Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China.
Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China.
Sci Rep. 2017 Aug 10;7(1):7758. doi: 10.1038/s41598-017-08227-z.
Chronic cerebral hypoperfusion induced cerebrovascular white matter lesions (WMLs) are closely associated with cognitive impairment and other neurological deficits. The mechanism of demyelination in response to hypoperfusion has not yet been fully clarified. Soluble epoxide hydrolase (sEH) is an endogenous key enzyme in the metabolic conversion and degradation of P450 eicosanoids called epoxyeicosatrienoic acids. Inhibition of sEH has been suggested to represent a prototype "combination therapy" targeting multiple mechanisms of stroke injury with a single agent. However, its role in the pathological process after WMLs has not been clarified. The present study was to investigate the role of a potent sEH inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), on multiple elements in white matter of mice brain after chronic hypoperfusion. Adult male C57BL/6 mice were subjected to bilateral carotid artery stenosis (BCAS) to induce WMLs. Administration of TPPU significantly inhibited microglia activation and inflammatory response, increased M2 polarization of microglial cells, enhanced oligodendrogenesis and differentiation of oligodendrocytes, promoted white matter integrity and remyelination following chronic hypoperfusion. Moreover, these cellular changes were translated into a remarkable functional restoration. The results suggest that sEH inhibition could exert multi-target protective effects and alleviate cognitive impairment after chronic hypoperfusion induced WMLs in mice.
慢性脑灌注不足引起的脑血管性脑白质病变（WML）与认知障碍和其他神经功能缺损密切相关。针对灌注不足导致脱髓鞘的机制尚未完全阐明。可溶性环氧化物水解酶（sEH）是 P450 类二十碳烯酸代谢转化和降解的内源性关键酶，称为环氧二十碳三烯酸。抑制 sEH 被认为是针对卒中损伤多种机制的单一药物“联合治疗”的原型。然而，其在 WML 后的病理过程中的作用尚未阐明。本研究旨在探讨强效 sEH 抑制剂 1-三氟甲氧基苯基-3-(1-丙酰基哌啶-4-基)脲（TPPU）在慢性低灌注后小鼠脑白质多个元素中的作用。成年雄性 C57BL/6 小鼠接受双侧颈总动脉狭窄（BCAS）以诱导 WML。TPPU 给药显著抑制小胶质细胞活化和炎症反应，增加小胶质细胞 M2 极化，增强少突胶质细胞发生和分化，促进慢性低灌注后白质完整性和髓鞘再生。此外，这些细胞变化转化为显著的功能恢复。结果表明，sEH 抑制可发挥多靶点保护作用，并减轻慢性低灌注诱导的 WML 后小鼠的认知障碍。
