Department of Neurology and Stroke Centre, the Fist Affiliated Hospital of Jinan University, Guangzhou 510632, China.
Clinical Neuroscience Institute of Jinan University, Guangzhou 510632, China.
ACS Chem Neurosci. 2021 Jan 6;12(1):63-78. doi: 10.1021/acschemneuro.0c00530. Epub 2020 Dec 10.
Receptor for advanced glycation end products (RAGEs), a multiligand receptor belonging to the cell-surface immunoglobulin superfamily, has been reported to play a crucial role in neuroinflammation and neurodegenerative diseases. Here, we tested our hypothesis that the RAGE-specific antagonist FPS-ZM1 is neuroprotective against ischemic brain injury. Distal middle cerebral artery occlusion (MCAO) or sham operation was performed on anesthetized Sprague-Dawley male rats ( = 60), which were then treated with FPS-ZM1 or vehicle (four groups in total = Vehicle + MCAO, FPS-ZM1 + MCAO, Vehicle + sham, and FPS-ZM1 + sham). After 1 week, neurological function was evaluated, and then, brain tissues were collected for 2,3,5-triphenyltetrazolium chloride staining, Nissl staining, TUNEL staining, Western blotting, and immunohistochemical analyses. FPS-ZM1 treatment after MCAO markedly attenuated neurological deficits and reduced the infarct area. More interestingly, FPS-ZM1 inhibited ischemia-induced astrocytic activation and microgliosis and decreased the elevated levels of proinflammatory cytokines. Furthermore, FPS-ZM1 blocked the increase in the level of RAGE and, notably, of DIAPH1, the key cytoplasmic hub for RAGE-ligand-mediated activation of cellular signaling. Accordingly, FPS-ZM1 also reversed the MCAO-induced increase in phosphorylation of NF-κB targets that are potentially downstream from RAGE/DIAPH1. Our findings reveal that FPS-ZM1 treatment reduces neuroinflammation in rats with focal cerebral ischemia and further suggest that the ligand/RAGE/DIAPH1 pathway contributes to this FPS-ZM1-mediated alleviation of neuroinflammation.
晚期糖基化终产物受体（RAGEs）是一种属于细胞表面免疫球蛋白超家族的多配体受体，据报道其在神经炎症和神经退行性疾病中发挥关键作用。在这里，我们检验了这样一个假设，即 RAGE 特异性拮抗剂 FPS-ZM1 对缺血性脑损伤具有神经保护作用。在麻醉的雄性 Sprague-Dawley 大鼠（n = 60）上进行大脑中动脉远端闭塞（MCAO）或假手术，然后用 FPS-ZM1 或载体（总共四组：Vehicle + MCAO、FPS-ZM1 + MCAO、Vehicle + sham 和 FPS-ZM1 + sham）进行处理。1 周后，评估神经功能，然后收集脑组织进行 2,3,5-三苯基氯化四氮唑染色、尼氏染色、TUNEL 染色、Western blot 和免疫组织化学分析。MCAO 后给予 FPS-ZM1 治疗可明显减轻神经功能缺损并减少梗死面积。更有趣的是，FPS-ZM1 抑制缺血诱导的星形胶质细胞活化和小胶质细胞增生，并降低促炎细胞因子的升高水平。此外，FPS-ZM1 阻断 RAGE 水平的升高，特别是 RAGE 配体介导的细胞信号激活的关键细胞质枢纽 DIAPH1 的升高。因此，FPS-ZM1 还逆转了 MCAO 诱导的 NF-κB 靶标磷酸化的增加，这些靶标可能是 RAGE/DIAPH1 下游的。我们的研究结果表明，FPS-ZM1 治疗可减轻局灶性脑缺血大鼠的神经炎症，并进一步表明配体/RAGE/DIAPH1 通路有助于这种 FPS-ZM1 介导的神经炎症缓解。
