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

Ischemia and reperfusion in myocardial infarction and stroke are associated with upregulation of leukocyte adhesion molecules, which contributes to tissue injury by facilitating leukocyte adhesion and infiltration in the affected tissues. Surgical repair of the abdominal aortic aneurysm involves clamping and declamping of the aorta, which necessarily results in ischemia and reperfusion of the lower half of the body. Given the large volume of the affected tissues and unimpeded venous return during reperfusion, we hypothesized that the procedure may result in upregulation of leukocyte integrins in the systemic circulation. To test this hypothesis, we studied neutrophil and monocyte surface densities of CD11b and CD18 in patients undergoing elective infrarenal abdominal aortic aneurysm repair. Serial blood samples were collected from the radial artery and femoral vein during the operation and leukocyte CD11b and CD18 surface densities were quantified by flow cytometry. Following reperfusion, CD11b expression in neutrophils and monocytes increased significantly in femoral venous and arterial blood. The mean time to peak expression of CD11 b in neutrophils and monocytes during reperfusion was 34.4 and 31.4 minutes in venous and 38.5 and 36.4 minutes in arterial blood, respectively. Similar rises in CD18 expression on neutrophils and monocytes were observed in venous and arterial blood. The mean time to peak expression of CD18 in neutrophils and monocytes during reperfusion was 34.0 and 40.0 minutes in venous and 47.5 and 50.0 minutes in arterial blood, respectively.
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PMID:Systemic upregulation of leukocyte integrins in response to lower body ischemia-reperfusion during abdominal aortic aneurysm repair. 1571 80

The class B scavenger receptor CD36 is involved in the cytotoxicity associated with inflammation, but its role in the inflammatory reaction that accompanies cerebral ischemia has not been examined. In this study, we investigated whether CD36 contributes to the brain damage produced by cerebral ischemia. The middle cerebral artery was transiently occluded in wild-type mice and in mice deficient in CD36. In wild-type mice, CD36 protein expression was increased in the ischemic brain, such that it was located predominantly in cells expressing the microglia/macrophage marker CD11b. The infarct produced by middle cerebral artery occlusion was 49% smaller in CD36-null mice than in wild-type controls, an effect associated with improved neurological function. The attenuation in brain injury in CD36 nulls could not be attributed to differences in cerebral blood flow during ischemia-reperfusion. However, the increase in reactive oxygen species (ROS) produced by cerebral ischemia was markedly attenuated in CD36-null mice in the early stage after reperfusion. The data unveil a previously unrecognized role of CD36 in ischemia-induced ROS production and brain injury. Modulation of CD36 signaling may provide a new strategy for the treatment of ischemic stroke.
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PMID:The class B scavenger receptor CD36 mediates free radical production and tissue injury in cerebral ischemia. 1575 58

Ischemic stroke and reperfusion (ISR) is associated with an inflammatory response characterized, in part, by the formation of leukocyte-platelet aggregates (LPA). Aggregate formation may amplify the immunologic and hemostatic functions of both cell types and thus exacerbate reperfusion injury after ischemic stroke. LPA formation in peripheral blood may also serve as a biomarker of the severity of injury. However, it is not fully known whether ISR causes LPA formation that can be detected in the peripheral blood. Therefore, the purpose of this study was to measure LPA in the peripheral blood after ISR using a rat model. The filament method was used to perform ISR. Blood was collected from the jugular vein before ischemia, after 4 hours of ischemia, and after 1 hour of reperfusion. Flow cytometry was used to quantify LPA in peripheral blood. Separate ISR groups were treated with tirofiban, a platelet GPIIb/IIIa inhibitor, and fucoidan, a selectin adhesion molecule inhibitor, and analyzed for LPA. Leukocyte CD11b expression and reactive oxygen species production were also analyzed to note the role of polymorphonuclear neutrophilic (PMN) activation on LPA formation. After ISR, LPA levels in peripheral blood were twice as large as preischemic levels. Both GPIIb/IIIa and selectin adhesion molecule inhibition (p < .05) decreased LPA to preischemic values. PMN CD11b expression was increased above baseline but did not differ between groups. Reactive oxygen species production did not differ between groups during reperfusion. These data suggest that ischemic stroke and reperfusion results in an increase in LPA that can be consistently measured in peripheral blood. LPA formation may be a useful biomarker and potential therapeutic target after ischemic stroke and reperfusion.
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PMID:Leukocyte-platelet aggregates in rat peripheral blood after ischemic stroke and reperfusion. 1578 37

