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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thrombin at low doses is an endogenous mediator of protection in ischaemic and haemorrhagic models of stroke. However, the mechanism of thrombin-induced protection remains unclear. Recently accumulating evidence has shown that astrocytes play an important role in the brain after injury. We report that thrombin and thrombin receptor agonist peptide (TRag) up-regulated secretion of the chemokine growth-regulated oncogene/cytokine-induced neutrophil chemoattractant-1 (GRO/CINC-1) in primary rat astrocytes in a concentration-dependent manner. However, we found no increase of interleukin (IL)-6, IL-1beta and tumour necrosis factor-alpha secretion. Protease-activated receptor 1 (PAR-1)-induced GRO/CINC-1 release was mainly mediated by c-Jun N-terminal kinase (JNK) activation. Extracellular signal-regulated kinase 1/2 might be partially involved, but not p38 mitogen-activated protein kinase. Further studies demonstrated that PAR-1 activation, as well as application of recombinant GRO/CINC-1, protected astrocytes from C(2)-ceramide-induced cell death. Protection occurred with suppression of cytochrome c release from mitochondria. The inhibition of cytochrome c release was largely reduced by the antagonist of chemokine receptor CXCR2, SB-332235. Importantly, a specific JNK inhibitor significantly abolished the protective action of PAR-1. These results demonstrate for the first time that PAR-1 plays an important role in anti-apoptosis in the brain by regulating the release of chemokine GRO/CINC-1, which gives a feedback through its receptor CXCR2 to preserve astrocytes from toxic insults.
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PMID:Protease-activated receptor-1 protects rat astrocytes from apoptotic cell death via JNK-mediated release of the chemokine GRO/CINC-1. 1674 7

Platelets play a central role in maintaining biological hemostasis. Inappropriate platelet activation is responsible for thrombotic diseases such as myocardial infarction and stroke. Therefore, novel agents that can inhibit platelet activation are necessary. However, assays that monitor platelet aggregation are generally time-consuming and require high volumes of blood and specialized equipment. Therefore, a medium- to high-throughput assay that can monitor platelet aggregation would be considered useful. Such an assay should be sensitive, comparable to the "gold standard" assay of platelet aggregometry, and able to monitor multiple samples simultaneously but with low assay volumes. We have developed such a microtiter assay. It can assay an average of 60 independent treatments per 60 ml blood donation and demonstrates greater sensitivity than the current gold standard assay, namely platelet aggregation in stirring conditions in a platelet aggregometer. The microtiter plate (MTP) assay can detect known inhibitors of platelet function such as indomethacin, aspirin, and ReoPro. It is highly reproducible when using standard doses of agonists such as thrombin receptor-activating peptide (20 microM) and collagen (0.19 mg/ml). Finally, the MTP assay is rapid and sensitive and can detect unknown platelet-modulating agents from a library of compounds.
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PMID:Monitoring modulators of platelet aggregation in a microtiter plate assay. 1692 64

Cardiopulmonary bypass, although remaining an indispensable asset in cardiac surgery, especially in more complex and repeat operations, is associated with significant thrombin generation in the bypass circuit, leading to the activation of platelets, the coagulation system, an inflammatory response, and perioperative stroke. Recent clinical studies and meta-analyses of clinical trials in coronary artery bypass grafting surgery have confirmed that aprotinin not only reduces transfusion requirements in cardiac surgery but also confers significant protection against platelet dysfunction, activation of the systemic inflammatory response, and perioperative stroke when administered at the full (or "Hammersmith") dose. This article reviews research from several independent groups to propose a novel mechanism through which the antithrombotic, anti-inflammatory, and neuroprotective mechanism might be mediated, via protection of the high-affinity thrombin receptor protease-activated receptor 1 (PAR1).
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PMID:Aprotinin and the protease-activated receptor 1 thrombin receptor: antithrombosis, inflammation, and stroke reduction. 1695 40

