Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acute ischaemic stroke is characterised by reductions in local cerebral blood flow (CBF) and activation of circulating platelets and leucocytes. Nitric oxide is a vasodilator and can inhibit these circulating cells. The aim of this study was to assess the effect of nitric oxide on platelet function and regional CBF in patients with acute ischaemic stroke. Sodium nitroprusside (SNP), a spontaneous nitric oxide donor, was administered at a dose which caused a 10 mm Hg fall in mean arterial blood pressure (MABP) in a pathophysiological study to 22 patients with acute ischaemic stroke and 12 matched control subjects. Platelet function (whole blood aggregation and flow cytometry) was assessed before and during SNP administration. Changes in regional CBF were measured using single photon emission computerised tomography (SPECT) scanning. SNP significantly reduced platelet aggregation in both the patient and control subject groups. Equally, the expression of platelet adhesion molecules P-selectin (CD62) and glycoprotein (GP) GP IIIa (CD61) were significantly reduced in both groups. GP Ia (CDw49b) expression was significantly attenuated in the patient but not in the control group. Four patients underwent SPECT scanning and improvements in local CBF corresponding to the penumbral area of the clinical stroke site were seen in 3 of these patients. A total of 24 regions of asymmetrical perfusion were examined, pre-SNP (median (SQR)), 0.68 (0.14) vs. peri-SNP 0.78 (0.17), 2p = 0.065. SNP, given at a dose which reduced MABP by 10 mm Hg, significantly inhibited platelet aggregation and adhesion molecule expression. Improved regional CBF was seen in some patients. SNP is a candidate therapeutic agent for patients with acute ischaemic stroke and warrants further study.
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PMID:Pathophysiological assessment of nitric oxide (given as sodium nitroprusside) in acute ischaemic stroke. 961 99

Although the role of an adhesion molecule such as P-selectin may be important in the pathogenesis of stroke, temporal, spatial, and cellular profiles of the expression of such a protein has not been fully studied in the case of the middle cerebral artery (MCA) occlusion and reperfusion in rat brain. Change in expression of immunoreactive P-selectin was examined in rat brain after transient MCA occlusion (MCAO) in comparison to that of permanent occlusion with an anti-P-selectin monoclonal antibody. Western blot analyses were performed to ensure the selective detection of immunoreactive P-selectin protein with the monoclonal antibody using brain homogenates before and after MCAO. Temporal, spacial, and cellular changes of P-selectin expressions were evaluated with rat brain sections at 2, 8h, 1 and 3 days of permanent MCAO, and at 2, 8h, 1, 3 and 7 days of reperfusion after 1 h of transient MCAO. Western blot showed a single band with a molecular weight of 140 kDa for both cases with permanent occlusion and reperfusion. P-selectin immunoreactivity was not normally present in rat brain sections. However, it was expressed mainly in the post-capillary venules of the cerebral cortex and caudate in the MCA territory with a peak at 2-8h after permanent occlusion and at 8h to 1 day after the reperfusion. The expression was diminished by 1 day of permanent occlusion and 3 days of reperfusion. The maximum staining in the case of permanent MCAO was stronger than the case with reperfusion. However, spacial distribution of the staining was similar in the cerebral cortex and caudate between the cases with permanent of transient MCAO. These results suggest a different temporal but similar spacial and cellular expression of P-selection immunoreactivity between permanent occlusion and reperfusion of MCA in rat brain.
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PMID:A change of P-selectin immunoreactivity in rat brain after transient and permanent middle cerebral artery occlusion. 966 96

