Abstract W P110: ABCA1 Partially Mediates D-4F Protection of White Matter After Stroke

Abstract

Introduction: White matter (WM) damage is associated with neurological deficits after stroke. Neuroinflammation increases WM damage. The ATP-binding cassette transporter A 1 (ABCA1) mediates the efflux of cholesterol to ApoA-1 and ApoE and is antiinflammatory and promotes axonal remodeling. D-4F is an ApoA-I mimetic peptide. We tested the hypothesis that D-4F treatment of stroke regulates WM damage and improves neurological functional outcome. Methods: C57BL/6 white type mice were subjected to permanent middle cerebral artery occlusion (MCAo) and were orally administered different doses of D-4F (2, 4, 8, 16 or 32mg/kg) starting at 2h after MCAo and daily for 7 days. Functional outcomes, blood biochemistry, BBB leakage, infarct volume, and WM and axonal changes were evaluated. Results: D-4F treatment did not alter the blood levels of HDL and total cholesterol, infarction volume and BBB leakage compared to control group. Treatment of stroke with D-4F 16mg/kg 1) significant improved neurological functional outcome (mNSS: 5.2±0.9 vs control 3.9±0.6; Left-foot-fault: 26.7±2.5 vs control 21.4±1.6); 2) did not change the number of oligodendrocyte progenitor cells (OPCs) and oligodendrocytes in the ischemic boundary zone (IBZ) of the striatum; 3) significant increased the density of axons (30.1±1.8% vs control: 19.9±1.7%), phosphorelated neurofilament (39.4±3.5 vs control: 25.3±2.7) and myelin (40.4±2.4 vs control: 25.2±3.6) in the WM bundles in the IBZ of the striatum; 4) increased ABCA1 and decreased TNFα expression in the ischemic brain (n=11/group). In vitro, neurite outgrowth in primary cultured neurons (PCNs) derived from brain specific ABCA1 deficient (ABCA1-B/-B) mice were significantly decreased after hypoxic ischemia compared with PCNs derived from floxed-control (ABCA1fl/fl) mice; D-4F (200ng/ml) treatment significantly increased neurite outgrowth in the ABCA1fl/fl-PCNs, but failed in ABCA1-B/-B-PCNs; D-4F treatment did not increase OPC proliferation, but decreased OPC death of cultured OPCs. Conclusions: D-4F treatment initiated 2h after MCAo decreases WM damage and improves functional outcome after stroke. Increasing ABCA1 expression in the ischemic brain may contribute to D-4F induced WM and axonal protection after stroke.