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

Abstract

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.

The Discovery of Novel PGK1 Activators as Apoptotic Inhibiting and Neuroprotective Agents

“…Ischemic injury is a severe and complex pathological process involving peroxidative stress, neuroexcitotoxicity, and inflammatory activation. These chain reactions ultimately lead to apoptosis of neural cells ( Jiang and Hao, 2020 ). The mechanism of apoptosis inhibition of the compounds found in this study may be similar to that of terazosin, by promoting the release of ATPase from PGK1 ( Li et al, 2016 ), which then activates the activity of the molecular chaperone Hsp90, thereby resulting the enhance of its interaction with client proteins ( Li and Buchner, 2013 ).…”

Recent Advances Regarding the Molecular Mechanisms of Triterpenic Acids: A Review (Part II)

“…Prophylactic treatment with BA was found to inhibit the expression of enzymes such as NADPH oxidase 4 (NOX4), an enzyme largely distributed in the blood vessels, and to diminish ROS formation [ 72 ]. The activation of pro-inflammatory and autophagy pathways can also be noticed after an ischemic stroke; BA downregulated the HIF-α/AMPK proinflammatory pathway [ 73 ] and activated SIRT/FoxO1 responsible for the inhibition of autophagy [ 74 ].…”