Department of Neurosurgery, Graduate School of Medicine, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan.
Central Institutes of Isotope Science (Laboratory of Integrated Molecular Imaging, Department of Biomedical Imaging, Graduate School of Biomedical Science and Engineering), Hokkaido University, Sapporo, Hokkaido, Japan.
Transl Stroke Res. 2020 Oct;11(5):1103-1116. doi: 10.1007/s12975-020-00789-x. Epub 2020 Feb 27.
Injury due to brain ischemia followed by reperfusion (I/R) may be an important therapeutic target in the era of thrombectomy. FTY720, a widely known sphingosine-1-phosphate receptor agonist, exerts various neuroprotective effects. The aim of this study was to examine the protective effect of FTY720 with respect to I/R injury, especially focusing on blood-brain barrier (BBB) protection and anti-inflammatory effects. Male rats were subjected to transient ischemia and administered vehicle or 0.5 or 1.5 mg/kg of FTY720 immediately before reperfusion. Positron emission tomography (PET) with [F]DPA-714 was performed 2 and 9 days after the insult to serially monitor neuroinflammation. Bovine and rat brain microvascular endothelial cells (MVECs) were also subjected to oxygen-glucose deprivation (OGD) and reperfusion, and administered FTY720, phosphorylated-FTY720 (FTY720-P), or their inhibitor. FTY720 dose-dependently reduced cell death, the infarct size, cell death including apoptosis, and inflammation. It also ameliorated BBB disruption and neurological deficits compared to in the vehicle group. PET indicated that FTY720 significantly inhibited the worsening of inflammation in later stages. FTY720-P significantly prevented the intracellular redistribution of tight junction proteins but did not increase their mRNA expression. These results suggest that FTY720 can ameliorate I/R injury by protecting the BBB and regulating neuroinflammation.
脑缺血后继发再灌注损伤（I/R）可能是取栓时代的一个重要治疗靶点。FTY720 是一种广泛应用的鞘氨醇-1-磷酸受体激动剂，具有多种神经保护作用。本研究旨在探讨 FTY720 对 I/R 损伤的保护作用，特别是关注血脑屏障（BBB）保护和抗炎作用。雄性大鼠接受短暂性脑缺血，再灌注前给予载体或 0.5 或 1.5 mg/kg 的 FTY720。损伤后 2 天和 9 天进行正电子发射断层扫描（PET），用[F]DPA-714 连续监测神经炎症。牛和大鼠脑微血管内皮细胞（MVEC）也进行氧葡萄糖剥夺（OGD）和再灌注，并给予 FTY720、磷酸化 FTY720（FTY720-P）或其抑制剂。FTY720 呈剂量依赖性降低细胞死亡、梗死面积、细胞死亡（包括凋亡）和炎症。与载体组相比，FTY720 还改善了 BBB 破坏和神经功能缺损。PET 表明 FTY720 显著抑制了晚期炎症的恶化。FTY720-P 显著防止了紧密连接蛋白的细胞内重分布，但并未增加其 mRNA 表达。这些结果表明，FTY720 通过保护 BBB 和调节神经炎症来改善 I/R 损伤。