Recent results in animal models suggest that thrombin may modulate brain injury in Parkinson's disease (PD). High doses of thrombin ( approximately 20U) can damage dopaminergic neurons, while we have found that low dose thrombin (1U), given several days before a brain insult (thrombin preconditioning), is protective in models of PD and stroke. However, the effects of such low levels of thrombin at the time of, or after, exposure to the dopamine neurotoxin 6-hydroxydopamine (6-OHDA) have not been examined and are the focus of this study. In the first set of experiments, rats received co-administration of thrombin (1U) or saline and 6-OHDA (5microg) into the medial forebrain bundle. 6-OHDA+thrombin resulted in striking increases in behavioral deficits, compared to 6-OHDA+saline. Similarly, co-administration of an agonist to protease-activated receptor (PAR)-1, a thrombin receptor, also resulted in significantly greater behavioral deficits. In a second set of experiments, thrombin (1U) or saline was administered 1 or 7 days after 6-OHDA to determine the effects of thrombin after 6-OHDA. Surprisingly, the rats that received saline had strikingly increased behavioral and neurochemical deficits resulting from the 6-OHDA lesion, while delayed thrombin administration prevented this effect. The results indicate that thrombin has differential effects in the 6-OHDA model, dependent on the time of administration. The ability of a second cannula insertion with saline infusion to increase dramatically deficits raises questions as to what role physical injury to already susceptible cells might play in the pathogenesis of some cases of PD.
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PMID:The effect of thrombin on a 6-hydroxydopamine model of Parkinson's disease depends on timing. 1762 81

The "systemic inflammatory response" is a multifaceted defensive reaction of the body to surgical trauma and cardiopulmonary bypass (CPB), characterized by systemic activation of fibrinolysis, coagulation, complement, immune cells, platelets, and oxidative pathways, all overlaid onto localized trauma to the grafted vessel or vascular beds susceptible to ischemia/reperfusion. There is going to be no single magic bullet to diminish such a broad host defense response to surgery. The best chance lies with combinatorial--or promiscuous--pharmacotherapy. Combinations of anti-fibrinolytics, anti-coagulants targeted higher up the coagulation cascade, anti-thrombin receptor therapy, improved coated circuits, anti-complement, anti-leukocyte, and antioxidant therapies may blunt sufficient arms of the systemic inflammatory response to be clinically effective. The alternative is a promiscuous drug like aprotinin, which targets plasmin in the fibrinolytic pathway, kallikrein in the coagulation pathway, thrombin receptors on platelets and endothelium, and leukocytes at the extravasation step. Because of the overriding safety concerns relating to the use of anti-fibrinolytics in cardiothoracic surgery, any future combinatorial or promiscuous pharmacotherapy involving anti-fibrinolytics will require solid underpinning with a known mechanism of action and clinical safety data powered to detect well-defined adverse events (stroke, myocardial injury, renal failure requiring dialysis), preferably in isolation and not as a composite endpoint.
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PMID:Pharmacologic strategies for combating the inflammatory response. 1829 23

For patients with ischemic stroke or transient ischemic attack caused by atherothromboembolism, immediate and long-term aspirin reduces the relative risk of recurrent stroke, MI, and death attributable to vascular causes. Oral anticoagulation is not more effective than aspirin. Long-term clopidogrel reduces the relative risk of stroke, MI, or vascular death by about 9% (0.3% to 16.5%) compared with aspirin. Any long-term benefits of clopidogrel combined with aspirin, compared with aspirin or clopidogrel alone, appear to be offset by increased major bleeding. The combination of aspirin and extended-release dipyridamole reduces the relative odds of stroke, MI, or vascular death by about 18% (odds ratio 0.82, 0.74 to 0.91) compared with aspirin alone without causing more bleeding. Cilostazole reduces the risk of stroke, MI, or vascular death by 39% compared to placebo. A large clinical trial comparing clopidogrel with the combination of aspirin and dipyridamole, in >20 000 patients with recent (<120 days) atherothrombotic ischemic stroke, is expected to report in 2008. Emerging antiplatelet therapies presently being evaluated for secondary prevention of atherothromboembolism include other P(2)Y(12) ADP receptor antagonists (prasugrel, cangrelor, AZD 6140), thromboxane receptor antagonists (eg, S18886 - terutroban), and thrombin receptor (PAR-1) antagonists (eg, SCH530348).
Stroke 2008 May
PMID:Antiplatelet therapy for secondary prevention of noncardioembolic ischemic stroke: a critical review. 1836 75

