute of postdecapitation ischemia induced PIP2 loss and accumulation of FFA and DG. BN52021 attenuated the accumulation of free 20:4 and 22:6 acids, decreased the content of oleic (18:1), 20:4, and 22:6 acids in DG, but had no effect on PIP2 loss. These data indicate that BN52021 reduces the injury-induced activation of phospholipase A2 and lysophospholipase, which mediate the accumulation of FFA in brain, while having a negligible effect on phospholipase C-mediated degradation of PIP2.
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PMID:Platelet-activating factor antagonist BN52021 decreases accumulation of free polyunsaturated fatty acid in mouse brain during ischemia and electroconvulsive shock. 284 88

The aim of this chapter was to highlight the major components of PAF actions which lead to a state of shock, i.e. inadequate perfusion of essential organs which if sustained over a critical period of time, leads to irreversible damage in essential organs and eventually death. The heart, the pulmonary vessels and the microcirculation seem to be the primary target organs to PAF-induced hypotension. The effects of PAF on the pulmonary airways in some species (bronchoconstriction) might lead to hypoxemia and further exacerbate organ function. Thrombocytopenia, leukopenia and activation of the complement system are also important in PAF-induced shock by promoting thrombi formation and generation of multiple secondary mediators (e.g. histamine kinins, TXA2, leukotrienes, oxygen radicals). Identification of PAF production during specific or generalized pathophysiological processes is a critical step to implicate this vasoactive lipid in disease processes. So far, only limited information has been derived from studies involving immune responses (anaphylaxis) or bacterial endotoxins. Yet, the growing number of selective and potent PAF antagonists provide important information on the potential role of PAF in shock states. Such evidence, summarized in table I, is of great importance in designing new therapeutic strategies to a highly complex and lethal disease such as septicemia. However, the data summarized in table I clearly show that little is known on the mechanism of action of the various PAF antagonists. It is also important to note that PAF-induced shock and death can be prevented by drugs which are not necessarily PAF antagonists. For example, dexamethasone is extremely efficient in preventing PAF-induced shock and death in the mouse [24, 39] and thyrotropin releasing hormone in the guinea pig [15]. Therefore, it is conceivable that pathological conditions in which PAF might play a fundamental role might be reversed by pharmacological interventions which activate physiological mechanisms which can overcome and reverse the pathological processes activated by PAF. In conclusion, PAF is a powerful vasoactive lipid which can produce severe derangements in essential biological functions which can lead to death. The role of PAF in pathological processes in vivo is well supported in conditions such as anaphylaxis and endotoxemia. Yet, direct proof for PAF production in other shock states, such as multiple trauma, ischemia, inflammation and hemorrhage, is still missing. Furthermore, it is important to keep in mind that in shock, trauma or inflammation, multiple mediators in addition to PAF are formed.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Platelet-activating factor and shock. 304 32

Platelet-activating factor has been implicated in a variety of disease processes including ischemic brain injury and endotoxic shock, but its effects on cerebral blood flow (CBF) and metabolism in normal brain have not been described. The effects of platelet-activating factor on global CBF (hydrogen clearance) and the global cerebral metabolic rate for oxygen (CMRO2) were studied in halothane-N2O anesthetized Wistar rats. Hexadecyl-platelet-activating factor infused into the right carotid artery (67 pmol/min) for 60 min decreased mean arterial pressure (MAP) from 122 +/- 4 (x +/- SEM) to 77 +/- 6 mm Hg and CBF from 159 +/- 12 to 116 +/- 14 ml/100 g/min (p less than 0.002). In contrast, CMRO2 increased from 9.7 +/- 0.9 to 11.7 +/- 1.1 ml/100 g/min after 15 min (p less than 0.05). In controls rendered similarly hypotensive by blood withdrawal and infused with the platelet-activating factor vehicle, CMRO2 was unchanged, whereas CBF transiently decreased then returned to baseline at 60 min. These cerebrovascular and cerebrometabolic effects of PAF are reminiscent of and may be relevant to hypoperfusion and hypermetabolism observed after global brain ischemia and in endotoxic shock.
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PMID:Cerebrovascular and cerebrometabolic effects of intracarotid infused platelet-activating factor in rats. 339 15

