Acute ischemic stroke is a serious disease that endangers human health. In our efforts to develop an effective therapy, we previously showed that the potent, highly selective inhibitor of soluble epoxide hydrolase called 1-trifuoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) protects the brain against focal ischemia in rats. Here we explored the mechanism of TPPU action by assessing whether it could preserve blood-brain barrier integrity and reduce apoptosis in the brain during permanent middle cerebral artery occlusion in male Sprague-Dawley rats. TPPU administration at the onset of stroke and once daily thereafter led to smaller infarct volume and brain edema as well as milder neurological deficits. TPPU significantly inhibited the activity of soluble epoxide hydrolase and matrix metalloproteases 2 and 9, reducing 14,15-DHET levels, while increasing expression of tight junction proteins. TPPU decreased numbers of apoptotic cells by down-regulating the pro-apoptotic proteins BAX and Caspase-3, while up-regulating the anti-apoptotic protein BCL-2. Our results suggest that TPPU can protect the blood-brain barrier and reduce the apoptosis of brain tissue caused by ischemia.

中文翻译：

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可溶性环氧化物水解酶抑制剂1-三氟甲氧基苯基-3-（1-丙酰基哌啶-4-基）尿素对永久性中脑动脉阻塞大鼠模型的保护作用。

急性缺血性中风是严重危害人类健康的疾病。在我们努力开发有效疗法的过程中，我们先前证明了一种有效的，高度选择性的可溶性环氧化物水解酶抑制剂，称为1-trifuoro甲氧基苯基-3-（1-丙酰基哌啶丁-4-基）尿素（TPPU），可保护大脑免受局部缺血的影响。大鼠。在这里，我们通过评估雄性Sprague-Dawley大鼠在永久性中脑动脉闭塞过程中TPPU是否可以保留血脑屏障完整性并减少脑中的细胞凋亡，来探索TPPU作用的机制。中风发作时以及之后每天一次的TPPU给药导致较小的梗塞体积和脑水肿以及较轻度的神经功能缺损。TPPU显着抑制了可溶性环氧化物水解酶和基质金属蛋白酶2和9的活性，降低了14,15-DHET的水平，同时增加紧密连接蛋白的表达。TPPU通过下调促凋亡蛋白BAX和Caspase-3减少凋亡细胞的数量，同时上调抗凋亡蛋白BCL-2。我们的结果表明，TPPU可以保护血脑屏障并减少缺血引起的脑组织凋亡。