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

Platelets contribute to arterial thrombosis by multiple mechanisms that promote blood clotting, favor vasoconstriction, activate the procoagulant capacity of endothelium, and stimulate inflammation. These activities are augmented by turbulent blood flow. Classic antiplatelet therapy with aspirin to prevent occlusive stroke offers significant clinical benefit (20-25% risk reduction), yet is less effective than in prevention of coronary artery occlusion (up to 50% risk reduction of myocardial infarction in unstable angina). Since aspirin's antiplatelet effects are limited to blocking a single metabolic pathway - namely inhibition of thromboxane A(2) formation -, and aspirin fails to alter platelet adhesion, other antiplatelet agents that target ADP receptors, platelet surface glycoproteins (such as the GPIIb/IIIa complex), or platelet-dependent thrombin generation offer additional clinical benefits by blocking additional separate pathways or the final common pathway of platelet activation. Combinations of antiplatelet agents, such as aspirin/dipyridamole, aspirin/clopidogrel, or aspirin/GPIIb/IIIa inhibitors, have recently been tested for improved efficacy in clinical trials. Soluble recombinant CD39, an ecto-ADPase, protects against stroke in animal models by metabolizing released ADP/ATP to antiplatelet derivatives. In general, combinations of antiplatelet agents promise greater efficacy than single drugs in preventing stroke, since interactions among different antiplatelet mechanisms can be synergistic. However, such combinations may also increase the risk of bleeding, so that precise understanding of risk/benefit ratios that address the possibility of intracranial as well as gastrointestinal bleeding will require careful monitoring in large clinical trials of patients at risk of stroke, with particular attention to the elderly.
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PMID:Antiplatelet agents in stroke prevention. combination therapy: present and future. 1109 82

Abnormal platelet reactivity has been linked to unstable angina, myocardial infarction, post angioplasty stenosis, cerebral ischemia, thrombotic stroke and a variety of inflammatory vascular disorders associated with transplantation. Drugs that inhibit blood coagulation, promote fibrinolysis or block platelet activation are important therapeutic agents in cardiovascular medicine. However, many of the current antiplatelet modalities are nonspecific, ineffective or associated with severe side effects that limit their usefulness. In this article, we discuss some basic aspects of platelet pathophysiology to illustrate the importance of ADP stimulation and signaling in platelet activation. CD39, the ATP diphosphohydrolase (ATPDase) expressed on quiescent vascular endothelium, modulates platelet purinoreceptor activity by the sequential hydrolysis of extracellular ATP or ADP directly to AMP. This thromboregulatory potential of CD39 has been recently demonstrated by the generation of mutant mice with disruption of the gene, and by a series of experiments where high level ATPDase expression has been attained by adenoviral vectors in the injured vasculature. Systemic administration of soluble derivatives of CD39 or targeted expression of the native protein to sites of vascular injury may have future therapeutic application.
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PMID:New developments in anti-platelet therapies: potential use of CD39/vascular ATP diphosphohydrolase in thrombotic disorders. 1146 20

During their 7-9 day lifespan in the circulation platelets are mainly responsible for maintaining the integrity of the vasculature. In thrombocytopenic states, there is an increase in vascular permeability and fragility, presumably due to absence of this platelet function. In sharp contrast, biochemical or physical injury in the coronary, carotid or peripheral arteries induces platelet activation and platelet recruitment, which can culminate in thrombotic vascular occlusion. Since there is one death every 33 s from vascular occlusion in the United States, this situation constitutes a major public health issue. In the course of studying interactions between cells of the vascular wall and those in the circulation, we observed that platelets in close proximity to endothelial cells do not respond to agonists in vitro. Experiments initiated in the late 1980's cumulatively indicated that endothelial cell CD39--an ecto-ADPase--was mainly responsible for this phenomenon. CD39 rapidly and preferentially metabolizes ADP released from activated platelets. ADP is the final common pathway for platelet recruitment and thrombus formation, and platelet aggregation and recruitment are abolished by CD39. Our current hypothesis is that CD39 will be a novel antithrombotic agent for treating high risk patients who have activated platelets in their circulation--the identifying characteristic of coronary artery occlusion and thrombotic stroke. A recombinant, soluble form of human CD39 has been generated. This is solCD39, a glycosylated protein of 66 kDa whose enzymatic and biological properties are identical to the full-length form of the enzyme. In our in vitro experiments, solCD39 blocks ADP-induced human platelet aggregation, and inhibits collagen- and thrombin receptor agonist peptide-induced platelet reactivity. We studied solCD39 in vitro in a murine model of stroke, which was shown to be driven by excessive platelet recruitment. In studies with CD39 wild-type (CD39+/+) mice solCD39 completely abolished ADP-induced platelet aggregation, and strongly inhibited collagen- and arachidonate-induced platelet reactivity ex vivo. When solCD39 was administered prior to transient intraluminal middle cerebral artery occlusion, it reduced ipsilateral fibrin deposition, decreased (111)In-platelet deposition, and increased post-ischemic blood flow 2-fold at 24 hours. These results were superior to those we obtained with aspirin pre-treatment. CD39 null (CD39-/-) mice, which we generated by deletion of exons 4-6 (apyrase conserved regions 2-4), have a normal phenotype, normal hematologic profiles and bleeding times, but exhibit a decrease in post-ischemic perfusion and an increase in cerebral infarct volume when compared to genotypic CD39+/+ controls in our stroke model. "Reconstitution" of CD39 null mice with solCD39 reversed these pathologic changes. Thus, the CD39-/- mice were actually rescued from cerebral injury by solCD39, thereby fulfilling Koch's postulates. These experiments have led us to hypothesize that solCD39 has potential as a novel therapeutic agent for thrombotic stroke. In this review, we summarize our recent research results with CD39 and solCD39, and discuss our viewpoints on its present and future possibilities as a novel treatment for thrombosis.
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PMID:Inhibition of platelet recruitment by endothelial cell CD39/ecto-ADPase: significance for occlusive vascular diseases. 1177 Aug 67