When human umbilical cord blood cells (HUCBCs) are administered intravenously after a middle cerebral artery occlusion, they reliably produce behavioral and anatomical recovery, and protect neural tissue from progressive change. However, our results indicate that the cells do not exert their effects by engraftment in the peri-infarct region, even though they migrate to the site of injury. The objective of the present study was to determine if the cells induce recovery by decreasing inflammation. We used a combination of in vivo and in vitro studies to show that HUCBCs decrease inflammation in the brain after stroke and thereby enhance neuroprotection. After stroke and transplantation, there was a decrease in CD45/CD11b- and CD45/B220-positive (+) cells. This decrease was accompanied by a decrease in mRNA and protein expression of pro-inflammatory cytokines and a decrease in nuclear factor kappaB (NF-kappaB) DNA binding activity in the brain of stroke animals treated with HUCBCs. In addition to modulating the inflammatory response, we demonstrate that the cord blood cells increase neuronal survival through non-immune mechanisms. Once thought of as "cell replacement therapy," we now propose that cord blood treatment in stroke reduces inflammation and provides neuroprotection. Both of these components are necessary for effective therapy.
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PMID:Anti-inflammatory effects of human cord blood cells in a rat model of stroke. 1630 44

Environmental enrichment (EE) alleviates sensorimotor deficits after brain infarcts but the cellular correlates are not well-known. This study aimed to test the effects of postischemic EE on neocortical cell genesis. A neocortical infarct was caused by distal ligation of the middle cerebral artery in adult spontaneously hypertensive rats, subsequently housed in standard environment or EE. Bromodeoxyuridine (BrdU) was administered during the first postischemic week to label proliferating cells and BrdU incorporation was quantified 4 weeks later in the periinfarct, ipsilateral medial and contralateral cortex. Immunohistochemistry and confocal microscopy were used to analyze co-localization of BrdU with neuronal (calbindin D28k, calretinin, parvalbumin, glutamic acid decarboxylase, tyrosine hydroxylase), astrocytic (glial fibrillary acidic protein, glutamine synthetase, vimentin, nestin), microglia/macrophage (CD11b/Ox-42, CD68/ED-1), oligodendrocyte progenitor/polydendrocyte (NG2, platelet-derived growth factor alpha receptor) or mature oligodendrocyte (myelin basic protein) markers. BrdU positive cells were increased in all analyzed cortical regions in stroke EE rats compared with stroke standard environment rats. Newly born cells in the periinfarct cortex were mostly reactive astroglia. Occasionally, BrdU positive cells in the periinfarct cortex that were negative for glial or microglia/macrophage markers co-expressed markers typical for interneurons but did not express appropriate functional markers. The majority of BrdU positive cells in intact cortical regions, ipsi- and contralaterally, were identified as NG2 positive polydendrocytes. Perineuronally situated newly born cells and polydendrocytes were found to be brain-derived neurotrophic factor immunoreactive. In conclusion, EE enhanced newborn glial scar astroglia and NG2+ polydendrocytes in the postischemic neocortex which might be beneficial for brain repair and poststroke plasticity.
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PMID:Enriched environment after focal cortical ischemia enhances the generation of astroglia and NG2 positive polydendrocytes in adult rat neocortex. 1642 25

