Description of a Novel Phosphodiesterase (PDE)-3 Inhibitor Protecting Mice From Ischemic Stroke Independent From Platelet Function
Description of a Novel Phosphodiesterase (PDE)-3 Inhibitor Protecting Mice From Ischemic Stroke Independent From Platelet Function
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DOI：
10.1161/strokeaha.118.023664
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发表时间：
2019-02-01
期刊：
影响因子：
8.3
通讯作者：
Kraft, Peter
中科院分区：
文献类型：
--
作者：
Bieber, Michael;Schuhmann, Michael K.;Kraft, Peter
背景和目的-乙酰水杨酸和氯吡格雷是两种主要的抗血栓药物，用于对没有抗凝指征的缺血性中风(IS)患者进行二级预防。由于其有限的疗效和潜在的副作用，迫切需要新的抗血小板药物。西洛他唑是一种特异性的磷酸二酯酶(PDE)3抑制剂，在主要由亚洲人群组成的临床研究中受到保护，不受IS的影响。然而，PDE-3抑制剂在IS病理生理学中的详细作用机制尚不清楚。在本项目中，我们分析了一种新的和最近才被报道的PDE-3抑制剂(物质V)在小鼠局灶性脑缺血模型中的疗效和病理生理机制。方法：6~8周龄雄性C57BL/6野生型小鼠在脑缺血诱导后1小时给予物质V或赋形剂，以大脑中动脉短暂阻断的方法诱导局灶性脑缺血。在第1天至第7天评估梗塞体积和功能结果，并通过磁共振成像对发现进行验证。结果：在实验性脑缺血后第1天和第7天，用V物质阻断PDE-3可显著缩小脑梗塞体积，改善神经功能恢复。减少血脑屏障损伤、减轻脑组织炎症和减少局部细胞死亡可能是潜在的机制。PDE-3抑制剂治疗不增加脑出血次数，也不影响血小板功能。结论：新型PDE-3抑制剂物质V对小鼠的保护作用不依赖于血小板功能。药物灭活PDE-3可能通过抑制血栓炎症机制和稳定血脑屏障而成为对抗IS的一种有前途的治疗方法。可视化概述--本文提供了在线可视化概述。
Background and Purpose-Acetylsalicylic acid and clopidogrel are the 2 main antithrombotic drugs for secondary prevention in patients with ischemic stroke (IS) without indication for anticoagulation. Because of their limited efficacy and potential side effects, novel antiplatelet agents are urgently needed. Cilostazol, a specific phosphodiesterase (PDE)3 inhibitor, protected from IS in clinical studies comprising mainly Asian populations. Nevertheless, the detailed mechanistic role of PDE-3 inhibitors in IS pathophysiology is hardly understood. In this project, we analyzed the efficacy and pathophysiologic mechanisms of a novel and only recently described PDE-3 inhibitor (substance V) in a mouse model of focal cerebral ischemia.Methods-Focal cerebral ischemia was induced by transient middle cerebral artery occlusion in 6- to 8-week-old male C57Bl/6 wild-type mice receiving substance V or vehicle 1 hour after ischemia induction. Infarct volumes and functional outcomes were assessed between day 1 and day 7, and findings were validated by magnetic resonance imaging. Blood-brain barrier damage, as well as the extent of local inflammatory response and cell death, was determined.Results-Inhibition of PDE-3 by pharmacological blockade with substance V significantly reduced infarct volumes and improved neurological outcome on day 1 and 7 after experimental cerebral ischemia. Reduced blood-brain barrier damage, attenuated brain tissue inflammation, and decreased local cell death could be identified as potential mechanisms. PDE-3 inhibitor treatment did neither increase the number of intracerebral hemorrhages nor affect platelet function.Conclusions-The novel PDE-3 inhibitor substance V protected mice from IS independent from platelet function. Pharmaceutical inactivation of PDE-3 might become a promising therapeutic approach to combat IS via inhibition of thromboinflammatory mechanisms and stabilization of the blood-brain barrier. Visual Overview-An online visual overview is available for this article.