2. Academic Validation
  3. PPARα Inhibits Astrocyte Inflammation Activation by Restoring Autophagic Flux after Transient Brain Ischemia

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

  • Biomedicines. 2023 Mar 21;11(3):973. doi: 10.3390/biomedicines11030973.
Doudou Luo 1 2 3,  Wenxuan Ye 1 2 3,  Ling Chen 1 2,  Xiaoqian Yuan 1 2 3,  Yali Zhang 1 2,  Caixia Chen 1 2,  Xin Jin 1 2,  Yu Zhou 1 2 3
Affiliations

Affiliations

  • 1 Department of Basic Medical Science, School of Medicine, Xiamen University, Xiamen 361102, China.
  • 2 Key Laboratory of Chiral Drugs, Xiamen 361102, China.
  • 3 State Key Laboratory of Cellular Stress Biology, Xiamen University, Xiamen 361102, China.
PMID: 36979952 DOI: 10.3390/biomedicines11030973
Abstract

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 α (PPARα) is a ligand-activated nuclear transcriptional factor. This study aims to further clarify the role of PPARα 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. PPARα-deficient mice were used to observe the effects of PPARα on astrocyte activation and autophagic flux. Our results showed that PPARα was mainly expressed in activated astrocytes during the chronic phase of brain ischemia and PPARα 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 PPARα deficit aggravated the autophagic flux block, while PPARα 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 PPARα Agonist on astrocyte activation inhibition. This study identifies a potentially novel function of PPARα in astrocyte autophagic flux and suggests a therapeutic target for the prevention and treatment of chronic brain ischemic injury.

Keywords

astrocyte activation; autophagic flux; ischemic stroke; lysosome; peroxisome proliferator-activated receptor α.

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