Peng Chenjia, Zhang Yang, Chai Jiaqing, Zhang Hengbo
School of Mathematics and Statistics, Hunan First Normal University, Changsha, China.
School of Physical Education, First Hunan Normal University, Changsha, China.
Front Pharmacol. 2025 May 22;16:1577954. doi: 10.3389/fphar.2025.1577954. eCollection 2025.
Ferroptosis is a newly described form of nonapoptotic, iron-dependent cell death that plays an essential role in the pathogenesis of ischemic stroke. Targeting ferroptosis may be an effective way to treat ischemic stroke. Mangiferin (MGF) is a natural polyphenol that has been shown to protect neurological function via multiple mechanisms. However, the mechanism by which MGF inhibits ferroptosis in stroke remains unclear.
An ischemic stroke rat model was established by middle cerebral artery occlusion. Neurological scoring, TTC staining, behavioral tests, Nissl staining, HE staining and immunochemistry were used to analyze the influences of MGF on neurological deficits, the infarct area, cognitive function, neuronal morphology, histopathological injury, and the morphology of microglia and astrocytes. Transmission electron microscopy and Perls' stain were used to evaluate the characteristics of ferroptosis. Western blotting was used to analyze the expression of NRF2, FTL, SLC7A11 and GPX4. ELISA was used to analyze the levels of cytokines, including IL-6, IL-1β and TNF-α, to evaluate neuroinflammation. Oxidative stress was evaluated by analyzing the levels of ROS, MDA, GSH, and SOD.
MGF clearly improved the neurological function and learning and memory ability of stroke rats. MGF significantly decreased ROS and MDA and increased GSH, SOD. MGF significantly suppressed neuroinflammation by downregulating IL-6, IL-1β and TNF-α. Ferroptosis in stroke rats was significantly inhibited by MGF. MGF significantly increased the expression of NRF2, FTL, SLC7A11 and GPX4. The NRF2 inhibitor ML385 significantly reversed the effects of MGF on stroke rats.
MGF protects neurological function and suppresses ferroptosis via activating NRF2/ARE pathway in ischemic stroke rats.
铁死亡是一种新描述的非凋亡性、铁依赖性细胞死亡形式，在缺血性中风的发病机制中起重要作用。靶向铁死亡可能是治疗缺血性中风的有效方法。芒果苷（MGF）是一种天然多酚，已被证明可通过多种机制保护神经功能。然而，MGF抑制中风中铁死亡的机制尚不清楚。
通过大脑中动脉闭塞建立缺血性中风大鼠模型。采用神经功能评分、TTC染色、行为测试、尼氏染色、HE染色和免疫化学分析MGF对神经功能缺损、梗死面积、认知功能、神经元形态、组织病理学损伤以及小胶质细胞和星形胶质细胞形态的影响。采用透射电子显微镜和普鲁士蓝染色评估铁死亡的特征。采用蛋白质免疫印迹法分析NRF2、FTL、SLC7A11和GPX4的表达。采用酶联免疫吸附测定法分析细胞因子（包括IL-6、IL-1β和TNF-α）水平，以评估神经炎症。通过分析ROS、MDA、GSH和SOD水平评估氧化应激。
MGF明显改善了中风大鼠的神经功能以及学习和记忆能力。MGF显著降低了ROS和MDA水平，并增加了GSH、SOD水平。MGF通过下调IL-6、IL-1β和TNF-α显著抑制了神经炎症。MGF显著抑制了中风大鼠的铁死亡。MGF显著增加了NRF2、FTL、SLC7A11和GPX4的表达。NRF2抑制剂ML385显著逆转了MGF对中风大鼠的作用。
在缺血性中风大鼠中，MGF通过激活NRF2/ARE途径保护神经功能并抑制铁死亡。