Here we report in vivo evidence of a neuroprotective role of proliferating microglial cells in cerebral ischemia. Using transgenic mice expressing a mutant thymidine kinase form of herpes simplex virus driven by myeloid-specific CD11b promoter and ganciclovir treatment as a tool, we selectively ablated proliferating (Mac-2 positive) microglia after transient middle cerebral artery occlusion. The series of experiments using green fluorescent protein-chimeric mice demonstrated that within the first 72 h after ischemic injury, the Mac-2 marker [unlike Iba1 (ionized calcium-binding adapter molecule 1)] was preferentially expressed by the resident microglia. Selective ablation of proliferating resident microglia was associated with a marked alteration in the temporal dynamics of proinflammatory cytokine expression, a significant increase in the size of infarction associated with a 2.7-fold increase in the number of apoptotic cells, predominantly neurons, and a 1.8-fold decrease in the levels of IGF-1. A double-immunofluorescence analysis revealed a approximately 100% colocalization between IGF-1 positive cells and Mac-2, a marker of activated/proliferating resident microglia. Conversely, stimulation of microglial proliferation after cerebral ischemia by M-CSF (macrophage colony stimulating factor) resulted in a 1.9-fold increase in IGF-1 levels and a significant increase of Mac2+ cells. Our findings suggest that a postischemic proliferation of the resident microglial cells may serve as an important modulator of a brain inflammatory response. More importantly, our results revealed a marked neuroprotective potential of proliferating microglia serving as an endogenous pool of neurotrophic molecules such as IGF-1, which may open new therapeutic avenues in the treatment of stroke and other neurological disorders.
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PMID:Selective ablation of proliferating microglial cells exacerbates ischemic injury in the brain. 1734 97

We have previously shown that exogenous melatonin improves the preservation of the blood-brain barrier (BBB) and neurovascular unit following cerebral ischemia-reperfusion. Recent evidence indicates that postischemic microglial activation exaggerates the damage to the BBB. Herein, we explored whether melatonin mitigates the cellular inflammatory response after transient focal cerebral ischemia for 90 min in rats. Melatonin (5 mg/kg) or vehicle was given intravenously at reperfusion onset. Immunohistochemistry and flow cytometric analysis were used to evaluate the cellular inflammatory response at 48 hr after reperfusion. Relative to controls, melatonin-treated animals did not have significantly changed systemic cellular inflammatory responses in the bloodstream (P > 0.05). Melatonin, however, significantly decreased the cellular inflammatory response by 41% (P < 0.001) in the ischemic hemisphere. Specifically, melatonin effectively decreased the extent of neutrophil emigration (Ly6G-positive/CD45-positive) and macrophage/activated microglial infiltration (CD11b-positive/CD45-positive) by 51% (P < 0.01) and 66% (P < 0.01), respectively, but did not significantly alter the population composition of T lymphocyte (CD3-positive/CD45-positive; P > 0.05). This melatonin-mediated decrease in the cellular inflammatory response was accompanied by both reduced brain infarction and improved neurobehavioral outcome by 43% (P < 0.001) and 50% (P < 0.001), respectively. Thus, intravenous administration of melatonin upon reperfusion effectively decreased the emigration of circulatory neutrophils and macrophages/monocytes into the injured brain and inhibited focal microglial activation following cerebral ischemia-reperfusion. The finding demonstrates melatonin's inhibitory ability against the cellular inflammatory response after cerebral ischemia-reperfusion, and further supports its pleuripotent neuroprotective actions suited either as a monotherapy or an add-on to the thrombolytic therapy for ischemic stroke patients.
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PMID:Intravenous administration of melatonin reduces the intracerebral cellular inflammatory response following transient focal cerebral ischemia in rats. 1734 29

