The Role And Mechanism Of PPARα In The Over-activated Astrocytes During Chronic Phase Of Cerebral Ischemia

Background:The over-activated astrocytes lead to the glial scar formation,which is the main obstacle of motor function recovery in cerebral ischemic patients.Currently,there are few of effective drugs for the treatment of the chronic injury after cerebral ischemia.Objective:To investigate the role of peroxisome proliferator activated receptor α(PPARα)in over-activated astrocytes and explore the underlying mechanism from the perspective of autophagy.Methods:Astrocyte over activation in vitro model was induced by transforming growth factor β1(TGF-β1)in C6 glial cells or by OGD/R in primary astrocytes,and in vivo model was induced by transient middle cerebral artery occlusion(tMCAO)in mice.PPARa agonist oleoylethanolamide(OEA)and the PPARa null mice,which respectively aroused activation and dysfunction of PPARα,were used to evaluate the role of PPARa in the over-activated astrocytes.The expressions of autophagy related proteins were detected,the autophagosomes were observed by transmission electron microscopy(TEM)and the autophagy flux was assessed by the mRFP-GFP-LC3 adenovirusinfection.Results:The expression of PPARa decreased,and the astrocytes activation related proteins such as Neurocan,GFAP,IL-1β and TNF-α increased after cerebral ischemia.PPARa agonist OEA inhibited the over activation of astrocytes,and PPARa dysfunction promoted the activation of astrocytes.After cerebral ischemia,the expressions of autophagy related proteins such as LC3-Ⅱ/LC3-Ⅰ and P62 both increased in vivo and in vitro;the results of TEM showed that lots of autophagosomes accumulated in cells,and adenovirus transfection results indicated that autophagy flux was blocked.PPARa dysfunction aggravated the block of autophagy flux,while OEA contributed to improve it.Autophagy flux inhibitor bafilomycin A1 and chloroquine antagonized the effect of OEA on inhibiting the over activation of astrocytes.Conclusion:PPARa inhibited the over-activation of astrocytes by improving the autophagy flux in astrocytes during chronic phase of cerebral ischemia.