Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
Department of Entomology and Nematology and UC Davis Comprehensive Cancer Center, University of California, Davis, CA 95817, USA.
Int J Mol Sci. 2021 Apr 28;22(9):4650. doi: 10.3390/ijms22094650.
Polyunsaturated fatty acids (PUFAs) are essential FAs for human health. Cytochrome P450 oxygenates PUFAs to produce anti-inflammatory and pain-resolving epoxy fatty acids (EpFAs) and other oxylipins whose epoxide ring is opened by the soluble epoxide hydrolase (sEH/), resulting in the formation of toxic and pro-inflammatory vicinal diols (dihydroxy-FAs). Pharmacological inhibition of sEH is a promising strategy for the treatment of pain, inflammation, cardiovascular diseases, and other conditions. We tested the efficacy of a potent, selective sEH inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), in an animal model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE). Prophylactic TPPU treatment significantly ameliorated EAE without affecting circulating white blood cell counts. TPPU accumulated in the spinal cords (SCs), which was correlated with plasma TPPU concentration. Targeted lipidomics in EAE SCs and plasma identified that TPPU blocked production of dihydroxy-FAs efficiently and increased some EpFA species including 12(13)-epoxy-octadecenoic acid (12(13)-EpOME) and 17(18)-epoxy-eicosatrienoic acid (17(18)-EpETE). TPPU did not alter levels of cyclooxygenase (COX-1/2) metabolites, while it increased 12-hydroxyeicosatetraenoic acid (12-HETE) and other 12/15-lipoxygenase metabolites. These analytical results are consistent with sEH inhibitors that reduce neuroinflammation and accelerate anti-inflammatory responses, providing the possibility that sEH inhibitors could be used as a disease modifying therapy, as well as for MS-associated pain relief.
多不饱和脂肪酸（PUFAs）是人体健康必需的脂肪酸。细胞色素 P450 将 PUFAs 氧化为具有抗炎和止痛作用的环氧化物脂肪酸（EpFAs）和其他氧化脂类，其环氧环由可溶性环氧化物水解酶（sEH/）打开，形成有毒和促炎的邻二醇（二羟脂肪酸）。抑制 sEH 是治疗疼痛、炎症、心血管疾病和其他疾病的有前途的策略。我们在多发性硬化症（MS）、实验性自身免疫性脑脊髓炎（EAE）的动物模型中测试了一种有效的、选择性的 sEH 抑制剂 1-三氟甲氧基苯基-3-（1-丙酰基哌啶-4-基）脲（TPPU）的疗效。预防性 TPPU 治疗可显著改善 EAE，而不影响循环白细胞计数。TPPU 在脊髓（SCs）中积累，这与血浆 TPPU 浓度相关。EAE SCs 和血浆中的靶向脂质组学鉴定表明，TPPU 可有效阻止二羟脂肪酸的产生，并增加某些 EpFA 种类，包括 12（13）-环氧十八烯酸（12（13）-EpOME）和 17（18）-环氧二十碳三烯酸（17（18）-EpETE）。TPPU 不改变环氧化酶（COX-1/2）代谢物的水平，而增加 12-羟基二十碳四烯酸（12-HETE）和其他 12/15-脂氧合酶代谢物。这些分析结果与降低神经炎症和加速抗炎反应的 sEH 抑制剂一致，这为 sEH 抑制剂可用于疾病修饰治疗以及治疗 MS 相关疼痛提供了可能性。
