From the Department of neurology and stroke center, Bichat hospital, Paris, France (C.D., P.A.).
Laboratory of Vascular Translational Science, U1148 Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Paris, Paris, France (C.D., J.-P.D., M.-A.M., S.D., B.H.-T.-N., V.O., L.D.M., B.L., J.-B.M., P.A.).
Stroke. 2020 Jun;51(6):1886-1890. doi: 10.1161/STROKEAHA.119.027898. Epub 2020 May 14.
Background and Purpose- Previous experimental studies found that the infusion of human purified nascent HDL (high-density lipoprotein) significantly reduced infarct volume and hemorrhagic transformation rate by decreasing neutrophil recruitment. ApoA1-M (apolipoprotein A1-Milano) is a natural variant of human ApoA1 that confers protection against atherosclerosis. Recombinant ApoA1-M has been formulated as a complex with phospholipids to mimic the properties of nascent HDL. The aim of this study was to assess the impact of intravenous ApoA1-M in a transient middle cerebral artery occlusion stroke model in rats. Methods- In a first experiment, rats were subjected to 120-minute transient middle cerebral artery occlusion and intravenous ApoA1-M was infused immediately or 4 hours after occlusion. In a second experiment, rats were subjected to 240-minute transient middle cerebral artery occlusion and intravenous ApoA1-M was infused with or without recombinant tPA (tissue-type plasminogen activator) immediately after recanalization. Primary outcome criteria were the infarct volume and hemorrhagic transformation rate measured at 24 hours. Platelets, coagulation, and neutrophil activation biomarkers were measured in brain homogenates and plasma. Additional in vitro experiments studied the effects of ApoA1-M on platelet aggregation and platelet-neutrophil interactions. Results- The infusion of ApoA1-M immediately or 4 hours after 120-minute transient middle cerebral artery occlusion significantly reduced the infarct volume compared with saline (=0.034 and =0.036, respectively). Compared with tPA alone, co-administration of ApoA1-M and tPA showed similar rates of hemorrhagic transformation. ApoA1-M had no significant inhibition effect on neutrophil activation biomarkers. Platelet activation was slightly decreased in rats treated with ApoA1-M compared with saline. In vitro, the incubation of human and rat platelet-rich plasma with ApoA1-M significantly reduced ADP-induced platelet aggregation (=0.001 and =0.02, respectively). Conclusions- ApoA1-Milano significantly decreased the infarct volume through an inhibition of platelet aggregation but did not reduce hemorrhagic transformation and neutrophils activation as expected after previous experimental studies with nascent HDL. Visual Overview- An online visual overview is available for this article.
背景与目的- 先前的实验研究发现，输注人源新生高密度脂蛋白（HDL）可通过减少中性粒细胞募集来显著降低梗死体积和出血转化率。载脂蛋白 A1-M（载脂蛋白 A1-Milano）是人类载脂蛋白 A1 的一种天然变体，可预防动脉粥样硬化。重组载脂蛋白 A1-M 已与磷脂制成复合物，以模拟新生 HDL 的特性。本研究旨在评估静脉内给予载脂蛋白 A1-M 对大鼠短暂性大脑中动脉闭塞性中风模型的影响。方法- 在第一项实验中，大鼠接受 120 分钟短暂性大脑中动脉闭塞，在闭塞后立即或 4 小时给予静脉内载脂蛋白 A1-M。在第二项实验中，大鼠接受 240 分钟短暂性大脑中动脉闭塞，在再通后立即给予或不给予重组组织型纤溶酶原激活剂（tPA）的情况下给予静脉内载脂蛋白 A1-M。主要终点标准为 24 小时时测量的梗死体积和出血转化率。脑匀浆和血浆中测定血小板、凝血和中性粒细胞激活生物标志物。另外的体外实验研究了载脂蛋白 A1-M 对血小板聚集和血小板-中性粒细胞相互作用的影响。结果- 在 120 分钟短暂性大脑中动脉闭塞后立即或 4 小时给予载脂蛋白 A1-M 输注，与盐水相比，梗死体积明显减小（分别为=0.034 和=0.036）。与 tPA 单独使用相比，载脂蛋白 A1-M 与 tPA 联合使用时出血转化率相似。载脂蛋白 A1-M 对中性粒细胞激活生物标志物没有明显的抑制作用。与盐水相比，用载脂蛋白 A1-M 处理的大鼠血小板活化略有降低。体外，用人和大鼠富含血小板的血浆孵育载脂蛋白 A1-M 可显著降低 ADP 诱导的血小板聚集（分别为=0.001 和=0.02）。结论- 载脂蛋白 A1-Milano 通过抑制血小板聚集显著降低梗死体积，但与先前用新生 HDL 进行的实验研究预期的结果不同，它并未降低出血转化率和中性粒细胞活化。可视化概述- 本文提供了一个在线可视化概述。