Focal cerebral ischemia elicits a strong inflammatory response involving early recruitment of granulocytes and delayed infiltration of ischemic areas and the boundary zones by T cells and macrophages. Infiltration of hematogenous leukocytes is facilitated by an upregulation of the cellular adhesion molecules P-selectin, intercellular adhesion molecule-1 and vascular adhesion molecule-1 on endothelial cells. Blocking of the leukocyte/endothelial cell adhesion process significantly reduces stroke volume after transient, but not permanent middle cerebral artery occlusion. In the infarct region microglia are activated within hours and within days transform into phagocytes. Astrocytes upregulate intermediate filaments, synthesize neurotrophins and form glial scars. Local microglia and infiltrating macrophages demarcate infarcts and rapidly remove debris. Remote from the lesion no cellular infiltration occurs, but astroglia and microglia are transiently activated. Astrocytic activation is induced by spreading depression. In focal ischemia neurons die acutely by necrosis and in a delayed fashion by programmed cell death, apoptosis. Proinflammatory cytokines such as tumor necrosis factor-alpha and interleukin-1 beta are upregulated within hours in ischemic brain lesions. Either directly or via induction of neurotoxic mediators such as nitric oxide, cytokines may contribute to infarct progression in the post-ischemic period. On the other hand, inflammation is tightly linked with rapid removal of debris and repair processes. At present it is unclear whether detrimental effects of inflammation outweigh neuroprotective mechanisms or vice versa. In global ischemia inflammatory responses are limited, but micro- and astroglia are also strongly activated. Glial responses significantly differ between brain regions with selective neuronal death and neighbouring areas that are more resistent to ischemic damage.
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PMID:Inflammation and glial responses in ischemic brain lesions. 976 Jun 99

The anti-inflammatory role of nitric oxide (NO) was studied in a model of hepatic ischemia-reperfusion (I/R) in rats. Male Fischer rats were subjected to 30 min of no-flow ischemia of the left and median lobes of the liver, and animals were examined for a 4-h period of reperfusion. The animals were divided into the following groups: control-vehicle; I/R-vehicle; I/R-Nomega-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg iv, 10 min before reperfusion); sham control-L-NAME, and I/R-S-nitroso-N-acetyl-penicillamine (SNAP, 25 micromol/kg iv, 10 min before reperfusion, followed by 20 micromol. kg-1. h-1 in 1.0 ml saline infused for 4 h). Results showed that mean arterial blood pressure was significantly increased in the sham control-L-NAME or I/R-L-NAME groups compared with either the I/R-vehicle or I/R-SNAP groups. However, cardiac index (CI) and stroke volume index (SVI) were markedly decreased, and systemic vascular resistance index (SVRI) was dramatically increased. Interestingly, the CI and SVI in rats treated with SNAP were markedly improved over that of the I/R group. Plasma nitrate and nitrite levels were significantly decreased in the I/R-L-NAME group; however, superoxide generation in the ischemic lobes and plasma alanine aminotransferase activity were higher compared with I/R-SNAP rats. The L-NAME-induced enhancement of hepatic injury in rats with I/R may be due in part to neutrophil infiltration, which was significantly increased compared with animals subjected to I/R or I/R-SNAP. The mechanism of L-NAME-enhanced neutrophil infiltration may be due to the fact that the ratios of P-selectin and intercellular adhesion molecule 1 (ICAM-1) mRNA to glyceraldehyde-3-phosphate dehydrogenase mRNA extracted from the ischemic lobes of I/R-L-NAME rats were significantly increased when compared with the I/R-SNAP group. These results suggest that 1) endogenous NO reduces the SVRI and permits an increased CI and SVI; 2) exogenous NO further improves CI and SVI; and 3) endogenous, but not exogenous, NO decreases P-selectin and ICAM-1 mRNA expression, thereby reducing polymorphonuclear neutrophil-dependent reperfusion tissue injury.
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PMID:NO modulates P-selectin and ICAM-1 mRNA expression and hemodynamic alterations in hepatic I/R. 984 19

Platelet activation is observed in patients with atrial fibrillation (AF). P-selectin, which is expressed on platelet activation, plays an important role in the formation of thromboemobli. Because adenosine is known to attenuate platelet activation, we evaluated adenosine levels and 2 indicators of platelet activation, i.e., expression of P-selectin on platelets and plasma levels of beta-thromboglobulin, in 28 patients with AF (20 men and 8 women, age range 64+/-2 years) with sex- and age-matched (+/-2 years) subjects with sinus rhythm. The incidence of risk factors for stroke except for coronary heart disease and in echocardiographic parameters did not differ between the 2 groups. Plasma adenosine levels were lower (p <0.05) in patients with AF than in controls (mean [interquartile range] 13.4 [19.3-9.3] vs 19.1 [30.8-11.9] nmol/L). The expression of P-selectin on platelets (6.8% [13.6-3.4] vs 4.0% [8.8-1.8]) and plasma levels of beta-thromboglobulin were higher (p <0.05) in patients with AF. Flow cytometric analysis revealed that an antagonist of adenosine receptors, 8-sulfophenyltheophylline, increased the expression of P-selectin on platelets in a dose-dependent manner in the in vitro study. These results suggest that decreased plasma levels of adenosine were associated with platelet activation in patients with AF. Substitution of adenosine may provide a strategy for preventing platelet activation in these patients.
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PMID:Plasma adenosine levels and platelet activation in patients with atrial fibrillation. 1007 20

