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.

内质网应激是导致脑缺血损伤的重要因素。Sappanone A (SA)，一种从Caesalpinia sappan L 中提取的天然高异黄烷酮, 已被证明具有抗炎和抗氧化特性。本研究旨在探讨 SA 在脑缺血再灌注损伤中的潜在神经保护作用。在允许再灌注的大脑中动脉闭塞 (MCAO) 大鼠模型和氧-葡萄糖剥夺和再灌注 (OGD/R) 的 PC12 细胞模型中测试了 SA 的潜在神经保护作用。通过 2, 3, 5-三苯基氯化四唑 (TTC) 和苏木精-伊红 (H&E) 染色评估缺血后神经元损伤。使用相应的试剂盒检测炎症因子和氧化应激相关标志物的水平。通过末端脱氧核苷酸转移酶 dUTP 缺口末端标记 (TUNEL) 或流式细胞术评估细胞凋亡，并且使用蛋白质印迹分析确定凋亡相关蛋白的表达。随后，通过蛋白质印迹分析检测内质网应激相关蛋白，并过表达 CCAAT/增强子结合蛋白 (C/EBP) 同源蛋白 (CHOP) 以证实 SA 抑制内质网应激对 OGD 后神经保护作用的贡献/R。结果表明，SA 可有效改善 MCAO 后的脑梗死和再灌注后病理损伤，这与 SA 在脑中减少炎症、氧化应激和细胞凋亡有关。一致地，在 OGD/R 的 PC12 细胞模型中也观察到 SA 缺血再灌注后的这些神经保护作用。重要的是，内质网应激源，包括 CHOP，SA 显着下调 78 kDa 葡萄糖调节蛋白 78 (GRP78) 和磷酸化真核起始因子 2α (EIF-2α)，而 CHOP 过表达减弱了 SA 对 OGD 炎症、氧化应激和细胞凋亡的有益作用/ R 诱导的 PC12 细胞。这些结果表明，SA 可减轻内质网应激，改善炎症、氧化应激和细胞凋亡，从而具有预防缺血性中风脑缺血再灌注损伤的治疗潜力。