Taraxerol Alleviates Cerebral Ischemia–Reperfusion Induced Inflammation and Ferroptosis via Regulating AKT/NF‐κB Pathway

Abstract

Taraxerol (Tar) is a natural triterpenoid which exhibited anti‐inflammatory and neuroprotective properties. Whereas, the roles of Tar in cerebral ischemia–reperfusion injury (CIRI) remain incompletely understood. The research investigated the protective effects and regulatory mechanism of Tar in CIRI. The middle cerebral artery occlusion (MCAO) model was established in vivo. Effects of Tar on brain injury and MCAO rats motor function were detected by HE staining and TUNEL assay. PC12 cells were subjected to oxygen–glucose deprivation/reoxygenation (OGD/R) and irritated with 20, 40, 80, and 160 μM Tar; the intracellular Fe2+, MDA, and ROS levels were detected utilizing interrelated assay kits. The pro‐inflammatory cytokines and ferroptosis‐related factors were examined through qRT‐PCR and western blot assay. Cell viability and apoptosis of PC12 cells were examined by CCK‐8 and flow cytometry assays. The AKT agonist (SC79) was used to investigate the regulatory functions of the AKT/NF‐κB pathway in OGD/R‐treated PC12 cells. Tar alleviated brain injury and motor function in MCAO rats. Tar eased inflammation, oxidative stress, and ferroptosis in MCAO rats. In vitro, OGD/R exposure reduced cell viability, promoted apoptosis, elevated IFN‐γ, TNF‐α, IL‐6, Fe2+, MDA, and ROS levels but declined GPX4 and SLC7A11 in PC12 cells. But, the above‐mentioned tendency of OGD/R‐triggered PC12 cells injury was overturned by Tar. Mechanistically, Tar treatment inactivated the AKT/NF‐κB pathway and decreased nuclear translocation of NF‐κB in OGD/R‐induced PC12 cells. The AKT agonist SC79 reversed the protective effects of Tar in OGD/R‐induced PC12 cells. Tar improved CIRI induced inflammation and ferroptosis through regulating the AKT/NF‐κB pathway.