The selectin family of adhesion molecules is involved in adhesion of leukocyte to microcirculatory system and the transmigration into brain parenchyma. Although the role of P-selectin may be important in the pathogenesis of brain ischemia, a possible protective effect on ischemic brain injury by blocking P-selectin has not been reported. We have examined the effects of a novel anti-P-selectin antibody on ischemic brain injury after 24 h of permanent middle cerebral artery occlusion (MCAO) in rat. Male Wistar rats were subjected to MCAO by an insertion of a silicone rubber cylinder for 24 h. Anti-rat P-selectin monoclonal antibody, ARP 2-4, was injected intravenously at a dose of 1 mg kg-1 at 5 min before the induction of MCAO. Control animals received the same volume of vehicle solution. Regional cerebral blood flow (rCBF) was measured immediately after and at 8 h of MCAO. At decapitation of rats at 24 h of permanent MCAO, infarct size was compared between the antibody and vehicle treated group. In addition, immunohistochemistry for leukocyte infiltration and HSP72, and histochemistry for TUNEL were also, compared. Pretreatment with ARP 2-4 improved rCBF at 8 h of MCAO (55.4% +/- 11.7% of control, n = 5) as compared to vehicle group (24.2% +/- 11.8%, n = 5, p < 0.02). Although leukocyte infiltration was not normally detected by monoclonal antibodies for CD11a and CD18, it became remarkably evident at 1 day of MCAO. Although HSP72 and TUNEL were not also detected in sham control brains, they were induced in neurons of the MCA area at 1 day of MCAO. Treatment with ARP 2-4 significantly reduced the numbers of leukocyte and neurons with positive HSP72 and TUNEL stainings. These results demonstrated that an administration of a monoclonal antibody against P-selectin improved rCBF, and attenuated infarct size that was associated with reduction of leukocyte infiltration. Furthermore, treatment with the antibody reduced both HSP72 and TUNEL stainings. These data suggest an important role of P-selectin in ischemic brain damage, and a future therapeutic potential to human stroke patients.
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PMID:Reduction of ischemic brain injury by anti-P-selectin monoclonal antibody after permanent middle cerebral artery occlusion in rat. 1031 35

In a previous report by Freedman et al (J Clin Invest. 1996;97:979-987), plasma from 2 brothers with stroke or transient ischemic attack inactivated the antiplatelet effects of nitric oxide (NO), and this effect was found to be a consequence of a deficiency of plasma glutathione peroxidase (GSH-Px). In this study, we attempted to define the generalizability of this deficiency by studying NO-mediated antiplatelet effects in 7 families with familial childhood stroke. Seven families with familial childhood stroke that consecutively presented to a large referral center were included in the study. We monitored ADP-induced aggregation of normal gel-filtered platelets (GFP) in platelet-poor plasma (PPP) from normal individuals and from patients in the presence or absence of an NO donor (S-nitroso-glutathione). Surface P-selectin expression of normal GFP in patients' PPP was analyzed by flow cytometry after incubation with a P-selectin-specific monoclonal antibody in the presence or absence of the NO donor. We also measured GSH-Px activity in plasmas from family members and normal controls using standard methods. In 6 of 7 families, NO failed to inhibit platelet P-selectin expression and platelet aggregation in PPP from the affected family members and some of their relatives. Of 4 families studied, 3 probands and their corresponding affected parent had 50% decrease in plasma GSH-Px activity. In some patients with childhood stroke, impaired metabolism of reactive oxygen species as a result of reduced GSH-Px activity results in NO insufficiency that affects normal platelet inhibitory mechanisms and predisposes to arterial thrombosis.
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PMID:Plasma glutathione peroxidase deficiency and platelet insensitivity to nitric oxide in children with familial stroke. 1044 87

