RAGE-Specific Inhibitor FPS-ZM1 Attenuates AGEs-Induced Neuroinflammation and Oxidative Stress in Rat Primary Microglia
作者
Shen, C;Ma, YJ;Zeng, ZL;Yin, QQ;Hong, Y;Hou, XY;Liu, XP
作者单位
[Shen, Chao; Ma, Yingjuan; Zeng, Ziling; Yin, Qingqing; Hong, Yan; Hou, Xunyao; Liu, Xueping] Shandong Univ, Shandong Prov Hosp, Dept Senile Neurol, 324 Jing Wu Rd, Jinan 250021, Shandong, Peoples R China.;-;[Liu, Xueping] Shandong Univ, Shandong Prov Hosp, Dept Antiageing, 324 Jing Wu Rd, Jinan 250021, Shandong, Peoples R China.;-;[Liu, Xueping] Shandong Univ, Shandong Prov Hosp, Antiaging Monitoring Lab, 324 Jing Wu Rd, Jinan 250021, Shandong, Peoples R China.
摘要
Advanced glycation end products (AGEs) enhance microglial activation and intensify the inflammatory response and oxidative stress in the brain. This process may occur due to direct cytotoxicity or interacting with AGEs receptors (RAGE), which are expressed on the surface of microglia. FPS-ZM1 is a high-affinity but nontoxic RAGE-specific inhibitor that has been recently shown to attenuate the A beta-induced inflammatory response by blocking the ligation of A beta to RAGE. In this study, we further investigated the effect of FPS-ZM1 on the AGEs/RAGE interaction and downstream elevation of neuroinflammation and oxidative stress in primary microglia cells. The results suggested that FPS-ZM1 significantly suppressed AGEs-induced RAGE overexpression, RAGE-dependent microglial activation, nuclear translocation of nuclear factor kappaB p65 (NF-kappa B p65), and the expression of downstream inflammatory mediators such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), cyclooxygenase 2 (COX-2)/prostaglandin E2 (PGE2) and inducible nitric oxide synthase (iNOS)/nitric oxide (NO). Furthermore, FPS-ZM1 attenuated AGEs-stimulated NADPH oxidase (NOX) activation and reactive oxygen species (ROS) expression. Finally, FPS-ZM1 elevated the levels of transcription factors nuclear-factor (erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase-1 (HO-1), as well as decreased antioxidant capacity and increased production of oxidative species. Our results suggest that FPS-ZM1 may be neuroprotective through attenuating microglial activation, oxidative stress and inflammation by blocking RAGE.
关键词
GLYCATION END-PRODUCTS; ALZHEIMERS-DISEASE; NADPH OXIDASE; CORTICAL-NEURONS; CELL-DEATH; ENDPRODUCTS; EXPRESSION; CYTOKINES; PATHOLOGY; PATHOPHYSIOLOGY
基本信息
