Abstract:Background and Purpose-High-density lipoprotein (HDL) levels are inversely associated with stroke incidence, suggesting a protective effect. Using a rat model, we tested the hypothesis that HDL exerts direct vasculo-/ neuroprotective effects when administered during the acute phase of embolic stroke. Methods-After embolic occlusion, Sprague-Dawley rats were randomly treated intravenously with purified HDL versus saline immediately (2, 10 mg/kg) or 3 or 5 hours (10 mg/kg) after stroke. The effects of HDL were a… Show more
“…Second, we observed that treatment of DOCA-salt or Ang II hypertensive mice with the ApoA1 mimetic peptide 4F largely prevents the blood cell recruitment responses normally elicited in untreated WT mice. These findings are consistent with reports describing an antiinflammatory action of HDL cholesterol, [31][32][33] genetic overexpression of ApoA1 34,35 as well as 4F treatment. 36,37 The antiinflammatory effects of HDL and ApoA1 have been attributed to an attenuation of leukocyte activation 38 and endothelial cell adhesion molecule expression, 39 possibly resulting from enhanced nitric oxide production.…”
Although an increased leukocyte and platelet adhesion is observed in cerebral venules of mice with either hypertension (HTN) or hypercholesterolemia (HCh), it remains unclear whether the combination of HTN and HCh exerts a comparable effect on leukocyte and platelet recruitment in the cerebral microvasculature. Thus, we examined whether HCh alters platelet and leukocyte adhesion, and blood-brain barrier (BBB) permeability, in cerebral venules in two models of murine HTN: DOCA salt-induced and angiotensin II (Ang II) induced. In both models, the mice were placed on either a normal or cholesterol-enriched diet. An enhanced recruitment of adherent leukocytes and platelets in cerebral venules was noted in both HTN models in the absence of HCh, but not in its presence. The Ang II-induced increase in BBB permeability was attenuated by HCh as well. Both total and high-density lipoprotein (HDL) cholesterol levels were elevated in the HCh mice. The HTN-induced increase in leukocyte and platelet adhesion was attenuated in apolipoprotein A-I transgenic mice (ApoA1-Tg) and blunted in wild-type mice treated with the ApoA1 mimetic peptide, 4F. Our findings indicate that mild HCh significantly blunts the cerebral microvascular responses to HTN and that HDL may have a role in mediating this beneficial effect of HCh.
“…Second, we observed that treatment of DOCA-salt or Ang II hypertensive mice with the ApoA1 mimetic peptide 4F largely prevents the blood cell recruitment responses normally elicited in untreated WT mice. These findings are consistent with reports describing an antiinflammatory action of HDL cholesterol, [31][32][33] genetic overexpression of ApoA1 34,35 as well as 4F treatment. 36,37 The antiinflammatory effects of HDL and ApoA1 have been attributed to an attenuation of leukocyte activation 38 and endothelial cell adhesion molecule expression, 39 possibly resulting from enhanced nitric oxide production.…”
Although an increased leukocyte and platelet adhesion is observed in cerebral venules of mice with either hypertension (HTN) or hypercholesterolemia (HCh), it remains unclear whether the combination of HTN and HCh exerts a comparable effect on leukocyte and platelet recruitment in the cerebral microvasculature. Thus, we examined whether HCh alters platelet and leukocyte adhesion, and blood-brain barrier (BBB) permeability, in cerebral venules in two models of murine HTN: DOCA salt-induced and angiotensin II (Ang II) induced. In both models, the mice were placed on either a normal or cholesterol-enriched diet. An enhanced recruitment of adherent leukocytes and platelets in cerebral venules was noted in both HTN models in the absence of HCh, but not in its presence. The Ang II-induced increase in BBB permeability was attenuated by HCh as well. Both total and high-density lipoprotein (HDL) cholesterol levels were elevated in the HCh mice. The HTN-induced increase in leukocyte and platelet adhesion was attenuated in apolipoprotein A-I transgenic mice (ApoA1-Tg) and blunted in wild-type mice treated with the ApoA1 mimetic peptide, 4F. Our findings indicate that mild HCh significantly blunts the cerebral microvascular responses to HTN and that HDL may have a role in mediating this beneficial effect of HCh.
