Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Elevated levels of free fatty acids (FFA) have been implicated in the pathogenesis of neuronal injury and death induced by cerebral ischemia. This study evaluated the effects of immunosuppressants agents, calcineurin inhibitors and blockade of endoplasmic reticulum (ER) calcium channels on free fatty acid formation and efflux in the ischemic/reperfused (I/R) rat brain. Changes in the extracellular levels of arachidonic, docosahexaenoic, linoleic, myristic, oleic and palmitic acids in cerebral cortical superfusates during four-vessel occlusion-elicited global cerebral ischemia were examined using a cortical cup technique. A 20-min period of ischemia elicited large increases in the efflux of all six FFAs, which were sustained during the 40 min of reperfusion. Cyclosporin A (CsA) and trifluoperazine, which reportedly inhibit the I/R elicited opening of a mitochondrial permeability transition (MPT) pore, were very effective in suppressing ischemia/reperfusion evoked release of all six FFAs. FK506, an immunosuppressant which does not directly affect the MPT, but is a calcineurin inhibitor, also suppressed the I/R-evoked efflux of FFAs, but less effectively than CsA. Rapamycin, a derivative of FK506 which does not inhibit calcineurin, did not suppress I/R-evoked FFA efflux. Gossypol, a structurally unrelated inhibitor of calcineurin, was also effective, significantly reducing the efflux of docosahexaenoic, arachidonic and oleic acids. As previous experiments had implicated elevated Ca(2+) levels in the activation of phospholipases with FFA formation, agents affecting endoplasmic reticulum stores were also evaluated. Dantrolene, which blocks the ryanodine receptor (RyR) channel of the ER, significantly inhibited I/R-evoked release of docosahexaenoic, arachidonic, linoleic and oleic acids. Ryanodine, which can either accentuate or block Ca(2+) release, significantly enhanced ischemia/reperfusion-elicited efflux of linoleic acid, with non-significant increases in the efflux of myristic, arachidonic, palmitic and oleic acids. Xestospongin C, an inhibitor of the inositol triphosphate (IP(3)R) channel, failed to affect I/R-evoked FFA efflux. Thapsigargin, an inhibitor of the Ca(2+)-ATPase ER uptake pump, elicited significant elevations in the efflux of myristic, arachidonic and linoleic acids, in the absence of ischemia. Collectively, the data suggest an involvement of both ER and mitochondrial Ca(2+) stores in the chain of events which lead to PLA(2) activation and FFA formation.
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PMID:Effects of immunosuppressants, calcineurin inhibition, and blockade of endoplasmic reticulum calcium channels on free fatty acid efflux from the ischemic/reperfused rat cerebral cortex. 1244 75

Neuroprotection by citicoline (CDP-choline) in transient cerebral ischemia has been demonstrated previously. Citicoline has undergone several Phase III clinical trials for stroke, and is being evaluated for treatment of Alzheimer's and Parkinson's diseases. Phospholipid degradation and generation of reactive oxygen species (ROS) are major factors causing neuronal injury in CNS trauma and neurodegenerative diseases. Oxidative metabolism of arachidonic acid (released by the action of phospholipases) contributes to ROS generation. We examined the effect of citicoline on phospholipase A(2) (PLA(2)) activity in relation to the attenuation of hydroxyl radical (OH.) generation after transient forebrain ischemia of gerbil. PLA(2) activity (requires mM Ca(2+)) increased significantly (P < 0.05) in both membrane (50.2 +/- 2.2 pmol/min/mg protein compared to sham 35.9 +/- 3.2) and mitochondrial fractions (77.0 +/- 1.2 pmol/min/mg protein compared to sham 33.9 +/- 1.2) after cerebral ischemia and 2 hr reperfusion in gerbil, which was significantly attenuated (P < 0.01) by citicoline (membrane, 39.9. +/- 2.2 and mitochondria, 41.9 +/- 3.2 pmol/min/mg protein). In vitro, citicoline and its components cytidine and choline had no effect on PLA(2) activity, and thus citicoline as such is not a PLA(2) inhibitor. Ischemia/reperfusion resulted in significant OH. generation (P < 0.01) and citicoline significantly (P < 0.01) attenuated their formation (expressed as 2,3-dihydroxybenzoic acid/salicylate ratio; ischemia/24 hr reperfusion, 6.30 +/- 0.23; sham, 2.56 +/- 0.27; ischemia/24 hr reperfusion + citicoline, 4.85 +/- 0.35). These results suggest that citicoline affects PLA(2) stimulation and decreases OH. generation after transient cerebral ischemia.
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PMID:Citicoline decreases phospholipase A2 stimulation and hydroxyl radical generation in transient cerebral ischemia. 1286 64