Fabry disease is an X-linked recessive disorder resulting in the deposition of globotriaosylceramide in numerous cell types including vascular endothelial cells. Because this disease is associated with vascular injury and a high recurrence rate of thrombotic events, measurements of factors regulating endothelium and leukocyte interaction may provide insight into the mechanisms leading to a prothrombotic state. Twenty-five patients with Fabry disease and 25 control subjects participated in the study. Plasma from all 25 Fabry patients and 15 of the 25 controls were studied for multiple endothelial factors. Leukocyte integrins were measured by flow cytometry in 21 Fabry patients and 10 controls. The concentrations of soluble intercellular adhesion molecule-1, vascular cell adhesion molecule-1, P-selectin, and plasminogen activator inhibitor were significantly higher and thrombomodulin was significantly lower in Fabry patients. Expression of the integrin CD11b on monocytes was also significantly higher in the Fabry patients. This study reveals measurable evidence for endothelium and leukocyte activation that is consistent with a prothrombotic state in Fabry patients compared with controls. Further investigations of these findings may help to understand the mechanism of stroke in Fabry disease and provide indicators (or markers) of efficacy of future therapeutic intervention.
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PMID:Profile of endothelial and leukocyte activation in Fabry patients. 1066 94

Platelet function in whole blood can be comprehensively evaluated by flow cytometry. Flow cytometry can be used to measure platelet reactivity, circulating activated platelets, platelet-platelet aggregates, leukocyte-platelet aggregates, procoagulant platelet-derived microparticles, and calcium flux. Clinical applications of whole blood flow cytometric assays of platelet function in disease states (e.g., acute coronary syndromes, angioplasty, and stroke) may include identification of patients who would benefit from additional antiplatelet therapy and prediction of ischemic events. Circulating monocyte-platelet aggregates appear to be a more sensitive marker of in vivo platelet activation than circulating P-selectin-positive platelets. Flow cytometry can also be used in the following clinical settings: monitoring of GPIIb-IIIa antagonist therapy, diagnosis of inherited deficiencies of platelet surface glycoproteins, diagnosis of storage pool disease, diagnosis of heparin-induced thrombocytopenia, and measurement of the rate of thrombopoiesis.
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PMID:Evaluation of platelet function by flow cytometry. 1087 80

In the present study, we examined the effects of peroxynitrite on reperfusion injury using a rat model of hepatic ischemia-reperfusion (HI/R). The left and median lobes of the liver were subjected to 30 min of ischemia, followed by 4 h of reperfusion. Groups A and B rats were sham-operated controls that received vehicle or peroxynitrite; groups C and D rats were subjected to HI/R and received peroxynitrite or vehicle, respectively. A dose of 2 micromol/kg body wt of peroxynitrite, diluted in saline (pH 9.0, 4 degrees C), was administered as a bolus through a portal vein catheter at 0, 60, and 120 min after reperfusion. Results showed that superoxide generation in the ischemic lobes of the liver and plasma alanine aminotransferase (ALT) activity of group C were decreased by 43% and 45%, respectively, compared with group D. Leukocyte accumulations in the ischemic lobes of liver and circulating leukocytes were decreased by 40% and 27%, respectively, in group C vs. D. The ratios of mRNA of P-selectin and intercellular adhesion molecule-1 (ICAM-1) to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA extracted from the ischemic lobes of the liver of group C were decreased compared with group D. There were no differences between the groups A and B in terms of plasma ALT activity, circulating leukocytes, superoxide generation, and leukocyte infiltration in the ischemic lobes of the liver. Moreover, hemodynamic parameters (i.e., mean arterial blood pressure, cardiac index, stroke index, and systemic vascular resistance) were not significantly different among groups B, C, and D. These results suggest that administration of peroxynitrite via the portal vein only has a local effect. Exogenous peroxynitrite at physiological concentrations attenuates leukocyte-endothelial interaction and reduces leukocyte infiltration. The mechanism of the reduction of leukocyte infiltration into ischemic lobes of the liver appears because of decreased expression of mRNA of P-selectin and ICAM-1. The net effect of administration of peroxynitrite may be to reduce adhesion molecule-mediated, leukocyte-dependent reperfusion injury.
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PMID:Peroxynitrite attenuates hepatic ischemia-reperfusion injury. 1107 13


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