Protective Effect of High-Density Lipoprotein-Based Therapy in a Model of Embolic Stroke

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 assessed blindly 24 hours later by evaluating neurological deficit score and measuring the infarct volume and blood-brain barrier breakdown. Protease activities and neutrophil infiltration were also evaluated. Results-HDL injection immediately after stroke (10 mg/kg) reduced by 68% the mortality at 24 hours (Pϭ0.015). HDL administration immediately or at 3 or 5 hours after stroke also reduced cerebral infarct volume by 74%, 68%, and 70.7%, respectively (Pϭ0.0003, Pϭ0.011, and Pϭ0.019; nϭ17 per group). The neurological deficit at 24 hours in the HDL-treated group was decreased versus the saline-treated group (Pϭ0.015). Ischemia-induced blood-brain barrier breakdown was significantly reduced in HDL-treated rats versus controls (Pϭ0.0045). Neuroprotective effects of HDL were associated with decreased neutrophil recruitment in the infarct area (Pϭ0.0027) accompanied by reduced matrix metalloproteinase gelatinase activity. Immunostaining showed that HDL was associated with endothelial and glial cells, and also that intercellular adhesion molecule-1 expression was decreased in vessels within the infarct area. Conclusions-Administration of HDL is neuroprotective when performed up to 5 hours after experimental stroke.This effect may be attributed to the ability of HDL to protect the blood-brain barrier and limit neutrophil recruitment. (Stroke. 2010;41:1536-1542.)

Mild Hypercholesterolemia Blunts the Proinflammatory and Prothrombotic Effects of Hypertension on the Cerebral Microcirculation

“…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.…”

Alteplase Reduces Downstream Microvascular Thrombosis and Improves the Benefit of Large Artery Recanalization in Stroke

“…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.…”

“…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.…”

High-Density Lipoproteins in Stroke

“…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.…”

“…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).…”