Laboratory of Pharmacology and Molecular Medicine of Central Nervous System, Department of Biology and Biotechnology, University of Pavia, Italy.
Laboratory of Pharmacology and Molecular Medicine of Central Nervous System, Department of Biology and Biotechnology, University of Pavia, Italy.
Pharmacol Ther. 2015 Feb;146:23-34. doi: 10.1016/j.pharmthera.2014.09.003. Epub 2014 Sep 6.
Stroke is the third cause of death worldwide and the main cause of chronic, severe adult disability. We focus on acute ischaemic stroke, which accounts for approximately 80% of all strokes. The current therapy aims at restoring cerebral blood flow within a narrow time window in order to prevent damaging the "penumbra" which surrounds the infarct core. Intravenous thrombolysis remains the fundamental treatment worldwide, though not ideal for various restrictions and complications, limiting to 10% or less the percentage of patients treated within the appropriate time window. Neuroprotection is an alternative or adjunct approach to thrombolysis, targeting cerebral parenchyma in the acute ischaemic phase. Furthermore, neurorepair attempts to restore neuronal function in the after-stroke phase in those patients (treated or untreated) with significant impairment. In the past decades, the efficacy and safety of numerous candidate neuroprotective agents were shown in various animal stroke models. However, in clinical trials, promising pre-clinical studies have not been translated into positive outcomes. Our review will analyse the possible reasons for this failure and the new approaches and recommendations to overcome it, as well as novel strategies targeting additional events in ischaemia cascade. The combination of thrombolysis with pharmacological and non-pharmacological neuroprotective approaches has also been tested. Finally, the neurorepair strategy will be described with special emphasis on the role of cell-based therapies and ischaemic conditioning. Hopefully, the future therapy of ischaemic stroke will encompass a combination of neuroprotection (to stabilise penumbra), thrombolysis, antithrombotics (for secondary prevention) and neurorepair based on cell therapy plus rehabilitation.
中风是全球第三大致死原因，也是导致慢性、重度成年残疾的主要原因。我们专注于急性缺血性中风，它约占所有中风的 80%。目前的治疗方法旨在在狭窄的时间窗内恢复脑血流，以防止损害梗死核心周围的“半影区”。静脉溶栓治疗仍然是全球的基本治疗方法，但由于各种限制和并发症，只有不到 10%的患者在合适的时间窗内接受治疗，效果并不理想。神经保护是溶栓治疗的替代或辅助方法，针对急性缺血期的脑实质。此外，神经修复试图在那些有明显损伤的中风后患者（治疗或未治疗）中恢复神经元功能。在过去的几十年里，许多候选神经保护剂在各种动物中风模型中显示出了疗效和安全性。然而，在临床试验中，有前景的临床前研究并没有转化为积极的结果。我们的综述将分析导致这种失败的可能原因，以及克服这些原因的新方法和建议，以及针对缺血级联中其他事件的新策略。溶栓治疗与药物和非药物神经保护方法的联合也已经进行了测试。最后，将描述神经修复策略，特别强调细胞治疗和缺血预处理的作用。希望未来的缺血性中风治疗将包括神经保护（稳定半影区）、溶栓、抗血栓形成（用于二级预防）和基于细胞治疗的神经修复以及康复的综合治疗。
