Prolonged Soluble Epoxide Hydrolase Reactivity in Brain Endothelial Cells Is Associated with Long Cognitive Deficits in Sepsis.

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.