Gong Cuilan, Fu Xinying, Ma Qiang, He Menghao, Zhu Xinhua, Liu Lijuan, Zhou Desheng, Yan Siyang
The First Hospital of Traditional Chinese Medicine in Changde, The Changde Affiliated Hospital of Hunan University of Chinese Medicine, Hunan, 415000 China; School of Integrated Chinese and Western Medicine, Key Laboratory of Hunan Provincial for Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Hunan, 410208, China.
School of Integrated Chinese and Western Medicine, Key Laboratory of Hunan Provincial for Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Hunan, 410208, China.
Phytomedicine. 2025 Jan;136:156331. doi: 10.1016/j.phymed.2024.156331. Epub 2024 Dec 27.
Ischemic stroke ranks as the second leading cause of global mortality and disability. Although reperfusion is crucial for salvaging brain tissue, it carries the risk of secondary injuries, such as ferroptosis. Gastrodin, a neuroprotective compound found in Chinese herbal medicine, may regulate this process. However, its impact on stroke-induced ferroptosis remains unclear.
This research endeavors to probe Gastrodin's influence on post-ischemic ferroptosis, deciphering its mechanisms and assessing its therapeutic promise.
We developed rat models of middle cerebral artery occlusion/reperfusion (MCAO/R) and created oxygen-glucose deprivation/reoxygenation (OGD/R)-damaged PC12 cell models. Gastrodin was administered to assess ferroptosis using Prussian blue staining and fluorescence probes. To investigate the effects of gastrodin on the xCT/GPX4 and ACSL4/LPCAT3 pathways, we employed molecular docking, immunofluorescence, Western blotting, and quantitative real-time polymerase chain reaction (qRT-PCR). Additionally, we used transmission electron microscopy and JC-1 fluorescence probes to examine mitochondrial integrity and function.
Our study demonstrated that gastrodin significantly reduced iron accumulation and lipid peroxidation in the brains of MCAO/R rats and OGD/R-injured PC12 cells. It suppressed reactive oxygen species (ROS) and ameliorated mitochondrial membrane potential. It potentiates the xCT/GPX4 axis while repressing the ACSL4/LPCAT3 pathway, leading to improved mitochondrial architecture and function, notably characterized by decreased mitochondrial membrane potential, reduced ROS levels, and increased formation of mitochondrial cristae. By modulating the xCT/GPX4 and ACSL4/LPCAT3 pathways, gastrodin mitigated ferroptosis in ischemic stroke, thereby preserving mitochondrial structural and functional integrity. This study provides novel mechanistic insights into gastrodin's therapeutic potential for treating ischemic stroke, highlighting the importance of traditional Chinese medicine in modern medical therapy.
缺血性中风是全球死亡和残疾的第二大主要原因。尽管再灌注对于挽救脑组织至关重要，但它存在继发性损伤的风险，如铁死亡。天麻素是一种在中药中发现的神经保护化合物，可能会调节这一过程。然而，其对中风诱导的铁死亡的影响仍不清楚。
本研究旨在探究天麻素对缺血后铁死亡的影响，阐明其机制并评估其治疗前景。
我们建立了大鼠大脑中动脉闭塞/再灌注（MCAO/R）模型，并创建了氧糖剥夺/复氧（OGD/R）损伤的PC12细胞模型。给予天麻素，使用普鲁士蓝染色和荧光探针评估铁死亡。为了研究天麻素对xCT/GPX4和ACSL4/LPCAT3途径的影响，我们采用了分子对接、免疫荧光、蛋白质印迹和定量实时聚合酶链反应（qRT-PCR）。此外，我们使用透射电子显微镜和JC-1荧光探针来检查线粒体的完整性和功能。
我们的研究表明，天麻素显著减少了MCAO/R大鼠大脑和OGD/R损伤的PC12细胞中的铁积累和脂质过氧化。它抑制了活性氧（ROS）并改善了线粒体膜电位。它增强了xCT/GPX4轴，同时抑制了ACSL4/LPCAT3途径，导致线粒体结构和功能得到改善，其显著特征是线粒体膜电位降低、ROS水平降低和线粒体嵴形成增加。通过调节xCT/GPX4和ACSL4/LPCAT3途径，天麻素减轻了缺血性中风中的铁死亡，从而保持了线粒体的结构和功能完整性。本研究为天麻素治疗缺血性中风的治疗潜力提供了新的机制见解，突出了传统中药在现代医学治疗中的重要性。
