Sepsis-associated encephalopathy (SAE) is known to cause long-term cognitive deficits which are related to sustained microglial activation, but the mechanisms are unclear. Recently, studies have shown soluble epoxide hydrolase (sEH) affects the chronic cognitive function or participates in long-term neuropsychiatric illness. We hypothesized that sEH may be involved in the long-term cognitive deficits of SAE. Male C57BL/6 mice were subjected to cecal ligation and puncture (CLP) and were administered vehicle or sEH inhibitor TPPU. CLP induced prolonged endothelial sEH reactivity and sustained activation of microglia in close vicinity to blood vessels at 14 days. We also observed that persistent loss of endothelial BBB function at 14 days following CLP. However, TPPU-treated septic mice exhibited improved BBB function and declined neuro-inflammation. We confirmed these beneficial effects in vitro, which indicated TPPU resulted in a significant improvement in IL-1β-induced loss of BBB integrity on hCMEC/D3 cell monolayers. Animals were also given a behavior test at 14 days after CLP. Mice showed normal basal locomotor activity in the open field compared with sham-operated animals, but performed fewer entries to the center zone, indicating increased anxiety-like behavior as avoidance of the center. TPPU-treated CLP mice showed normal crossing into the center zone during an open-field test and improved recovery of the ability to learn the novel object recognition (NOR) task compared with saline-treated CLP animals. Our data indicated that prolonged sEH reactivity in brain endothelial cells is associated with long cognitive deficits in sepsis. sEHIs such as TPPU can improve the endothelial barrier function and decrease CLP-induced long-term encephalopathy, at least in part, through anti-inflammatory effects.

中文翻译：

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脓毒症中长时间的认知缺陷与脑内皮细胞中长期可溶性环氧水解酶反应性有关。

已知败血症相关性脑病（SAE）会引起与持续性小胶质细胞活化有关的长期认知缺陷，但其机制尚不清楚。最近，研究表明可溶性环氧化物水解酶（sEH）影响慢性认知功能或参与长期的神经精神疾病。我们假设sEH可能与SAE的长期认知缺陷有关。对雄性C57BL / 6小鼠进行盲肠结扎和穿刺（CLP），并给予媒介物或sEH抑制剂TPPU。在14天时，CLP诱导了延长的内皮sEH反应性并持续激活了靠近血管的小胶质细胞。我们还观察到CLP后14天，内皮BBB功能持续丧失。但是，TPPU处理的败血症小鼠表现出改善的血脑屏障功能和减少的神经炎症。我们在体外证实了这些有益作用，这表明TPPU导致IL-1β诱导的hCMEC / D3细胞单层BBB完整性丧失的显着改善。CLP后第14天也对动物进行了行为测试。与假手术动物相比，小鼠在旷野中显示出正常的基础运动能力，但是进入中心区的次数较少，这表明逃避中心会增加焦虑样行为。TPPU处理的CLP小鼠在开放视野测试中显示正常越过中心区域，并且与盐水处理的CLP动物相比，学习新物体识别（NOR）任务的能力得到了改善。我们的数据表明，脑内皮细胞中sEH反应性延长与脓毒症中长期的认知缺陷有关。