Neurovascular Research Unit, Department of Neurology, Herlev Gentofte Hospital, University of Copenhagen, Herlev Ringvej 75, 2730 Herlev, Denmark.
Clinical Neuroscience, Molecular & Clinical Sciences Research Institute, St George's University of London, Cranmer Terrace, London SW17 0RE, UK.
Cell Signal. 2017 Oct;38:39-48. doi: 10.1016/j.cellsig.2017.06.015. Epub 2017 Jun 22.
Phosphodiesterase 5 inhibitors (PDE5i), such as sildenafil (Viagra®) are widely used for erectile dysfunction and pulmonary hypertension. Preclinical studies suggest that PDE5i may improve functional outcome following ischemic stroke. In this systematic review we aimed to evaluate the effects of selective PDE5i in animal models of brain ischaemia. A systematic search in Medline, Embase, and The Cochrane Library was performed including studies in English assessing the effects of selective PDE5i. 32 publications were included describing outcome in 3646 animals. Neuroprotective effects of PDE5i were dependent on the NO-cGMP-PKG-pathway. These included reduced neuronal apoptosis (n=3 studies), oxidative stress (n=5), and neuroinflammation (n=2). PDE5i increased angiogenesis and elevated regional cerebral blood flow in the ischemic penumbra, and improved functional recovery. Some studies found that PDE5i treatment reduced lesion volume (n=9), others found no effect (n=9). Treatment was effective when administered within 24h post-ischemia, though treatment delayed to seven days improved outcome in one study. This review demonstrates both neuroprotective and neurorestorative effects of PDE5i in animal models of stroke, though the specific underlying signaling pathways relating to PDE5 inhibition and cGMP may remain serendipitous in some studies. There is currently limited evidence on the effects of selective PDE5i in human stroke patients, hence translation of preclinical results into clinical trials may be warranted.
磷酸二酯酶 5 抑制剂（PDE5i），如西地那非（伟哥），被广泛用于治疗勃起功能障碍和肺动脉高压。临床前研究表明，PDE5i 可能改善缺血性卒中后的功能预后。在本系统评价中，我们旨在评估选择性 PDE5i 在脑缺血动物模型中的作用。在 Medline、Embase 和 The Cochrane Library 中进行了系统搜索，包括评估选择性 PDE5i 作用的英文研究。共纳入 32 篇文献，描述了 3646 只动物的结果。PDE5i 的神经保护作用依赖于 NO-cGMP-PKG 通路。这包括减少神经元凋亡（n=3 项研究）、氧化应激（n=5 项）和神经炎症（n=2 项）。PDE5i 增加了缺血半影区的血管生成和局部脑血流，改善了功能恢复。一些研究发现 PDE5i 治疗减少了病变体积（n=9），其他研究则没有发现效果（n=9）。治疗在缺血后 24 小时内进行是有效的，尽管有一项研究发现延迟至 7 天治疗也可改善结果。本综述表明，PDE5i 在卒中动物模型中具有神经保护和神经修复作用，尽管与 PDE5 抑制和 cGMP 相关的特定潜在信号通路在一些研究中可能仍是偶然的。目前，选择性 PDE5i 在人类卒中患者中的作用的证据有限，因此将临床前结果转化为临床试验可能是必要的。