Endothelial CD39 metabolizes ADP released from activated platelets. Recombinant soluble human CD39 (solCD39) potently inhibited ex vivo platelet aggregation in response to ADP and reduced cerebral infarct volumes in mice following transient middle cerebral artery occlusion, even when given 3 hours after stroke. Postischemic platelet and fibrin deposition were decreased and perfusion increased without increasing intracerebral hemorrhage. In contrast, aspirin did not increase postischemic blood flow or reduce infarction volume, but did increase intracerebral hemorrhage. Mice lacking the enzymatically active extracellular portion of the CD39 molecule were generated by replacement of exons 4-6 (apyrase-conserved regions 2-4) with a PGKneo cassette. Although CD39 mRNA 3' of the neomycin cassette insertion site was detected, brains from these mice lacked both apyrase activity and CD39 immunoreactivity. Although their baseline phenotype, hematological profiles, and bleeding times were normal, cd39(-/-) mice exhibited increased cerebral infarct volumes and reduced postischemic perfusion. solCD39 reconstituted these mice, restoring postischemic cerebral perfusion and rescuing them from cerebral injury. These data demonstrate that CD39 exerts a protective thromboregulatory function in stroke.
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PMID:Elucidation of the thromboregulatory role of CD39/ectoapyrase in the ischemic brain. 1195 40

Platelets are responsible for maintaining vascular integrity. In thrombocytopenic states, vascular permeability and fragility increase, presumably due to the absence of this platelet function. Chemical or physical injury to a blood vessel induces platelet activation and platelet recruitment. This is beneficial for the arrest of bleeding (hemostasis), but when an atherosclerotic plaque is ulcerated or fissured, it becomes an agonist for vascular occlusion (thrombosis). Experiments in the late 1980s cumulatively indicated that endothelial cell CD39-an ecto-ADPase-reduced platelet reactivity to most agonists, even in the absence of prostacyclin or nitric oxide. As discussed herein, CD39 rapidly and preferentially metabolizes ATP and ADP released from activated platelets to AMP, thereby drastically reducing or even abolishing platelet aggregation and recruitment. Since ADP is the final common agonist for platelet recruitment and thrombus formation, this finding highlights the significance of CD39. A recombinant, soluble form of human CD39, solCD39, has enzymatic and biological properties identical to the full-length form of the molecule and strongly inhibits human platelet aggregation induced by ADP, collagen, arachidonate, or TRAP (thrombin receptor agonist peptide). In sympathetic nerve endings isolated from guinea pig hearts, where neuronal ATP enhances norepinephrine exocytosis, solCD39 markedly attenuated norepinephrine release. This suggests that NTPDase (nucleoside triphosphate diphosphohydrolase) could exert a cardioprotective action by reducing ATP-mediated norepinephrine release, thereby offering a novel therapeutic approach to myocardial ischemia and its consequences. In a murine model of stroke, driven by excessive platelet recruitment, solCD39 reduced the sequelae of stroke, without an increase in intracerebral hemorrhage. CD39 null mice, generated by deletion of apyrase-conserved regions 2 to 4, exhibited a decrease in postischemic perfusion and an increase in cerebral infarct volume when compared with controls. "Reconstitution" of CD39 null mice with solCD39 reversed these changes. We hypothesize that solCD39 has potential as a novel therapeutic agent for thrombotic diatheses.
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PMID:Metabolic control of excessive extracellular nucleotide accumulation by CD39/ecto-nucleotidase-1: implications for ischemic vascular diseases. 1264 47

