The Role Of Soluble Epoxide Hydrolase Inhibitor In Chronic Cerebral Hypoperfusion Induced White Matter Injury

Objective—The present study was to investigate the role of a soluble epoxide hydrolase(sEH)inhibitor,1-(1-propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea(TPPU),on multiple elements of oligovascular niche of the mice brain after chronic hypoperfusion induced white matter injury.Methods—Adult male C57BL/6J mice were subjected to bilateral carotid artery stenosis(BCAS)to induce whiter matter injury.The laser doppler and laser speckle contrast imaging were applied to monitor blood flow changes in mice during the operation.Immunostaining,LFB staining and western blot were used to evaluate the changes of sEH expression,assess white matter integrity,myelin loss,glial activation,and inflammation reaction.Bromodeoxyuridine(BrdU)was injected for measurements of proliferating of oligodendrocyte precursor cells and newly generated oligodendrocytes.Electron microscopy was used to examine the myelin thickness and neuronal fiber integrity.An eight-arm radial maze was performed to examine the cognitive functions at 4 weeks after BCAS.In order to observe the effects of TPPU in chronic cerebral hypoperfusion induced white matter injury,TPPU was injected intraperitoneally once daily from 1 day after BCAS until 1 day before sacrificed.Results—We successfully established the BCAS mice model,according to the evaluation of laser doppler,laser speckle contrast imaging,immunostaining,LFB staining,western blot,electron microscopy and an eight-arm radial maze.This mice model could give rise to significant white matter degradation and changes of glia cells.The administration of TPPU significantly inhibited microglia activation and inflammatory response,favored microglial polarization toward to the M2 phenotype,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.Conclusions—The results suggest that sEH inhibitor TPPU could exert multiple targets protective effects and alleviate cognitive impairment after chronic hypoperfusion induced white matter injury and cognitive impairment in mice.