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Therapeutic activity of inhibition of the soluble epoxide hydrolase in a mouse model of scrapie

机译：抑制瘙痒病小鼠模型中可溶性环氧化物水解酶的治疗活性

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Aims The misfolding and the aggregation of specific proteins are key features of neurodegenerative diseases, specifically Transmissible Spongiform Encephalopathies (TSEs). In TSEs, neuronal loss and inflammation are associated with the accumulation of the misfolded isoform (PrPsc) of the cellular prion protein (PrPc). Therefore we tested the hypothesis that augmenting a natural anti-inflammatory pathway mediated by epoxygenated fatty acids (EpFAs) will delay lethality. EpFAs are highly potent but enzymatically labile molecules produced by the actions of a number of cytochrome P450 enzymes. Stabilization of these bioactive lipids by inhibiting their degradation mediated by the soluble epoxide hydrolase (sEH) results in potent anti-inflammatory effects in multiple disease models. Main methods Mice were infected with the mouse-adapted RML strain of scrapie by intracerebral or intraperitoneal routes. Animals received the sEH inhibitor, by oral route, administrated in drinking water or vehicle (PEG400). Infected mice were euthanized at a standard clinical end point. Histopathological, immunohistochemical and Western blot analyses of brain tissue confirmed the presence of pathology related to prion infection. Key findings Oral administration of the sEHI did not affect the very short survival time of the intracerebral prion infection group. However, mice infected by intraperitoneal route and treated with t-AUCB survived significantly longer than the control group mice (p 0.001). Significance These findings support the idea that inhibition of sEH or augmentation of the natural EpFA signaling in the brain offers a potential and different route to understand prion diseases and may become a therapeutic strategy for diseases involving neuroinflammation.
机译：目的特定蛋白质的错误折叠和聚集是神经退行性疾病，特别是可传播的海绵状脑病（TSE）的关键特征。在TSE中，神经元丢失和炎症与细胞病毒蛋白（PrPc）的错误折叠亚型（PrPsc）的积累有关。因此，我们测试了以下假设：增加由环氧化脂肪酸（EpFAs）介导的天然抗炎途径会延迟致死率。 EpFAs是​​由许多细胞色素P450酶的作用产生的高效但对酶不稳定的分子。通过抑制可溶性环氧化物水解酶（sEH）介导的降解来稳定这些生物活性脂质，可在多种疾病模型中产生有效的抗炎作用。主要方法通过脑内或腹膜内途径用小鼠适应的RML瘙痒病菌株感染小鼠。动物通过口服途径在饮用水或媒介物（PEG400）中接受sEH抑制剂。在标准临床终点对安乐死的小鼠实施安乐死。对脑组织的组织病理学，免疫组织化学和蛋白质印迹分析证实了与病毒感染有关的病理学的存在。主要发现口服sEHI并没有影响脑内病毒感染组的非常短的生存时间。但是，经腹膜内途径感染并用t-AUCB处理的小鼠存活时间明显长于对照组小鼠（p <0.001）。意义这些发现支持这样的想法，即抑制sEH或增强大脑中天然EpFA信号提供了理解and病毒疾病的潜在途径和不同途径，并可能成为涉及神经炎症的疾病的治疗策略。

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