Department of Neurology, The First Affiliated Hospital of Jinzhou Medical University, 121001 Jinzhou, Liaoning, China.
Institute of Cerebrovascular Disease Research, Xuanwu Hospital of Capital Medical University, 100053 Beijing, China.
J Integr Neurosci. 2024 Aug 12;23(8):142. doi: 10.31083/j.jin2308142.
Clinically, ischemic reperfusion injury is the main cause of stroke injury. This study aimed to assess the effectiveness of fingolimod in suppressing inflammation caused by ischemic brain injury and explore its pharmacological mechanisms.
In total, 75 male Sprague-Dawley rats were randomly and equally assigned to five distinct groups: sham, middle cerebral artery occlusion/reperfusion (MCAO/R) surgery, fingolimod low-dose (F-L), fingolimod medium-dose (F-M), and fingolimod high-dose (F-H). Neurobehavioral tests, 2,3,5-triphenyltetrazolium chloride staining, and the brain tissue drying-wet method were conducted to evaluate neurological impairment, cerebral infarction size, and brain water content. Enzyme-linked immunosorbent assay was employed to quantify pro-inflammatory cytokines interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α) protein levels. Western blotting and immunohistochemical staining were performed to assess high mobility group box 1 (HMGB1), toll-like receptor 4 (TLR4), and nuclear factor kappa-B p65 (NF-κBp65) levels.
Rats in the F-L, F-M, and F-H groups exhibited lower Longa scores, reduced infarction volumes, and decreased brain edema than those in the MCAO/R group. Additionally, the F-L, F-M, and F-H groups exhibited lower serum levels of IL-1β, IL-6, and TNF-α than those of the MCAO/R group. Additionally, F-L, F-M, and F-H treatments resulted in decreased HMGB1, TLR4, and NF-κBp65 protein expression levels in the hippocampus of MCAO/R rats.
Fingolimod was found to reduce ischemic brain injury in a dose-dependent manner. Moreover, it was also found to alleviate inflammation following ischemic brain injury via the HMGB1/TLR4/NF‑κB signaling pathway.
临床上，缺血再灌注损伤是脑卒中损伤的主要原因。本研究旨在评估芬戈莫德抑制缺血性脑损伤引起的炎症的有效性，并探讨其药理学机制。
将 75 只雄性 Sprague-Dawley 大鼠随机平均分为五组：假手术组、大脑中动脉闭塞/再灌注（MCAO/R）手术组、芬戈莫德低剂量（F-L）组、芬戈莫德中剂量（F-M）组、芬戈莫德高剂量（F-H）组。神经行为学测试、2,3,5-氯化三苯基四氮唑染色和脑组织干燥-湿重法用于评估神经功能缺损、脑梗死面积和脑水含量。酶联免疫吸附试验用于定量促炎细胞因子白细胞介素（IL）-1β、IL-6 和肿瘤坏死因子-α（TNF-α）蛋白水平。Western blot 和免疫组织化学染色用于评估高迁移率族蛋白 B1（HMGB1）、Toll 样受体 4（TLR4）和核因子-κB p65（NF-κBp65）水平。
F-L、F-M 和 F-H 组大鼠的 Longa 评分较低，梗死体积减小，脑水肿减轻，MCAO/R 组大鼠的血清 IL-1β、IL-6 和 TNF-α水平降低。此外，F-L、F-M 和 F-H 组治疗后 MCAO/R 大鼠海马 HMGB1、TLR4 和 NF-κBp65 蛋白表达水平降低。
芬戈莫德呈剂量依赖性减轻缺血性脑损伤，通过 HMGB1/TLR4/NF-κB 信号通路减轻缺血性脑损伤后的炎症反应。
