Ping Niu, Zuo Kuiyang, Cai Jiahan, Rong Chunshu, Yu Ziqiao, Zhang Xu, Wang Gaihua, Ma Chunyu, Yang Huirong, Li Jinhua, Wang Xu, Zhao Dexi
Department of Encephalopathy, Hospital of Changchun University of Chinese Medicine, Changchun, Jilin, China.
School of Public Health, Jilin University, Changchun, Jilin, China.
Front Pharmacol. 2024 Apr 30;15:1362301. doi: 10.3389/fphar.2024.1362301. eCollection 2024.
Oxidative stress is an important pathological process in ischemic stroke (IS). Apigenin (APG) is a natural product with favorable antioxidative effects, and some studies have already demonstrated the antioxidative mechanism of APG in the treatment of IS. However, the mechanism of APG on DNA damage and repair after IS is not clear. The aim of this study was to investigate the mechanism of APG on DNA repair after IS.
Male Sprague-Dawley rats were used to establish a model of permanent middle cerebral artery occlusion (pMCAO) on one side, and were pre-treated with gavage of APG (30, 60, or 120 mg/kg) for 7 days. One day after pMCAO, the brain tissues were collected. Cerebral infarct volume, brain water content, HE staining and antioxidant index were analyzed to evaluated the brain damage. Molecular Docking, molecular dynamics (MD) simulation, immunohistochemistry, and Western blot were used to explore the potential proteins related to DNA damage repair.
APG has a low binding score with DNA repair-related proteins. APG treatment has improved the volume of cerebral infarction and neurological deficits, reduced brain edema, and decreased parthanatos and apoptosis by inhibiting PARP1/AIF pathway. In addition, APG improved the antioxidative capacity through reducing reactive oxygen species and malondialdehyde, and increasing glutathione and superoxide dismutase. Also, APG has reduced DNA damage- and cell death-related proteins such as PARP1, γH2A.X, 53BP1, AIF, cleaved caspase3, Cytochrome c, and increased DNA repair by BRCA1 and RAD51 through homologous recombination repair, and reduced non-homologous end link repair by KU70.
APG can improve nerve damage after IS, and these protective effects were realized by reducing oxidative stress and DNA damage, and improving DNA repair.
氧化应激是缺血性脑卒中（IS）的重要病理过程。芹菜素（APG）是一种具有良好抗氧化作用的天然产物，一些研究已经证实了APG在治疗IS中的抗氧化机制。然而，APG对IS后DNA损伤和修复的机制尚不清楚。本研究旨在探讨APG对IS后DNA修复的机制。
采用雄性Sprague-Dawley大鼠建立一侧永久性大脑中动脉闭塞（pMCAO）模型，并通过灌胃给予APG（30、60或120mg/kg）预处理7天。pMCAO术后1天，收集脑组织。分析脑梗死体积、脑含水量、HE染色和抗氧化指标以评估脑损伤。采用分子对接、分子动力学（MD）模拟、免疫组织化学和蛋白质印迹法探讨与DNA损伤修复相关的潜在蛋白质。
APG与DNA修复相关蛋白的结合分数较低。APG治疗通过抑制PARP1/AIF途径改善了脑梗死体积和神经功能缺损，减轻了脑水肿，减少了细胞程序性坏死和细胞凋亡。此外，APG通过降低活性氧和丙二醛水平，增加谷胱甘肽和超氧化物歧化酶水平，提高了抗氧化能力。同时，APG降低了PARP1、γH2A.X、53BP1、AIF、裂解的caspase3、细胞色素c等与DNA损伤和细胞死亡相关的蛋白水平，并通过同源重组修复增加了BRCA1和RAD51介导的DNA修复，降低了KU70介导的非同源末端连接修复。
APG可改善IS后的神经损伤，这些保护作用是通过减轻氧化应激和DNA损伤以及改善DNA修复来实现的。
