The Effects Of PPARα Agonists On White Matter Injury After Cerebral Ischemia

Background:Stroke is one of the vascular diseases with high incidence and the largest risk coefficient.Among them,white matter was most affected in ischemic stroke,accounting for half of the lesion volume,but white matter injury was often ignored in stroke studies.Therefore,the neuroprotective effect of white matter should be more widely considered in the design of therapeutic strategies.Our previous studies showed that PPARa agonist oleylethanolamine(OEA)and its derivatives Z-octadecyl-9-ene-propyl sulfamide(N15)reduced the volume of cerebral infarction and the degree of cerebral edema,inhibited inflammation after ischemic stroke.However,it is not clear whether it has protective effect on white matter injury after ischemic stroke.Objective:the effects of PPARa agonists on white matter injury after cerebral ischemia.Methods:(1)the animal experiment selected 250～280g SD(Sprague-Dawley)male rats to establish the model of middle cerebral artery infarction(MCAO)for 7 days or 28 days;the expression of myelin basic protein(MBP)and demyelinating protein(SMI-32)in cortex,corpus callosum and striatum were detected by immunofluorescence double staining or western blot test,the detecting demyelination of corpus callosum or striatum was examined by Luxol fast blue or transmission electron microscopy.(2)Primary cells were extracted and induced by 15 nmol triiodothyronine(T3)and 1 ng/mL ciliary neurotrophic factor(CNF);the fluorescence images immunolabled with A2B5+oligodendrocyte precursor cells or MBP+oligodendrocyte cells;the hypoxia model(OGD/R)was used to simulate the cerebral ischemia in cell level;the CCK-8 method was used to detect OEA,Fenofibrate and GW6471(PPARa blockers)optimal pre-protective dose and time,and immunofluorescence was used to detect the expression of PPARa in oligodendrocyte lineage cells;the effect of PPARa agonists or blocker on cell differentiation of oligodendrocytes was detected by immunofluorescence or western blot/RT-PCR methods.Results:(1)the PPARa agonists increased the expression of MBP and reduced SMI-32 protein after stroke,improved demyelination,reduced the G-ratio ratio,and protected the white matter integrity after cerebral ischemia.(2)PPARa protein is expressed in oligodendrocyte lineage cells,and as the degree of differentiation of oligodendrocyte lineage cells increases,the expression of PPARa protein also increases.(3)PPARa agonists promoted the differentiation of oligodendrocyte lineage cells,in contrast,blockers inhibited the differentiation of oligodendrocyte lineage cells.Conclusion:PPARa agonists improve the integrity of white matter injury after cerebral ischemia by promoting oligodendrocyte precursor cell differentiation.