Oleoylethanolamide inhibits glial activation via moudulating PPARα and promotes motor function recovery after brain ischemia

Pharmacol Res. 2019 Mar:141:530-540. doi: 10.1016/j.phrs.2019.01.027. Epub 2019 Jan 17.

Abstract

Glial activation and scar formation impede the neurological function recovery after cerebral ischemia. Oleoylethanolamide (OEA), a bioactive lipid mediator, shows neuroprotection against acute brain ischemia, however, its long-term effect, especially on glial scar formation, has not been characterized. In this research, we investigate the effect of OEA on glial activation and scar formation after cerebral ischemia in vitro and in vivo experiments. Glial scar formation in vitro model was induced by transforming growth factor β1 (TGF-β1) in C6 glial cell culture, and experiment model in vivo was induced by middle cerebral artery occlusion (MCAO) in mice. The protein expressions of the markers of glial activation (S100β, GFAP, or pSmads) and glial scar (neurocan) were detected by Western blot and/or immunofluorescence staining; To evaluate the role of PPARɑ in the effect of OEA on glial activation, the PPARɑ antagonist GW6471 was used. Behavior tests were used to assay the effect of OEA on motor function recovery 14 days after brain ischemia in mice. Our results show that OEA (10-50 μM) concentration-dependently inhibited the upregulation of S100β, GFAP, pSmads and neurocan induced by TGF-β1 in C6 glial cells. At the same time, OEA promoted the protein expression and nuclear transportation of PPARɑ in glial cells. PPARα antagonist GW6471 abolished the effect of OEA on glial activation. In addition, we found that delay administration of OEA inhibited the astrocyte activation and promoted the recovery of motor function after brain ischemia in mice. These results indicate that OEA may be developed into a new candidate for attenuating astrocytic scar formation and improving motor function after ischemic stroke.

Keywords: Cerebral ischemia; Glial scar; Motor function; Oleoylethanolamide; PPARɑ.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Ischemia / drug therapy*
  • Brain Ischemia / metabolism
  • Brain Ischemia / pathology
  • Brain Ischemia / physiopathology
  • Cell Line
  • Endocannabinoids / pharmacology
  • Endocannabinoids / therapeutic use*
  • Hand Strength
  • Infarction, Middle Cerebral Artery / drug therapy
  • Infarction, Middle Cerebral Artery / metabolism
  • Infarction, Middle Cerebral Artery / pathology
  • Infarction, Middle Cerebral Artery / physiopathology
  • Male
  • Mice
  • Neuroglia / drug effects*
  • Neuroglia / metabolism
  • Neuroglia / pathology
  • Neuroprotective Agents / pharmacology
  • Neuroprotective Agents / therapeutic use*
  • Oleic Acids / pharmacology
  • Oleic Acids / therapeutic use*
  • PPAR alpha / metabolism*
  • Rats
  • Recovery of Function
  • Walking

Substances

  • Endocannabinoids
  • Neuroprotective Agents
  • Oleic Acids
  • PPAR alpha
  • oleoylethanolamide