The haematopoietic hormone erythropoietin (EPO) has neuroprotective properties and is currently being explored for treatment of stroke and other neurological disorders. Short-term, high-dose treatment with EPO seems to improve neurological function of stroke patients but may be associated with increased thrombotic risk, whereas alternative non-erythropoietic neuroprotective derivatives of EPO, such as carbamylated EPO (CEPO), may be devoid of such side-effects. We investigated the effects of short-term, high-dose treatment with EPO and CEPO on platelet function and haemostasis in healthy mice and rats. Animals received three daily doses of EPO or CEPO (50 microg/kg), and blood was compared with respect to alterations in haematology and platelet reactivity. In rats, treatment with EPO increased the haematocrit to >50% and the mean platelet volume by 37%, while CEPO had no effect on these parameters. Platelets from EPO-treated rats showed an increased sensitivity to thrombin receptor agonist peptides and elevated plasma levels of soluble P-selectin (sP-selectin) were found in treated mice. Further indicators of platelet hyperreactivity in EPO, but not CEPO-treated animals, were significantly increased aggregatory responses to collagen in whole blood and platelet-rich plasma (PRP). The increased platelet reactivity was paralleled by a decreased bleeding time after tail transection in rats. Samples from EPO-treated rats showed an attenuated response to ADP in whole blood aggregometry and thrombelastography (TEG) platelet mapping but not in apyrase-treated PRP, suggesting involvement of ADP receptor desensitization. These findings suggest that while EPO affects various aspects of platelet function, CEPO is devoid of such effects.
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PMID:High-dose erythropoietin alters platelet reactivity and bleeding time in rodents in contrast to the neuroprotective variant carbamyl-erythropoietin (CEPO). 1839 30

Microglial cells are the innate immune cells of the central nervous system and quickly respond to injury by proliferation, cytokine release, and increased cell surface antigen expression. Thrombin is a multifunctional serine proteinase, which has the capability to activate microglial cells. Here, we report that pharmaceutical-grade thrombin dose-dependently increases the expression of CD40 in N9 microglial cells. This effect is blocked by a thrombin inhibitor, mimicked by thrombin receptor-activating peptide and modified by mitogen-activated protein kinase pathway inhibitors. Thrombin-induced CD40 regulation might play a role in diseases with breakdown of the blood-brain barrier such as multiple sclerosis or stroke.
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PMID:Thrombin regulates CD40 expression in microglial cells. 1841 52

Atherothrombosis is an acute complication that develops on the surface of a ruptured atheromatous plaque or as a consequence of endothelial erosion that may cause myocardial infarction or ischemic stroke. Anti-platelet therapy has been highly effective at reducing atherothrombotic risk. However, patients continue to experience thrombotic events despite the use of agents such as aspirin and clopidogrel. Many of these events occur, in part, because of the inadequate response to these drugs. This has prompted the pursuit of novel agents with aspirations of optimizing anti-platelet therapy. New opportunities have emerged to address the deficiencies in current anti-platelet agents. Among these are thrombin receptor antagonists, such as SCH530348 and P2Y12 receptor antagonists, such as prasugrel, cangrelor, and AZD6140. The patents describe these novel compounds and compositions, their ability to inhibit platelet activation and/or aggregation and their use in the treatment of atherothrombotic diseases. These drugs have pharmacologic properties that translate into increased potency, more rapid onset of action, and less variability in response compared to standard therapy. In this review, we highlight the current data on these potential drugs and the role they could play in atherothrombotic disease.
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PMID:Future prospects in anti-platelet therapy: a review of potential P2Y12 and thrombin receptor antagonists. 1899 94

Thrombin is involved in mediating neuronal death in cerebral ischemia. We investigated its so far unknown mode of activation in ischemic neural tissue. We used an in vitro approach to distinguish the role of circulating coagulation factors from endogenous cerebral mechanisms. We modeled ischemic stroke by subjecting rat organotypic hippocampal slice cultures to 30-min oxygen (5%) and glucose (1 mmol/L) deprivation (OGD). Perinuclear activated factor X (FXa) immunoreactivity was observed in CA1 neurons after OGD. Selective FXa inhibition by fondaparinux during and after OGD significantly reduced neuronal death in the CA1 after 48 h. Thrombin enzyme activity was increased in the medium 24 h after OGD and this increase was prevented by fondaparinux suggesting that FXa catalyzes the conversion of prothrombin to thrombin in neural tissue after ischemia in vitro. Treatment with SCH79797, a selective antagonist of the thrombin receptor protease-activated receptor-1 (PAR-1), significantly decreased neuronal cell death indicating that thrombin signals ischemic damage via PAR-1. The c-Jun N-terminal kinase (JNK) pathway plays an important role in excitotoxicity and cerebral ischemia and we observed activation of the JNK substrate, c-Jun in our model. Both the FXa inhibitor, fondaparinux and the PAR-1 antagonist SCH79797, decreased the level of phospho-c-Jun Ser73. These results indicate that FXa activates thrombin in cerebral ischemia, which leads via PAR-1 to the activation of the JNK pathway resulting in neuronal death.
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PMID:Coagulation factor Xa activates thrombin in ischemic neural tissue. 1971 23


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