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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Neurosci. | doi: 10.3389/fnins.2019.01127

ApoA-I mimetic peptide reduces vascular and white matter damage after stroke in type-2 diabetic mice

 Xiaohui Wang1, Rongwen Li2, Alex Zacharek2, Julie Landschoot-Ward2,  Michael Chopp2, Jieli Chen2 and  Xu Cui2, 3*
  • 1Department of Pathology, School of Basic Medical Sciences, Shanxi Medical University, Department of Microbiology and Immunology, School of Basic Medical Sciences, Shanxi Medical University, China
  • 2Department of Neurology, Henry Ford Hospital, United States
  • 3Henry Ford Health System, United States

Diabetes leads to an elevated risk of stroke and worse functional outcome compared to the general population. We investigate whether L-4F, an economical ApoA-I mimetic peptide, reduces neurovascular and white-matter damage in db/db type-2 diabetic (T2DM) stroke mice. L-4F (16mg/kg, subcutaneously administered initially 2h after stroke and subsequently daily for 4 days) reduced hemorrhagic transformation, decreased infarct-volume and mortality, and treated mice exhibited increased cerebral arteriole diameter and smooth muscle cell number, decreased blood-brain barrier leakage and white-matter damage in the ischemic brain as well as improved neurological functional outcome after stroke compared with vehicle-control T2DM mice (p<0.05, n=11/group). Moreover, administration of L-4F mitigated macrophage infiltration, and reduced the level of proinflammatory mediators tumor necrosis factor alpha (TNFα), high-mobility group box-1 (HMGB-1)/ advanced glycation end-product receptor (RAGE) and plasminogen activator inhibitor-1 (PAI-1) in the ischemic brain in T2DM mice (p<0.05, n=6/group). In vitro, L-4F treatment did not increase capillary-like tube formation in mouse-brain endothelial cells, but increased primary artery explant cell migration derived from C57BL/6-aorta 1 day after middle cerebral artery occlusion (MCAo), and enhanced neurite-outgrowth after 2h of oxygen-glucose deprivation and axonal-outgrowth in primary cortical neurons derived from the C57BL/6-embryos subjected to high-glucose condition. This study suggests that early treatment with L-4F provides a potential strategy to reduce neuroinflammation and vascular and white-matter damage in the T2DM stroke population.

Keywords: diabetes, Stroke, Blood-brain barrier (BBB), White matter (WM), Inflammation

Received: 01 May 2019; Accepted: 04 Oct 2019.

Copyright: © 2019 Wang, Li, Zacharek, Landschoot-Ward, Chopp, Chen and Cui. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Xu Cui, Henry Ford Hospital, Department of Neurology, Detroit, United States, xcui1@hfhs.org