The novel N-methyl-d-aspartate receptor antagonist MN-08 ameliorates lipopolysaccharide-induced acute lung injury in mice.
Acute lung injury (ALI) is a clinically severe respiratory disorder, and effective therapy is urgently needed. MN-08, a novel synthetic N-methyl-d-aspartate receptor (NMDAR) antagonist, was investigated for its effect on lipopolysaccharide (LPS)-induced ALI. In vitro, the protective effect of MN-08 on inflammatory response, oxidative stress, and tight junctions (TJs) structure was explored in LPS-induced RAW 264.7 cells and A549 cells. MN-08 markedly decreased (p < 0.001) the levels of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and reactive oxygen species (ROS), whereas it moderately upregulated (p < 0.05) heme oxygenase (HO)-1 protein expression in LPS-induced RAW 264.7 cells. Moreover, MN-08 significantly inhibited (p < 0.001) cell apoptosis and improved (p < 0.001) protein expression of TJs in LPS-induced A549 cells. In vivo, the therapeutic effect of MN-08 was evaluated in the LPS-induced ALI model through intratracheal instillation in BALB/c mice. MN-08 administration dramatically attenuated (p < 0.001) pulmonary pathological changes and reduced (p < 0.001) the levels of glutamate, myeloperoxidase (MPO), malondialdehyde (MDA), and number of cells in BALF, whereas it increased (p < 0.05) superoxide dismutase (SOD) and glutathione (GSH) activities in ALI mice. Furthermore, MN-08 markedly blocked the mitogen-activated protein kinases (MAPKs)/nuclear translocation of nuclear factor-κB (NF-κB) signaling pathways in RAW 264.7 cells and lung tissues. These results indicate that MN-08 exhibits lung protection in an LPS-induced ALI model via anti-inflammatory and anti-oxidative activities.
['Jiang|Jinxin|J|', 'Jian|Qianqian|Q|', 'Jing|Mei|M|', 'Zhang|Zaijun|Z|', 'Zhang|Gaoxiao|G|', 'Shan|Luchen|L|', 'Yu|Pei|P|', 'Wang|Yuqiang|Y|', 'Xu|Lipeng|L|']
D000072283:A549 Cells D055371:Acute Lung Injury D000218:Adamantane D000818:Animals D000893:Anti-Inflammatory Agents D004195:Disease Models, Animal D006801:Humans D007249:Inflammation D053583:Interleukin-1beta D008070:Lipopolysaccharides D008297:Male D051379:Mice D008807:Mice, Inbred BALB C D016328:NF-kappa B D018384:Oxidative Stress D000067996:RAW 264.7 Cells D017382:Reactive Oxygen Species D016194:Receptors, N-Methyl-D-Aspartate D015398:Signal Transduction D019108:Tight Junctions D014409:Tumor Necrosis Factor-alpha
MN-08 Acute lung injury NMDAR Oxidative stress Tight junctions Inflammation