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

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Conference Proceeding

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Diabetes mellitus leads to a higher risk of ischemic stroke and worse functional outcome compared to the general population. We investigate whether L-4F, an economical apolipoprotein A-I mimetic peptide, reduces neurovascular and white matter damage in a clinically relevant stroke model using type-2 diabetic (T2DM) db/db mice. Methods: Adult male db/db mice were subjected to 2h middle cerebral artery occlusion (MCAo) and were orally administered saline (n=52) or L-4F (16mg/kg, n=34) with treatment initiated 2h after stroke and continued daily until sacrifice 4 days after MCAo. Mouse-brain endothelial cells, primary arterial cells derived from the aorta of C57BL/6 mice 1 day after MCAo, and primary cortical neurons derived from E15 C57BL/6-embryos were employed. These cells were subjected to high glucose conditions to simulate diabetes. L-4F treatment of T2DM-stroke mice exhibited reduced hemorrhage/infarct volume and mortality rate, as well as improved neurological functional outcome 4 days after MCAo compared with vehicle control T2DM-stroke mice (p<0.05, n=11/group); L-4F treatment also decreased BBB leakage and white matter damage measured by Belshowsky silver stained axons, Luxol Fast Blue stained myelin, SMI31 immunostained phosphorylated neurofilament and platelet derived growth factor receptor α immunostained oligodendrocyte-progenitor cells, and increased arteriolar diameter and smooth muscle cell number in the ischemic brain (p<0.05, n=11/group). Moreover, the proinflammatory mediator high mobility group box 1 and advanced glycation end product receptor, and the cerebral hemorrhage factors plasminogen activator inhibitor-1 and Annexin II were decreased in the ischemic brain in L-4F treatment T2DM-stroke mice. In vitro, L-4F treatment did not increase capillary-like tube formation in the mouse-brain endothelial cells cultured with high glucose medium. However, L-4F treatment increased primary artery cell migration, and enhanced neurite outgrowth after 2h of oxygen-glucose deprivation and axonal outgrowth in high glucose condition. Conclusion: This study suggests that early use of L-4F may provide a potential strategy to reduce neuroinflammation and reduce vascular and white matter damage in T2DM stroke patients.




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