Endoplasmic reticulum stress is an important contributor to the cerebral ischemic injury. Sappanone A (SA), a kind of natural homoisoflavanone extracted from Caesalpinia sappan L, has been evidenced to exhibit anti-inflammatory and antioxidative properties. The present study aimed to investigate the potential neuroprotective effects of SA in cerebral ischemia-reperfusion injury. The potential neuroprotective effect of SA was tested in a rat model of middle cerebral artery occlusion (MCAO) allowing reperfusion and PC12 cell model of oxygen-glucose deprivation and reperfusion (OGD/R). Post-ischemic neuronal injury was evaluated by 2, 3, 5-triphenyltetrazolium chloride (TTC) and hematoxylin-eosin (H&E) staining. The levels of inflammatory factors and oxidative stress-related markers were detected using corresponding kits. Cell apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) or flow cytometry, and the expression of apoptosis-associated proteins was determined using western blot analysis. Subsequently, endoplasmic reticulum stress-related proteins were detected through western blot analysis, and CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP) was overexpressed to confirm the contribution of endoplasmic reticulum stress inhibition by SA to the neuroprotective effects post OGD/R. Results revealed that SA was effective in ameliorating cerebral infarction and pathological injuries post-reperfusion following MCAO, which is associated with reduced inflammation, oxidative stress, and cell apoptosis by SA in the brain. Consistently, these neuroprotective effects of SA post ischemia-reperfusion were also observed in a PC12 cell model of OGD/R. Importantly, endoplasmic reticulum stressors, including the CHOP, the 78 kDa glucose-regulated protein 78 (GRP78), and phosphorylated eukaryotic initiation factors 2α (EIF-2α), were significantly downregulated by SA, while CHOP overexpression attenuated the beneficial effects of SA on inflammation, oxidative stress, and apoptosis in OGD/R-induced PC12 cells. These results demonstrated that SA alleviates endoplasmic reticulum stress, ameliorating inflammation, oxidative stress, and apoptosis, and thereby serves as therapeutic potential for protection against cerebral ischemia-reperfusion injury in ischemic stroke.
Keywords: cerebral ischemia-reperfusion injury; endoplasmic reticulum stress; inflammation; oxidative stress; sappanone A.