Blood platelets maintain vascular integrity and promote primary and secondary hemostasis following interruption of vessel continuity. Biochemical or physical damage to the coronary, carotid or peripheral arteries is followed by excessive platelet activation and recruitment culminating in vascular occlusion and tissue ischemia. Currently inadequate therapeutic approaches to stroke and coronary artery disease are a public health issue. Following our demonstration of neutrophil leukotriene production from arachidonate released from activated aspirin-treated platelets, we studied interactions between platelets and other blood cells, leading to concepts of transcellular metabolism and thromboregulation. Thrombosis has a proinflammatory component whereby biologically active substances are synthesized by interactions between different cell types that could not individually synthesize the product(s). Endothelial cells control platelet reactivity via three biochemical systems-autacoids leading to production of prostacyclin and nitric oxide, and endothelial ecto-ADPase/CD39/NTPDase-1. The autacoids are fluid-phase reactants, not produced by tissues in the basal state. They are only synthesized intracellularly and released upon interactions of cells with an agonist. When released, autacoids exert fleeting actions in the immediate milieu, and are rapidly inactivated. CD39 is an integral component of the endothelial cell surface and is substrate-activated. It maintains vascular fluidity in the complete absence of prostacyclin and nitric oxide, indicating that they are ancillary components of hemostasis. Therapeutic implications for the autacoids have not been compelling because of their transient, local and fleeting action, and limited potency. Conversely, CD39, acting solely on the platelet releasate, is efficacious in three different animal models. It metabolically neutralizes a prothrombotic platelet releasate via deletion of ADP--the major recruiting agent responsible for formation of an occlusive thrombus. In addition, solCD39 reduced ATP- and ischemia-induced norepinephrine release in the heart. This reduction can prevent fatal arrhythmia. Moreover, solCD39 ameliorated the sequelae of stroke in CD39 null mice. CD39 represents the next generation of cardioprotective and cerebroprotective molecules.
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PMID:Heterologous cell-cell interactions: thromboregulation, cerebroprotection and cardioprotection by CD39 (NTPDase-1). 1467 84

Blood platelets maintain vascular integrity and promote primary and secondary hemostasis following interruption of vessel continuity. Biochemical or physical damage to coronary, carotid, or peripheral arteries promotes excessive platelet activation and recruitment culminating in vascular occlusion and tissue ischemia. Currently, inadequate therapeutic approaches to stroke and coronary artery disease (CAD) are a public health issue. Following our demonstration of neutrophil leukotriene production from arachidonate released from activated aspirin-treated platelets, we studied interactions among platelets and other blood cells. This led to concepts of transcellular metabolism and thromboregulation. Thrombosis has a proinflammatory component whereby biologically active substances are synthesized by different cell types that could not individually synthesize the metabolite(s). Endothelium controls platelet reactivity via at least three biochemical systems: autacoids leading to production of prostacyclin and nitric oxide (NO) and endothelial ecto-adenosine phosphatase (ADPase)/CD39/nucleoside triphosphate diphosphohydrolase (NTPDase-1). The autacoids are fluid phase reactants, not produced by tissues in the basal state, but are only synthesized intracellularly and released upon interactions of cells with an agonist. When released, they exert fleeting actions in the immediate milieu and are rapidly inactivated. CD39 is an integral component of the endothelial cell (EC) surface and is substrate activated. It maintains vascular fluidity in the complete absence of prostacyclin and NO, indicating that the latter are ancillary components of hemostasis. Therapeutic implications for the autacoids have not been compelling because of their transient and local action and limited potency. Conversely, CD39, acting solely on the platelet releasate, is efficacious in animal models. It metabolically neutralizes a prothrombotic releasate via deletion of ADP-the major recruiting agent responsible for formation of an occlusive thrombus. In addition, solCD39 reduced adenosine triphosphate (ATP)- and ischemia-induced norepinephrine release in the heart. This action can prevent fatal arrhythmia. Moreover, solCD39 ameliorated the sequelae of stroke in cd39 null mice. Thus, CD39 represents the next generation of cardioprotective and cerebroprotective molecules. This article focuses on our interpretations of recent data and their implications for therapeutics.
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PMID:Role of CD39 (NTPDase-1) in thromboregulation, cerebroprotection, and cardioprotection. 1585 26