The administration of CD34-positive cells after stroke has been shown to have a beneficial effect on functional recovery by accelerating angiogenesis and neurogenesis in rodent models. Granulocyte colony-stimulating factor (G-CSF) is known to mobilize CD34-positive cells from bone marrow and has displayed neuroprotective properties after transient ischemic stress. This led us to investigate the effects of G-CSF administration after stroke in mouse. We utilized permanent ligation of the M1 distal portion of the left middle cerebral artery to develop a reproducible focal cerebral ischemia model in CB-17 mice. Animals treated with G-CSF displayed cortical atrophy and impaired behavioral function compared with controls. The negative effect of G-CSF on outcome was associated with G-CSF induction of an exaggerated inflammatory response, based on infiltration of the peri-infarction area with CD11b-positive and F4/80-positive cells. Although clinical trials with G-CSF have been started for the treatment of myocardial and limb ischemia, our results indicate that caution should be exercised in applying these results to cerebral ischemia.
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PMID:Granulocyte colony-stimulating factor has a negative effect on stroke outcome in a murine model. 1761 44

Ischemia-reperfusion injury is a common pathological occurrence causing tissue damage in heart attack and stroke. Entrapment of neutrophils in the vasculature during ischemic events has been implicated in this process. In this study, we examine the effects that lactacidosis and consequent reductions in intracellular pH (pH(i)) have on surface expression of adhesion molecules on neutrophils. When human neutrophils were exposed to pH 6 lactate, there was a marked decrease in surface L-selectin (CD62L) levels, and the decrease was significantly enhanced by inclusion of Na(+)/H(+) exchanger (NHE) inhibitor 5-(N,N-hexamethylene)amiloride (HMA). Similar effects were observed when pH(i) was reduced while maintaining normal extracellular pH, by using an NH(4)Cl prepulse followed by washes and incubation in pH 7.4 buffer containing NHE inhibitors [HMA, cariporide, or 5-(N,N-dimethyl)amiloride (DMA)]. The amount of L-selectin shedding induced by different concentrations of NH(4)Cl in the prepulse correlated with the level of intracellular acidification with an apparent pK of 6.3. In contrast, beta(2)-integrin (CD11b and CD18) was only slightly upregulated in the low-pH(i) condition and was enhanced by NHE inhibition to a much lesser extent. L-selectin shedding was prevented by treating human neutrophils with inhibitors of extracellular metalloproteases (RO-31-9790 and KD-IX-73-4) or with inhibitors of intracellular signaling via p38 MAP kinase (SB-203580 and SB-239063), implying a transmembrane effect of pH(i). Taken together, these data suggest that the ability of NHE inhibitors such as HMA to reduce ischemia-reperfusion injury may be related to the nearly complete removal of L-selectin from the neutrophil surface.
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PMID:Inhibition of Na+/H+ exchanger enhances low pH-induced L-selectin shedding and beta2-integrin surface expression in human neutrophils. 1882 97

Epidemiological and experimental studies have correlated hyperhomocysteinemia to a range of neurodegenerative conditions, including Alzheimer's disease, stroke, and Parkinson's disease. Although homocysteine-induced apoptosis in neurons has been extensively studied, little information is available regarding the effect of homocysteine on microglia. In this report, we demonstrated that homocysteine promoted proliferation and up-regulated the expression of CD11b (a marker of microglial activation). Consistent with our in vitro results, a significant increase in the number of CD11b-positive microglia was also observed in brain sections of mice with hyperhomocysteinemia. Homocysteine promoted the activity of NAD(P)H oxidases, resulting in the generation of reactive oxygen species. Up-regulation of NAD(P)H oxidase activity by homocysteine appears to be due to its ability to induce the phosphorylation of p47phox through the p38 MAPK pathway. Furthermore, inhibition of reactive oxygen species significantly blocked cellular proliferation and activation in microglia. Since microglial proliferation and activation play an important role in the development of several neurodegenerative disorders, our results reveal a novel role of homocysteine in the pathogenesis of neurodegenerative diseases.
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PMID:Homocysteine promotes proliferation and activation of microglia. 1913 Nov 43


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