FTY720 通过减少血栓炎症而不是直接神经保护来改善小鼠的急性缺血性中风。
FTY720 ameliorates acute ischemic stroke in mice by reducing thrombo-inflammation but not by direct neuroprotection.
机构信息
From the University Clinic Würzburg, Departments of Neurology (P.K., E.G., M.K.S., G.S., C.K.) and Anesthesiology and Critical Care (M.B.), Rudolf Virchow Center, the Deutsche Forschungsgemeinschaft Research Center for Experimental Biomedicine (C.D., I.T., B.N.), Institute of Pharmacology and Toxicology, University of Würzburg (K.L.), Würzburg, Germany; Department of Neurology (K.G., A.M.H., S.G.M.), Institute of Physiology and Neuropathophysiology (S.G.M.), University of Münster, Germany; and University Clinic Frankfurt, Department of Neurology, Frankfurt, Germany (W.P.).
出版信息
Stroke. 2013 Nov;44(11):3202-10. doi: 10.1161/STROKEAHA.113.002880. Epub 2013 Sep 12.
BACKGROUND AND PURPOSE
Lymphocytes are important players in the pathophysiology of acute ischemic stroke. The interaction of lymphocytes with endothelial cells and platelets, termed thrombo-inflammation, fosters microvascular dysfunction and secondary infarct growth. FTY720, a sphingosine-1-phosphate receptor modulator, blocks the egress of lymphocytes from lymphoid organs and has been shown to reduce ischemic neurodegeneration; however, the underlying mechanisms are unclear. We investigated the mode of FTY720 action in models of cerebral ischemia.
METHODS
Transient middle cerebral artery occlusion (tMCAO) was induced in wild-type and lymphocyte-deficient Rag1(-/-) mice treated with FTY720 (1 mg/kg) or vehicle immediately before reperfusion. Stroke outcome was assessed 24 hours later. Immune cells in the blood and brain were counted by flow cytometry. The integrity of the blood-brain barrier was analyzed using Evans Blue dye. Thrombus formation was determined by immunohistochemistry and Western blot, and was correlated with cerebral perfusion.
RESULTS
FTY720 significantly reduced stroke size and improved functional outcome in wild-type mice on day 1 and day 3 after transient middle cerebral artery occlusion. This protective effect was lost in lymphocyte-deficient Rag1(-/-) mice and in cultured neurons subjected to hypoxia. Less lymphocytes were present in the cerebral vasculature of FTY720-treated wild-type mice, which in turn reduced thrombosis and increased cerebral perfusion. In contrast, FTY720 was unable to prevent blood-brain barrier breakdown and transendothelial immune cell trafficking after transient middle cerebral artery occlusion.
CONCLUSIONS
Induction of lymphocytopenia and concomitant reduction of microvascular thrombosis are key modes of FTY720 action in stroke. In contrast, our findings in Rag1(-/-) mice and cultured neurons argue against direct neuroprotective effects of FTY720.
背景与目的
淋巴细胞是急性缺血性脑卒中病理生理学的重要参与者。淋巴细胞与内皮细胞和血小板的相互作用，称为血栓炎症，促进微血管功能障碍和继发性梗死扩大。FTY720 是一种鞘氨醇-1-磷酸受体调节剂，可阻止淋巴细胞从淋巴器官迁出，并已被证明可减少缺血性神经变性；然而，其潜在机制尚不清楚。我们研究了 FTY720 在脑缺血模型中的作用模式。
方法
在接受 FTY720（1mg/kg）或载体处理的野生型和淋巴细胞缺陷型 Rag1(-/-) 小鼠中诱导短暂性大脑中动脉闭塞（tMCAO），并在再灌注前立即进行。24 小时后评估卒中结果。通过流式细胞术计数血液和大脑中的免疫细胞。使用 Evans Blue 染料分析血脑屏障的完整性。通过免疫组织化学和 Western blot 确定血栓形成，并与脑灌注相关联。
结果
FTY720 可显著减少野生型小鼠短暂性大脑中动脉闭塞后第 1 天和第 3 天的卒中面积并改善功能结果。在淋巴细胞缺陷型 Rag1(-/-) 小鼠和缺氧培养神经元中，这种保护作用消失。FTY720 处理的野生型小鼠脑血管中的淋巴细胞较少，从而减少血栓形成并增加脑灌注。相比之下，FTY720 无法防止短暂性大脑中动脉闭塞后血脑屏障破裂和跨内皮免疫细胞迁移。
结论
诱导淋巴细胞减少和伴随的微血管血栓形成是 FTY720 在卒中中的关键作用模式。相比之下，我们在 Rag1(-/-) 小鼠和培养神经元中的发现表明 FTY720 没有直接的神经保护作用。
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