Animal models of focal ischaemia induced by middle cerebral artery occlusion (MCAO) provide most evidence for cellular inflammatory responses in stroke. Permanent MCAO results in a modest neutrophil infiltration at 24 h after ischaemia, predominantly around arterial vessels at the margins of infarction, whereas MCAO with subsequent reperfusion is associated with substantial infiltration by neutrophils throughout the entire infarct. Several studies show that C-reactive protein (CRP), an inflammatory marker, is associated with stroke outcomes and future vascular events. Several drugs, especially hydroxymethylglutaryl coenzyme A reductase inhibitors (statins), have been demonstrated to reduce hsCRP levels independently of their effects on plasma cholesterol. Various cytokines were shown to be expressed in the injured brain. Recent investigations demonstrated that mRNAs of above cytokines were induced in the ischemic rat brain. TNF-alpha is a pleiotropic cytokine that mediates key roles in many physiological and pathological cellular processes including acute and chronic inflammation, programmed cell death or apoptosis, anti-tumor responses, and infection. Pharmaceutical industry to search a small molecule TNF inhibitor have taken multiple strategies. Significant protection after in vivo oral use of SB-239063 from brain injury and neurological deficits was observed in one study. In the same study significant protection from brain injury and neurological deficits was also demonstrated due to i.v post-stroke treatment with the same compound. Leukocyte-endothelial adhesion process consists of several steps, beginning with rolling of the leukocyte on the endothelial surface until it has slowed down to such a degree that it sticks to the endothelium. Treatment with a murine anti-ICAM-1 antibody (enlimomab) has been investigated in patients with acute ischemic stroke in the Enlimomab Acute Stroke Trial (EAST). Unfortunately, the case fatality rate in this trial was significantly higher in the enlimomab patient group than in the placebo group. Furthermore, experimental data have shown that focal cerebral ischemia induces a time-dependent activation of granulocytes, lymphocytes, and macrophages. Dissipation of ATP by CD39 reduced P2X7 receptor stimulation and thereby suppressed baseline leukocyte alphaMbeta2-integrin expression. As alphaMbeta2-integrin blockade reversed the postischemic, inflammatory phenotype of Cd39-/- mice, these data suggest that phosphohydrolytic activity on the leukocyte surface suppresses cell-cell interactions that would otherwise promote thrombosis or inflammation.
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PMID:Inflammation as a therapeutic target in acute ischemic stroke treatment. 1984 65

Extracellular nucleotides play a critical role in vascular thrombosis and inflammation. Alterations in purinergic extracellular nucleotide concentrations activate pathways that result in platelet degranulation and aggregation, and endothelial and leukocyte activation and recruitment. CD39, the dominant vascular nucleotidase, hydrolyzes ATP and ADP to provide the substrate for generation of the anti-inflammatory and antithrombotic mediator adenosine. The purinergic signaling system, with CD39 at its center, plays an important role in modulating vascular homeostasis and the response to vascular injury, as seen in clinically relevant diseases such as stroke, ischemia-reperfusion injury, and pulmonary hypertension. A growing body of knowledge of the purinergic signaling pathway implicates CD39 as a critical modulator of vascular thrombosis and inflammation. Therapeutic strategies targeting CD39 offer promising opportunities in the management of vascular thromboinflammatory diseases.
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PMID:CD39: Interface between vascular thrombosis and inflammation. 2483 75

This study aimed to examine whether the neuroprotective effects of Mdivi-1 are attributable to extracellular ATP and adenosine. Mdivi-1 was administered prior to or post middle cerebral artery occlusion (MCAO). The extracellular adenosine was measured by in vivo microdialysis and high-pressure liquid chromatography (HPLC) in MCAO mouse model. Western blot was done to determine the influence of Mdivi-1 on the expression of CD39 and CREB phosphorylation both in vivo and in the cultured astrocytes. Intracellular cAMP and protein kinase A (PKA) activity were detected in primary astrocytes. Results showed that Mdivi-1 significantly reduced infarct volume and neurological scores when administered either prior to or post MCAO. Interestingly, pretreatment with Mdivi-1 resulted in marked increase of extracellular adenosine and concomitant decrease in ATP. The expression of CD39, but not CD73, was upregulated by Mdivi-1, which was associated with the elevated phosphorylated cAMP response element-binding protein (CREB), a transcription factor potentially regulating CD39 expression. In primary astrocytes, Mdivi-1 treatment induced increases in intracellular cAMP, PKA activity and CREB phosphorylation, and PKA-specific inhibitor completely reversed Mdivi-1-induced CD39 expression. Our results demonstrate that Mdivi-1 protects against ischemic brain injury through increasing extracellular adenosine, a process involving elevated CD39 expression that is likely modulated by cAMP/PKA/CREB cascade. Figure Potential mechanisms by which Mdivi-1 mediates the neuroprotection on cerebral ischemic stroke. Results from the present study indicate that Mdivi-1 protects against ischemic brain injury through increasing extracellular adenosine, a process involving elevated CD39 expression that is likely modulated by the cAMP/PKA/CREB cascades.
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PMID:Mdivi-1 Protects Against Ischemic Brain Injury via Elevating Extracellular Adenosine in a cAMP/CREB-CD39-Dependent Manner. 2542 21


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