PPAR alpha Inhibits Astrocyte Inflammation Activation by Restoring Autophagic Flux after Transient Brain Ischemia

Astrocyte inflammation activation is an important cause that hinders the recovery of motor function after cerebral ischemia. However, its molecular mechanism has not yet been clearly clarified. The peroxisome proliferator-activated receptor a (PPARa) is a ligand-activated nuclear transcriptional factor. This study aims to further clarify the role of PPARa in astrocyte inflammation activation after cerebral ischemia and to explore the underlying mechanism. Astrocyte activation was induced in an in vivo model by transient middle cerebral artery occlusion (tMCAO) in mice. The in vitro model was induced by an oxygen-glucose deprivation/reoxygenation (OGD/R) in a primary culture of mouse astrocyte. PPARa-deficient mice were used to observe the effects of PPARa on astrocyte activation and autophagic flux. Our results showed that PPARa was mainly expressed in activated astrocytes during the chronic phase of brain ischemia and PPARa dysfunction promoted astrocyte inflammatory activation. After cerebral ischemia, the expressions of LC3-II/I and p62 both increased. Autophagic vesicle accumulation was observed by electron microscopy in astrocytes, and the block of autophagic flux was indicated by an mRFP-GFP-LC3 adenovirus infection assay. A PPARa deficit aggravated the autophagic flux block, while PPARa activation preserved the lysosome function and restored autophagic flux in astrocytes after OGD/R. The autophagic flux blocker bafilomycin A1 and chloroquine antagonized the effect of the PPARa agonist on astrocyte activation inhibition. This study identifies a potentially novel function of PPARa in astrocyte autophagic flux and suggests a therapeutic target for the prevention and treatment of chronic brain ischemic injury.