CQMUH-011, a novel adamantane sulfonamide compound,inhibits lipopolysaccharide- and D-galactosamine-induced fulminant hepatic failure in mice |
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Affiliation: | 1. Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing 400016, China;2. College of Pharmacology, Chongqing Medical University, Chongqing 400016, China;3. College of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China;1. Department of Pharmacology, Chongqing Medical University, Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing 400016, China;2. Department of Heptobiliary Surgery, 1st Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China;1. Neuroimmunology Laboratory, Department of Neurology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel;2. Department of Neurology and Laboratory of Neuroimmunology, Agnes-Ginges Center for Neurogenetics, Hadassah Medical Center, Ein-Karem, Jerusalem, Israel;3. Sackler''s Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel |
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Abstract: | CQMUH-011, a novel adamantane sulfonamide compound, was shown to suppress macrophage activation and proliferation in our previous study. However, it is unknown whether CQMUH-011 has anti-inflammatory and hepatoprotective properties. In this study, we investigated the potential effects and mechanisms of CQMUH-011 on lipopolysaccharide (LPS)-induced RAW264.7 cell activation in vitro and LPS- and D-galactosamine (D-GalN)-induced fulminant hepatic failure (FHF) in vivo. The results showed that in RAW264.7 cells challenged by LPS, CQMUH-011 inhibited cell proliferation and induced cell cycle arrest and apoptosis. Furthermore, CQMUH-011 reduced tumor necrosis factor (TNF)-α and interleukin (IL)-1β production and down-regulated the overexpression of toll-like receptor 4 (TLR4) and nuclear factor (NF)-κB induced by LPS in RAW264.7 cells. In vivo, CQMUH-011 reduced serum levels of aspartic aminotransferase and alanine transaminase and improved the mortality and hepatic pathological damage induced by LPS/D-GalN in mice. Moreover, CQMUH-011 significantly inhibited the serum levels of proinflammatory mediators, including TNF-α, IL-6, IL-1β, nitric oxide (NO), and prostaglandin E2 (PGE2), and down-regulated the protein expression of TLR4, p38 mitogen-activated protein kinases, NF-κB, NF-κB inhibitor α (IκBα), IκB kinase β (IKKβ), cyclooxygenase-2 (COX-2) and inducible NO synthases (iNOS) induced by LPS/D-GalN in mice. In conclusion, these results demonstrated that CQMUH-011 has a notable anti-inflammatory effect and protects mice from LPS/D-GalN-induced FHF and that the molecular mechanisms might be related to the inhibition of the TLR4/NF-κB signaling pathway activation, the subsequent decrease in proinflammatory mediator production, and the inhibition of macrophage activation. |
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