Drug repurposing for vascular protection after acute ischemic stroke.
Drug repurposing for vascular protection after acute ischemic stroke.
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DOI：
10.1007/978-3-7091-0693-8_49
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发表时间：
2011
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影响因子：
--
通讯作者：
Fagan, Susan C
中科院分区：
文献类型：
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作者：
Guan, Weihua;Kozak, Anna;Fagan, Susan C
开发治疗急性缺血性中风的新疗法的尝试充满了代价高昂且令人失望的失败。改变安全、陈旧药物的用途提供了一种风险较低的替代方案。血管保护是改善卒中预后的一种新策略。卒中后血管保护的有希望的靶点已经被确定，其中几个靶点可以用“改变用途”的旧药物来接近，包括他汀类药物、血管紧张素受体阻滞剂(ARB)和米诺环素。我们使用三种不同品系的大鼠[Wistar、自发性高血压大鼠(SHR)和2型糖尿病Goto-Kakizaki(GK)大鼠]，在实验性卒中模型中测试了三种市售药物(坎地沙坦、米诺环素和阿托伐他汀)的血管保护(减少出血转化的能力)。所有药物均可缩小梗塞面积，改善神经预后，减少出血。已发现的机制包括抑制基质金属蛋白酶-9，激活Akt，以及增加促血管生成生长因子的表达。病前血管损伤(存在糖尿病或高血压)增加了缺血和再灌流后血管损伤的可能性，并改善了对血管保护的反应。
The attempts to develop new treatments for acute ischemic stroke have been fraught with costly and spectacularly disappointing failures. Repurposing of safe, older drugs provides a lower risk alternative. Vascular protection is a novel strategy for improving stroke outcome. Promising targets for vascular protection after stroke have been identified, and several of these targets can be approached with “repurposed” old drugs, including statins, angiotensin receptor blockers (ARBs), and minocycline. We tested the vascular protection (ability to reduce hemorrhagic transformation) of three marketed drugs (candesartan, minocycline, and atorvastatin) in the experimental stroke model using three different rat strains [Wistar, spontaneously hypertensive rats (SHR) and type 2 diabetic Goto-Kakizaki (GK) rats]. All agents decreased the infarct size, improved the neurological outcome and decreased bleeding. Mechanisms identified include inhibition of MMP-9, activation of Akt, and increased expression of proangiogenic growth factors. Premorbid vascular damage (presence of either diabetes or hypertension) increased the likelihood of vascular injury after ischemia and reperfusion and improved the response to vascular protection.