Small molecules targeting cyclooxygenase/prostanoid cascade in experimental brain ischemia: Do they translate?
Small molecules targeting cyclooxygenase/prostanoid cascade in experimental brain ischemia: Do they translate?
复制标题
靶向环氧化酶/前列腺素级联的小分子在实验性脑缺血中的作用：它们是否翻译？
DOI：
10.1002/med.21744
复制
发表时间：
2021-03
影响因子：
13.3
通讯作者：
Yu Y
中科院分区：
文献类型：
--
作者：
Jiang J;Yu Y
急性脑缺血占大多数中风病例，是成年人死亡和幸存者终身残疾的主要原因。目前，静脉溶栓是治疗缺血性卒中的唯一有效药物；机械取栓是一种新兴的治疗大动脉闭塞的替代方法，在特定的患者亚群中显示出一定的前景。然而，整体狭窄的治疗窗口和潜在的风险在很大程度上限制了患者的资格。创新脑缺血治疗需要新的药物靶点。环氧化酶（COX），尤其是其诱导异构体COX-2，作为类前列腺素生物合成中的限速酶，长期以来被认为与急性脑卒中引起的脑损伤和炎症机制有关。然而，在过去的二十年中，由于长期使用COX-2抑制剂药物导致心脑血管系统的严重并发症，治疗靶向COX的概念已经减少。针对下游调节COX级联有害效应的前列腺素信号受体，提出了新的治疗策略。因此，在各种脑缺血动物模型中，大量选择性小分子负或正调节这些重要的炎症调节因子已被评估为神经保护和其他有益作用。这些及时的临床前研究虽然尚未导致临床创新，但为缺血性脑炎症反应的调节提供了新的见解，并可以指导药物开发工作，旨在开发新的辅助策略，以及当前的再灌注治疗，以更高的特异性和更长的治疗窗口治疗急性脑缺血。
Acute brain ischemia accounts for most of stroke cases and constitutes a leading cause of deaths among adults and permanent disabilities in survivors. Currently, the intravenous thrombolysis is the only available medication for ischemic stroke; mechanical thrombectomy is an emerging alternative treatment for occlusion of large arteries and has shown some promise in selected subsets of patients. However, the overall narrow treatment window and potential risks largely limit the patient eligibility. New druggable targets are needed to innovate the treatment of brain ischemia. As the rate-limiting enzyme in the biosyntheses of prostanoids, cyclooxygenase (COX), particularly the inducible isoform COX-2, has long been implicated in mechanisms of acute stroke-induced brain injury and inflammation. However, the notion of therapeutically targeting COX has been diminished over the past two decades due to significant complications of the cardiovascular and cerebrovascular systems caused by long-term use of COX-2 inhibitor drugs. New treatment strategies targeting the downstream prostanoid signaling receptors regulating the deleterious effects of COX cascade have been proposed. As such, a large number of selective small molecules that negatively or positively modulate these important inflammatory regulators have been evaluated for neuroprotection and other beneficial effects in various animal models of brain ischemia. These timely preclinical studies, though not yet led to clinical innovation, provided new insights into the regulation of inflammatory reactions in the ischemic brain and could guide drug discovery efforts aiming for novel adjunctive strategies, along with current reperfusion therapy, to treat acute brain ischemia with higher specificity and longer therapeutic window.
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影响因子：
4.7
作者：
Caggiano, AO;Kraig, RP
通讯作者：
Kraig, RP
DOI：
10.1038/jcbfm.2008.88
发表时间：
2009-01
期刊：
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
影响因子：
--
作者：
通讯作者：
--
影响因子：
3.3
作者：
Ahmad, Muzamil;Ahmad, Abdullah Shafique;Dore, Sylvain
通讯作者：
Dore, Sylvain
影响因子：
8.3
作者：
Del Zoppo GJ;Saver JL;Jauch EC;Adams HP Jr;American Heart Association Stroke Council
通讯作者：
American Heart Association Stroke Council
影响因子：
1.9
作者：
Brose SA;Baker AG;Golovko MY
通讯作者：
Golovko MY