The potential involvement of platelet activating factor (PAF, 1-O-alkyl 2-O-acetyl-sn-glycero-3-phosphocholine) in aggravation of ischemic brain injury has been recently postulated. Reported evidences in support of this thesis include increases of brain PAF concentration during ischemia and the neuroprotective effect exerted by PAF antagonists. In this article, we demonstrate that several PAF-mediated biochemical responses in synaptoneurosomes in vitro resemble these observed previously in ischemic brain and are widely acknowledged as the potentially causal factors in this pathology. In synaptoneurosomes prepared from rat hippocampus, 10 nM PAF caused an observable elevation of intracellular calcium as measured by fluorescence Fura-2A probe. A similar elevation of synaptoneurosomal [Ca2+]i was evoked by 1 mM glutamate treatment. As an effect of calcium entry after PAF application, a translocation of protein kinase C (PKC) toward plasma membranes was demonstrated by 3H-labeled phorbol-binding method. It was followed by an increase of 50 kDa proteolytic fragment of the enzyme (PKM) recognized on Western blots with anti-PKC antibody. Incubation of synaptoneurosomes in the presence of calcium chelators abolished these effects of PAF and significantly decreased the content of PKC in the membranes. Furthermore, PAF treatment markedly attenuated the receptor- and postreceptor-activated cAMP accumulation in synaptoneurosomes. The decrease of cAMP level seems to be secondary to the PAF-induced calcium entry with subsequent activation of cAMP-specific phosphodiesterase, since it was completely blocked by IBMX, a potent inhibitor of this enzyme. Our observations indicate that PAF in a concentration found in ischemic brain can elevate [Ca2+]i and potentiate calcium-dependent intracellular signalling in synaptoneurosomes in vitro, including PKC translocation/activation and proteolysis, followed by IBMX-sensitive inhibition of cAMP production. The relative contribution of these events to ischemic brain injury is currently under extensive investigation.
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PMID:Modulation of signal transduction in rat synaptoneurosomes by platelet activating factor. 754 18

The study deals with an animal model for the problems of surgical intensive care patients. Following repeated applications of E. coli endotoxin WO 111:B4 under standard conditions, specific hemodynamic and biochemical (TNF, TXA2, PGI2, IL-6, PAF) and morphological (endothelium of the lung) alterations were detected. ARDS patterns induced by the sepsis were analyzed by high-frequency measurement of pressure and flow (385 measurements per breathing cycle). The role of the intestine in sepsis was investigated by ion-selective monitoring of surface potassium activity comparing mucosa and serosa. Every injection of endotoxin was followed by a selective increase of the potassium activity revealing relative ischemia induced by the endotoxin. The profile of the potassium levels on the surface correlates both with the cardiac output and with the prostacyclin levels. The continuous narrowing of the difference between mucosa and serosa, potassium during the period of investigation can be regarded as evidence for pathologic change in permeability fostering the septic course.
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PMID:[Septic shock and multiple organ failure in surgical intensive care. An animal experiment model on the analysis of pulmonary and intestinal dysfunction]. 769 Jan 6

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

Platelet-activating factor (1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphocholine [PAF]) is a potent lipid autocoid produced by many cell types. PAF is produced by cultured rat cerebellar neurons and human fetal brain cells, and has been extracted from brain tissue. Multiple PAF receptors have been demonstrated in brain tissue. PAF stimulates intracellular Ca2+ mobilization and phosphatidylinositol (PI) metabolism in transformed neuronal cell lines via the PAF receptor, to which both pertussis toxin (PTX)-sensitive and -insensitive G protein appear to couple. PAF has potent actions on cerebral vessels and cerebral metabolism when administered in vivo. Direct neuronal effects of PAF, such as inhibition of acetylcholine release, are observed in vitro. Excessive PAF production in pathological states of the nervous system, such as neurotrauma and stroke, has been shown. In multiple studies in rodent and non-rodent models using highly specific and potent PAF antagonists, reversal or prevention of key consequences of brain injury, such as hypoperfusion following ischemia, reperfusion and edema, inflammatory cell accumulation, neurologic/motor deficits, and neuronal salvage, has been demonstrated. These studies taken together support a role for PAF as an important mediator in the pathophysiology of brain injury.
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PMID:Platelet-activating factor: a putative neuromodulator and mediator in the pathophysiology of brain injury. 790 80

LTC4, which enhances vascular permeability and promotes tissue edema, and LTB4, which is a potent chemotactic and activating factor for leukocytes, were measured in rat brain after ischemia and several time periods of reperfusion. Forebrain ischemia was induced by 4-vessel occlusion. LTC4/LTB4 in the brain were measured by RIA. We also studied the effects of a 5-lipoxygenase inhibitor, AA-861 and a PAF antagonist, CV-3988 on LTC4/LTB4 concentrations. LTC4 in brain tissue increased during 30 min forebrain ischemia (p < 0.001). After reperfusion, LTC4 increased further, but at 15 min reperfusion LTC4 returned to the control level. Tissue levels of LTB4 in the brain increased during 30 min ischemia and remained high until 5 min after reperfusion (p < 0.01) returning at 15 min reperfusion to the control level. AA-861 inhibited elevation of LTC4/LTB4 in the reperfusion phase, but was not effective during ischemia. CV-3988 had a similar effect. LTC4 and LTB4 may be involved in the pathogenesis of ischemia brain edema and leukocyte infiltration. Further, PAF and LTs have many similarities of their pathophysiological properties, and may interact therefore in pathologic process.
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PMID:LTC4/LTB4 alterations in rat forebrain ischemia and reperfusion and effects of AA-861, CV-3988. 797 70


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