Roflumilast, a cyclic nucleotide phosphodiesterase 4 inhibitor, protects against cerebrovascular endothelial injury following cerebral ischemia/reperfusion by activating the Notch1/Hes1 pathway.
Roflumilast, a cyclic nucleotide phosphodiesterase 4 inhibitor, protects against cerebrovascular endothelial injury following cerebral ischemia/reperfusion by activating the Notch1/Hes1 pathway.
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DOI：
10.1016/j.ejphar.2022.175027
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发表时间：
2022-05
影响因子：
5
通讯作者：
Ningbo Cai;Bingtian Xu;Xing Li;Yunyun Qin;Mengfan Li;Kechun Chen;Jiangping Xu;Haitao Wang
中科院分区：
文献类型：
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作者：
Ningbo Cai;Bingtian Xu;Xing Li;Yunyun Qin;Mengfan Li;Kechun Chen;Jiangping Xu;Haitao Wang
脑缺血时紧密连接蛋白(TJ)和黏附连接蛋白(AJ)的丢失导致血脑屏障(BBB)的损伤。罗氟司特(Roflumilast)抑制环核苷酸磷酸二酯酶4(PDE4)对缺血性中风诱导的神经元损伤具有保护作用。然而，罗氟沙星对血管内皮损伤和血脑屏障完整性的影响仍不清楚。在这里，我们研究了罗氟沙星是否以及如何保护脑缺血/再灌流引起的脑血管内皮损伤。本研究证实PDE4B基因敲除可增加缺氧缺糖再灌流(OGD/R)后人脑微血管内皮细胞(HBMECs)TJ和AJ蛋白的表达。罗氟沙星(1.0μM)对PDE4的抑制作用与敲除PDE4B的作用相似。然后我们发现Rofu激活了Notch1/Hary和Split 1增强子(Hes1)信号。一贯地，罗氟沙星对TJ和AJ蛋白的影响可以被γ分泌酶抑制剂DAPT或Hes1基因敲除所逆转。此外，罗氟(1.0 mg/kg)改善了缺血性中风后大鼠的神经行为结果，并改善了血脑屏障的破坏。RoFlu还增加了体内TJ蛋白和AJ蛋白的水平。总而言之，这些数据表明，罗氟沙星是一种很有前途的预防血脑屏障损害的化合物。罗氟沙星的保护作用是通过激活Notch1/Hes1途径实现的。
The loss of tight junction (TJ) and adherens junction (AJ) proteins leads to the damage of the blood-brain barrier (BBB) during cerebral ischemia. Inhibition of cyclic nucleotide phosphodiesterase 4 (PDE4) by roflumilast (Roflu) protects against ischemic stroke-induced neuronal damage. However, the effects of Roflu on vascular endothelial injury and BBB integrity remain unknown. Here, we investigated whether and how Roflu protects against cerebrovascular endothelial injury caused by cerebral ischemia/reperfusion. We demonstrated that PDE4B knocking-down increased the expression of TJ and AJ proteins in human brain microvascular endothelial cells (HBMECs) subjected to oxygen-glucose deprivation reperfusion (OGD/R). Inhibition of PDE4 by Roflu (1.0 μM) showed similar effects as PDE4B knocking-down. We then found that Roflu activated Notch1/Hairy and enhancer of split 1 (Hes1) signaling. Consistently, the effects of Roflu on TJ and AJ proteins were reversed by the γ-secretase inhibitor DAPT or Hes1 knocking-down. Furthermore, Roflu (1.0 mg/kg) improved neurobehavioral outcomes and ameliorated BBB disruption in rats following ischemic stroke. Roflu also increased the levels of TJ proteins and AJ proteinsin vivo. Collectively, these data suggest that Roflu is a promising compound for the prevention of BBB damage. The protective effects of Roflu are mediated through activation of the Notch1/Hes1 pathway.