An Qi, Zhu Yuequan, Shi Wenjuan, Li Wei, Yang Xueqi, Huang Minqi, Li Yakun, Zhao Yongmei
Institute of Cerebrovascular Diseases Research, Xuanwu Hospital of Capital Medical University, Beijing, China; Beijing Geriatric Medical Research Center, Beijing, China.
Institute of Cerebrovascular Diseases Research, Xuanwu Hospital of Capital Medical University, Beijing, China; Beijing Geriatric Medical Research Center, Beijing, China.
Brain Res. 2025 Mar 1;1850:149382. doi: 10.1016/j.brainres.2024.149382. Epub 2024 Dec 4.
4-(2-Aminoethyl)-benzenesulfonyl fluoride (AEBSF) is a serine protease inhibitor that may alleviate endoplasmic reticulum (ER) stress, a significant contributing factor to cerebral ischemia/reperfusion injury. The molecular crosstalk between ER stress, oxidative stress and autophagy represents a vicious cycle that can be pharmacologically targeted to minimize neuronal death after acute injuries to the central nervous system. However, the neuroprotective effects of AEBSF in the context of cerebral ischemia/reperfusion injury remain unknown. In this study,we reported the neuroprotective effect of AEBSF against cerebral ischemia/reperfusion injury and explored the mechanisms involved, particularly its role in reducing ER stress, oxidative stress and autophagy. Rats were pretreated with AEBSF or a vehicle before a 90 min middle cerebral artery occlusion (MCAO) followed by 24 h of reperfusion. Our results demonstrate that AEBSF treatment reduced infarct volume and improved neurological function compared to vehicle treated rats after 24 h of reperfusion. Furthermore,AEBSF treatment decreased the expression of caspase-3, suggesting a decrease in neuronal apoptosis. Additionally, AEBSF treatment lowered levels of key ER stress biomarkers, including glucose-regulated protein 78 (GRP78), phosphorylated eukaryotic initiation factor 2α (p-eIF2α), and CCAAT-enhancer-binding protein homologous protein (CHOP), while the levels of inositol-requiring enzyme 1α (IRE1α) remained unchanged. AEBSF also decreased the oxidative stress biomarker neuronal nitric oxide synthase (nNOS) and its related molecule pro-MMP-9. Importantly, treatment with AEBSF reversed the trends of autophagy biomarker LC3B II/α-tubulin, Beclin1, and SQSTM1 at 24 h after reperfusion. In conclusion, AEBSF significantly mitigates ischemic brain damage and promotes neurological recovery by inhibiting ER stress, oxidative stress, and autophagy, highlighting its potential as a therapeutic option for ischemic stroke.
4-（2-氨基乙基）苯磺酰氟（AEBSF）是一种丝氨酸蛋白酶抑制剂，可能减轻内质网（ER）应激，而内质网应激是脑缺血/再灌注损伤的一个重要促成因素。内质网应激、氧化应激和自噬之间的分子相互作用代表了一个恶性循环，在药理学上可以针对这个循环来尽量减少中枢神经系统急性损伤后的神经元死亡。然而，AEBSF在脑缺血/再灌注损伤背景下的神经保护作用仍不清楚。在本研究中，我们报告了AEBSF对脑缺血/再灌注损伤的神经保护作用，并探讨了其中涉及的机制，特别是其在减轻内质网应激、氧化应激和自噬方面的作用。在大鼠大脑中动脉闭塞（MCAO）90分钟并再灌注24小时之前，用AEBSF或赋形剂对大鼠进行预处理。我们的结果表明，与赋形剂处理的大鼠相比，再灌注24小时后，AEBSF处理减少了梗死体积并改善了神经功能。此外，AEBSF处理降低了caspase-3的表达，表明神经元凋亡减少。此外，AEBSF处理降低了关键内质网应激生物标志物的水平，包括葡萄糖调节蛋白78（GRP78）、磷酸化真核起始因子2α（p-eIF2α）和CCAAT增强子结合蛋白同源蛋白（CHOP），而肌醇需求酶1α（IRE1α）的水平保持不变。AEBSF还降低了氧化应激生物标志物神经元型一氧化氮合酶（nNOS）及其相关分子前基质金属蛋白酶-9（pro-MMP-9）。重要的是，AEBSF处理在再灌注24小时后逆转了自噬生物标志物LC3B II/α-微管蛋白、Beclin1和SQSTM1的变化趋势。总之，AEBSF通过抑制内质网应激、氧化应激和自噬，显著减轻缺血性脑损伤并促进神经功能恢复，突出了其作为缺血性中风治疗选择的潜力。
