Stroke Unit and Neurovascular Research Unit, Department of Neurology, Herlev Gentofte Hospital, Herlev Ringvej 75, Herlev, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
Clinical Neuroscience, Molecular & Clinical Sciences Research Institute, St George's University of London, Cranmer Terrace, London SW17 0RE, UK.
Cell Signal. 2019 Sep;61:108-119. doi: 10.1016/j.cellsig.2019.05.011. Epub 2019 May 24.
Endothelial dysfunction is a hallmark of cerebrovascular disease, including ischemic stroke. Modulating endothelial signalling by cyclic nucleotides, cAMP and cGMP, is a potential therapeutic target in stroke. Inhibitors of the cyclic nucleotide degrading phosphodiesterase (PDE) enzymes may restore cerebral endothelial function. Current knowledge on PDE distribution and function in cerebral endothelial cells is sparse. This review explores data on PDE distribution and effects of PDEi in cerebral endothelial cells and identifies which PDEs are potential treatment targets in stroke.
We performed a systematic search of electronic databases (Medline and Embase). Our search terms were cerebral ischaemia, cerebral endothelial cells, cyclic nucleotide, phosphodiesterase and phosphodiesterase inhibitors.
We found 23 publications which described effects of selective inhibitors of only three PDE families on endothelial function in ischemic stroke. PDE3 inhibitors (PDE3i) (11 publications) and PDE4 inhibitors (PDE4i) (3 publications) showed anti-inflammatory, anti-apoptotic or pro-angiogenic effects. PDE3i also reduced leucocyte infiltration and MMP-9 expression. Both PDE3i and PDE4i increased expression of tight junction proteins and protected the blood-brain barrier. PDE5 inhibitors (PDE5i) (6 publications) reduced inflammation and apoptosis. In preclinical models, PDE5i enhanced cGMP/NO signalling associated with microvascular angiogenesis, increased cerebral blood flow and improved functional recovery. Non-specific PDEi (3 publications) had mainly anti-inflammatory effects.
This review demonstrates that non-selective and selective PDEi of PDE3, PDE4 and PDE5 modulated endothelial function in cerebral ischemic stroke by regulating processes involved in vascular repair and neuroprotection and thus reduced cell death and inflammation. Of note, they promoted angiogenesis, microcirculation and improved functional recovery; all are important in stroke prevention and recovery, and effects should be further evaluated in humans.
血管内皮功能障碍是包括缺血性中风在内的脑血管疾病的一个标志。通过环核苷酸（cAMP 和 cGMP）调节内皮信号转导是中风的一个潜在治疗靶点。环核苷酸降解磷酸二酯酶（PDE）抑制剂可能恢复脑内皮功能。目前关于脑内皮细胞中 PDE 的分布和功能的知识还很匮乏。本综述探讨了 PDE 分布和 PDEi 在脑内皮细胞中的作用的相关数据，并确定了哪些 PDE 是中风的潜在治疗靶点。
我们对电子数据库（Medline 和 Embase）进行了系统搜索。我们的检索词包括脑缺血、脑内皮细胞、环核苷酸、磷酸二酯酶和磷酸二酯酶抑制剂。
我们发现了 23 篇描述仅三种 PDE 家族的选择性抑制剂对缺血性中风内皮功能影响的文献。PDE3 抑制剂（PDE3i）（11 篇文献）和 PDE4 抑制剂（PDE4i）（3 篇文献）显示出抗炎、抗凋亡或促血管生成作用。PDE3i 还减少了白细胞浸润和 MMP-9 表达。PDE3i 和 PDE4i 均增加了紧密连接蛋白的表达并保护了血脑屏障。PDE5 抑制剂（PDE5i）（6 篇文献）减少了炎症和凋亡。在临床前模型中，PDE5i 增强了与微血管血管生成相关的 cGMP/NO 信号转导，增加了脑血流量并改善了功能恢复。非特异性 PDEi（3 篇文献）主要具有抗炎作用。
本综述表明，非选择性和选择性 PDE3、PDE4 和 PDE5 的抑制剂通过调节与血管修复和神经保护相关的过程调节了脑缺血性中风中的内皮功能，从而减少了细胞死亡和炎症。值得注意的是，它们促进了血管生成、微循环并改善了功能恢复；所有这些都对中风的预防和恢复很重要，并且应该在人类中进一步评估其效果。