Brain recovery after cardiac arrest (CA) was assessed in cats using arterial spin tagging perfusion-weighted imaging (PWI), diffusion-weighted imaging (DWI), and 1H-spectroscopy (1H-MRS). Cerebral reperfusion and metabolic recovery was monitored in the cortex and in basal ganglia for 6 h after cardiopulmonary resuscitation (CPR). Furthermore, the effects of an hypertonic/hyperoncotic solution (7.5% NaCl/6% hydroxyl ethyl starch, HES) and a tissue-type plasminogen activator (TPA), applied during CPR, were assessed on brain recovery. CA and CPR were carried out in the MR scanner by remote control. CA for 15-20 min was induced by electrical fibrillation of the heart, followed by CPR using a pneumatic vest. PWI after successful CPR revealed initial cerebral hyperperfusion followed by delayed hypoperfusion. Initial cerebral recirculation was improved after osmotic treatment. Osmotic and thrombolytic therapy were ineffective in ameliorating delayed hypoperfusion. Calculation of the apparent diffusion coefficient (ADC) from DWI demonstrated complete recovery of ion and water homeostasis in all animals. 1H-MRS measurements of lactate suggested an extended preservation of post-ischaemic anaerobic metabolism after TPA treatment. The combination of noninvasive MR techniques is a powerful tool for the evaluation of therapeutical strategies on circulatory and metabolic cerebral recovery after experimental cerebral ischaemia.
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PMID:Time course of circulatory and metabolic recovery of cat brain after cardiac arrest assessed by perfusion- and diffusion-weighted imaging and MR-spectroscopy. 1296 12

The regulation of cerebrovascular permeability is critical for normal brain homeostasis, and the "breakdown" of the blood-brain barrier (BBB) is associated with the development of vasogenic edema and intracranial hypertension in a number of neurological disorders. In this study we demonstrate that an increase in endogenous tissue-type plasminogen activator (tPA) activity in the perivascular tissue following cerebral ischemia induces opening of the BBB via a mechanism that is independent of both plasminogen (Plg) and MMP-9. We also show that injection of tPA into the cerebrospinal fluid in the absence of ischemia results in a rapid dose-dependent increase in vascular permeability. This activity is not seen with urokinase-type Plg activator (uPA) but is induced in Plg-/- mice, confirming that the effect is Plg-independent. However, the activity is blocked by antibodies to the LDL receptor-related protein (LRP) and by the LRP antagonist, receptor-associated protein (RAP), suggesting a receptor-mediated process. Together these studies demonstrate that tPA is both necessary and sufficient to directly increase vascular permeability in the early stages of BBB opening, and suggest that this occurs through a receptor-mediated cell signaling event and not through generalized degradation of the vascular basement membrane.
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PMID:Tissue-type plasminogen activator induces opening of the blood-brain barrier via the LDL receptor-related protein. 1461 49

