Protective Action of Betulinic Acid on Cerebral Ischemia/Reperfusion Injury through Inflammation and Energy Metabolic Homeostasis

This work evaluated the protective effects of betulinic acid (BA) in vitro cerebral ischemia/reperfusion and provides clues about its pharmacological mechanism. A rat model of middle cerebral artery occlusion (MCAO) was established to investigate the effects of BA on cerebral ischemia. SHSY5Y cell injury was induced by oxygen–glucose deprivation and recovery (OGD/R) to further verify the action of BA in vitro. Our data show a significant improvement in infarct size, neurological score, and cerebral edema after BA treatment. Enzyme linked immunosorbent assay (ELISA) data show that BA inhibited interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in vivo and in vitro. Protein expression results show that BA down-regulated hypoxia-inducible factor-1α (HIF-1α), up-regulated adenosine monophosphate activated protein kinase (AMPK), peroxisome proliferative activated receptor (PPAR)-α, and PPAR-γ coactivator-1α (PGC-1α), and blocked phosphorylation of IκBα and nuclear factor kappa Bp65 (NF-κB-p65) in the brains of MCAO rats and OGD/R-stimulated SHSY5Y cells. The results reveal the potent effects of BA on cerebral ischemia, suggesting that HIF-1α might be a crucial therapeutic target to regulate energy metabolism and inflammation.