“…Planimetric measurements (Image J software, National Institutes of Health, Bethesda, MD) were performed blinded to the treatment group and were used to calculate infarct volumes and brain edema. 26 The occurrence of hemorrhagic transformation (HT) was macroscopically assessed on whole brains and again after the 2-mm thick coronal brain slices were cut before 2,3,5-triphenyltetrazolium chloride staining.…”
Section: Determination Of Infarct Size Brain Edema and Hemorrhagic mentioning
confidence: 99%
“…26 Neurological function was graded on a scale of 0 to 10 ( Figure II in the online-only Data Supplement). Neurological Severity Score was assessed immediately before euthanization at 24 hours after stroke onset.…”
Background and Purpose-Downstream microvascular thrombosis (DMT) is known to be a contributing factor to incomplete reperfusion in acute ischemic stroke. The aim of this study was to determine the timing of DMT with intravital imaging and to test the hypothesis that intravenous alteplase infusion could reduce DMT in a transient middle cerebral artery occlusion (MCAO) rat stroke model. Methods-Rats were subjected to 60-minute transient MCAO. Alteplase (10 mg/kg) was administered 30 minutes after the beginning of MCAO. Real-time intravital fluorescence microscopy through a dura-sparing craniotomy was used to visualize circulating blood cells and fibrinogen. Cerebral microvessel patency was quantitatively evaluated by fluorescein isothiocyanate-dextran perfusion. Results-Immediately after MCAO, platelet and leukocyte accumulation were observed mostly in the venous compartment.Within 30 minutes after MCAO, microthrombi and parietal fibrin deposits were detected in postcapillary microvessels. Alteplase treatment significantly (P=0.006) reduced infarct volume and increased the percentage of perfused vessels during MCAO (P=0.02) compared with saline. Plasma levels of fibrinogen from alteplase-treated rats showed a rapid and profound hypofibrinogenemia. In vitro platelet aggregation demonstrated that alteplase reduced platelet aggregation (P=0.0001) and facilitated platelet disaggregation (P=0.001). These effects were reversible in the presence of exogenous fibrinogen. Conclusions-Our data demonstrate that DMT is an early phenomenon initiated before recanalization. We further show that alteplase-dependent maintenance of downstream perfusion during MCAO improves acute ischemic stroke outcome through a fibrinogen-dependent platelet aggregation reduction. Our results indicate that early targeting of DMT represents a therapeutic strategy to improve the benefit of large artery recanalization in acute ischemic stroke. (Stroke. 2015;46:3241-3248.
“…They showed that high doses of rHDLs (120 mg/kg) infused 2 h before the onset of stroke reduced the brain necrotic area by 61 and 76 %, respectively, in an excitotoxic (NMDA) and a transient MCAO model of stroke in rats. More recently, we have shown that plasma HDLs (10 mg/kg), injected immediately or at 3 or 5 h after stroke, also reduced cerebral infarct volume by 74, 68 and 70 %, respectively, in a rat model of thromboembolic stroke (Lapergue et al 2010). This was associated with a reduced BBB breakdown and decreased neutrophil recruitment in the infarct area.…”
Section: Hdls and Acute Stroke: Experimental Modelsmentioning
confidence: 82%
“…In rat type I astrocytes and glioma cells, HDLs stimulated DNA synthesis and expression of fibroblast growth factor-2, a potent neurotrophic factor, which was associated with the activation of proliferative intracellular signalling (Malchinkhuu et al 2003). It is likely that in pathological conditions (haemorrhage or transient increase of BBB permeability), HDLs have an improved access to the cerebral parenchymal compartment and then act on both neurons and astrocytes (Lapergue et al 2010 Under acute stroke conditions, the lipid profile has been reported to be modified (Santos-Silva et al 2002). These authors have shown that patients with diagnosed ischaemic stroke (CT imaging, n ¼ 21) had lower plasma concentrations of both HDL and apo A-I than healthy subjects with no history of cardiovascular events and normal haematologic values (n ¼ 29).…”
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