Neuroserpin is a member of the serine proteinase inhibitor (serpin) gene family that reacts preferentially with tissue-type plasminogen activator (tPA) and is primarily localized to neurons in regions of the brain where tPA is also found. Outside of the central nervous system (CNS) tPA is predominantly found in the blood where its primary function is as a thrombolytic enzyme. However, tPA is also expressed within the CNS where it has a very different function, promoting events associated not only with synaptic plasticity but also with cell death in a number of settings, such as cerebral ischemia and seizures. Neuroserpin is released from neurons in response to neuronal depolarization and plays an important role in the development of synaptic plasticity. Following the onset of cerebral ischemia there is an increase in both tPA activity and neuroserpin expression in the area surrounding the necrotic core (ischemic penumbra), and treatment with neuroserpin following ischemic stroke or overexpression of the neuroserpin gene results in a significant decrease in the volume of the ischemic area as well as in the number of apoptotic cells. TPA activity and neuroserpin expression are also increased in specific areas of the brain by seizures, and treatment with neuroserpin slows the progression of seizure activity throughout the CNS and results in significant neuronal survival in the hippocampus. Mutations in human neuroserpin result in a form of autosomal dominant inherited dementia which is characterized by the presence of intraneuronal inclusion bodies and is known as Familial Encephalopathy with Neuroserpin Inclusion Bodies.
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PMID:Neuroserpin: a selective inhibitor of tissue-type plasminogen activator in the central nervous system. 1498 20

Cytidine-5'-diphosphocholine (CDP-choline, also referred as citicoline), the key intermediate in phosphatidylcholine (PtdCho) synthesis, provided significant benefit in experimental central nervous system (CNS) injury including cerebral ischemia. CDP-choline is synthesized by CTP:phosphocholine cytidylyltransferase (CCT), the key rate-limiting enzyme in PtdCho synthesis. Phospholipase A(2) (PLA(2)) hydrolyzes PtdCho to produce free fatty acids and lyso-PtdCho, an inhibitor of CCT. We investigated the status of CCT and lyso-PtdCho after 10-min transient brain ischemia in gerbils with reperfusion up to 2 days. Ischemia with no reperfusion resulted in loss of CCT activity in cytosol (408 +/- 8 pmol/min/mg protein compared to sham 695 +/- 45; P < 0.01) and membrane (383 +/- 61 compared to sham 532 +/- 54; P < 0.05). CCT activity remained low over 24-hr reperfusion, and returned to sham levels at Day 2 in membrane but remained low in cytosol. CDP-choline significantly increased CCT activity in cytosol at 1 hr reperfusion (saline, 339 +/- 35 compared to CDP-choline, 430 +/- 70; P < 0.05) and in membrane at 6 hr (saline, 381 +/- 32 compared to CDP-choline, 489 +/- 50; P < 0.01) and 24 hr (saline, 417 +/- 24 compared to CDP-choline, 594 +/- 45; P < 0.01), but had no effect on CCT activity at Day 2. Lyso-PtdCho increased at 1-hr reperfusion (219 +/- 5 nmol/g tissue compared to sham, 92 +/- 8; P < 0.01), and remained elevated over 2 days. CDP-choline attenuated lyso-PtdCho levels at 1-hr reperfusion (162 +/- 21, P < 0.01 compared to saline). These data indicate that PtdCho synthesis is impaired after brain ischemia, and CDP-choline may increase PtdCho levels by attenuating the loss of CCT activity and lyso-PtdCho formation.
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PMID:Cytidine-5'-diphosphocholine affects CTP-phosphocholine cytidylyltransferase and lyso-phosphatidylcholine after transient brain ischemia. 1507 68

Catheter-based cerebral angiography remains an essential tool for evaluating patients with acute cerebral ischemia. Noninvasive vascular imaging techniques have yet to achieve the accuracy and wide availability necessary for this purpose. Angiography is rarely indicated when patients present within the short 3-hour time window for treatment with intravenous alteplase. For the many patients who present later in their course, however, angiography is useful for the accurate evaluation of the cerebral vasculature. In addition, angiography serves as the foundation for the endovascular therapies that may be performed to treat acute ischemic stroke beyond the 3-hour time window.
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PMID:Cerebral angiography in the assessment of acute cerebral ischemia: guidelines and recommendations. 1510 16

