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Sci Rep. 2017 Aug 10;7(1):7758. doi: 10.1038/s41598-017-08227-z.

Soluble epoxide hydrolase inhibition Promotes White Matter Integrity and Long-Term Functional Recovery after chronic hypoperfusion in mice.

Chen Y1, Tian H1, Yao E1, Tian Y1, Zhang H2, Xu L1,3, Yu Z1,3, Fang Y1, Wang W1,3, Du P4, Xie M5,6.

Author information

1
Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China.
2
Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China.
3
Key Laboratory of Neurological Diseases of Chinese Ministry of Education, the School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China.
4
Department of Neurology, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Shanghai, 200032, PR China. dupenghhz@126.com.
5
Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China. xiemj@tjh.tjmu.edu.cn.
6
Key Laboratory of Neurological Diseases of Chinese Ministry of Education, the School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, PR China. xiemj@tjh.tjmu.edu.cn.

Abstract

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.

PMID:
28798352
PMCID:
PMC5552839
DOI:
10.1038/s41598-017-08227-z
[Indexed for MEDLINE]
Free PMC Article

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