The aim of this study is to investigate disturbances in fibrinolytic components in diabetic rats with middle cerebral artery occlusion (MCAO). Comparison of cerebral injury at 23 h after reperfusion indicated that infarction volumes were increased in diabetic rats as compared with normal rats. Cerebral ischemia/reperfusion in normal and diabetic rats was accompanied by increased expression of tissue plasminogen activator (t-PA), urokinase plasminogen activator (u-PA), plasminogen activator inhibitor 1 (PAI-1) and neuroserpin (NSP) mRNA after reperfusion. Most importantly, the expression of NSP mRNA, but not t-PA, u-PA and PAI-1 mRNA, was reduced to undetectable levels at 11 and 23 h after reperfusion in diabetic rats as compared with normal rats. Although activity of PA (t-PA and u-PA) and the ratio of PA/PAI were increased at 5 h after reperfusion in both ischemic brains of diabetic and normal rats, the levels in diabetic rats were lower than that in normal rats. We speculate that the exacerbation of ischemic injury in diabetic rats may be related to the reduction of fibrinolytic component and the neuroprotective role of NSP. Further study of the efficacy of NSP in the pathogenesis and treatment of cerebral ischemia may provide novel insights.
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PMID:Reductions in mRNA of the neuroprotective agent, neuroserpin, after cerebral ischemia/reperfusion in diabetic rats. 1522 82

Tissue-type plasminogen activator (tPA) is a highly specific serine proteinase that activates the zymogen plasminogen to the broad-specificity proteinase plasmin. Tissue-type plasminogen activator is found not only in the blood, where its primary function is as a thrombolytic enzyme, but also in the central nervous system (CNS), where it promotes events associated with synaptic plasticity and acts as a regulator of the permeability of the neurovascular unit. Tissue-type plasminogen activator has also been associated with pathological events in the CNS such as cerebral ischemia and seizures. Neuroserpin is an inhibitory serpin that reacts preferentially with tPA and is located in regions of the brain where either tPA message or tPA protein are also found, indicating that neuroserpin is the selective inhibitor of tPA in the CNS. There is a growing body of evidence demonstrating the participation of tPA in a number of physiological and pathological events in the CNS, as well as the role of neuroserpin as the natural regulator of tPA's activity in these processes. This review will focus on nonhemostatic roles of tPA in the CNS with emphasis on its newly described function as a regulator of permeability of the neurovascular unit and on the regulatory role of neuroserpin in these events.
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PMID:New functions for an old enzyme: nonhemostatic roles for tissue-type plasminogen activator in the central nervous system. 1556 35

The aim of this study was to investigate the effects of different doses of exogenous recombinant human tissue plasminogen activator (rt-PA) on the endogenous cerebral plasminogen-plasmin system in focal ischemia in rats. Ischemia was induced using the suture model. Each group of rats (n = 6) received either treatment (0.9, 9 or 18 mg rt-PA/kg body weight) or saline (control group) at the end of ischemia; a sham-operated group was added. The activity of the plasminogen activators was measured by casein-dependent plasminogen zymography. In the cortex urokinase (u-PA) rose from sham (no ischemia), 91 +/- 7% to ischemia, 176 +/- 10% (P < 0.005). Increasing rt-PA doses led to further significant (P < 0.001) cortical u-PA activation which was maximal at 18 mg: 249 +/- 13%. An extreme increase in the u-PA activity was observed in the basal ganglia to 1019 +/- 22% (P < 0.001). This increase was further aggravated by higher rt-PA doses (18 mg, 1236 +/- 15%; P < 0.001). The t-PA level did not change I3R24 during (3 h ischemia followed by reperfusion for 24 h); however, during low and moderate doses of rt-PA, endogenous t-PA was reduced. In conclusion, while ischemia leads to a significant increase in u-PA, mainly in the basal ganglia, t-PA is not altered. Increasing doses of rt-PA lead to a further elevation of u-PA. Thus, u-PA seems to play a major role in the endogenous plasminogen activator system following focal cerebral ischemia.
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PMID:Rt-PA causes a significant increase in endogenous u-PA during experimental focal cerebral ischemia. 1557 44


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