title: N-adamantyl-4-methylthiazol-2-amine suppresses lipopolysaccharide-induced brain inflammation by regulating NF-κB signaling in mice.
abstract: We report that N-adamantyl-4-methylthiazol-2-amine (KHG26693), a novel thiazole derivative, can prevent lipopolysaccharide (LPS)-induced brain inflammation in mice. In this LPS-induced model of brain inflammation, administration of KHG26693 effectively prevented increases in the levels of IL-1β, TNF-α, prostaglandin E2, malondialdehyde, and nitric oxide, and mitigated reductions in the levels of superoxide dismutase in the hippocampus. KHG26693 also prevented reductions in the levels of hippocampal brain-derived neurotrophic factors. Furthermore, pretreatment with KHG26693 prior to LPS treatment dramatically attenuated the elevation of inducible nitric oxide synthase and cyclooxygenase-2 protein levels. Moreover, pretreatment with KHG26693 significantly suppressed LPS-induced phosphorylation of NF-κB and IκBα through the inactivation of IKKβ. Additionally, KHG26693 caused the downregulation of LPS-induced cystathionine-b-synthase gene expression in the brain. Although the clinical relevance of our findings remains to be determined, our data suggest that KHG26693 might prevent neuronal cell injury via the reduction of inflammation and oxidative stress in the brain.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
authors.forename: Chang Hun
authors.initials: CH
authors.lastname: Cho
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
authors.forename: Jiae
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Molecular Cell Biology, Center for Molecular Medicine, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 440-746, Republic of Korea.
authors.forename: Jee-Yin
authors.initials: JY
authors.lastname: Ahn
authors.affiliation: Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul 136-791, Republic of Korea.
authors.forename: Hoh-Gyu
authors.initials: HG
authors.lastname: Hahn
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea. Electronic address: swcho@amc.seoul.kr.
authors.forename: Sung-Woo
authors.initials: SW
authors.lastname: Cho
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000704:Analysis of Variance; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004660:Encephalitis / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D008315:Malondialdehyde / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism; D011458:Prostaglandins E; D013482:Superoxide Dismutase / Q000378:metabolism; D013844:Thiazoles / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D019208:Brain-Derived Neurotrophic Factor; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D008565:Membrane Proteins; C000594799:N-adamantyl-4-methylthiazol-2-amine; D011458:Prostaglandins E; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D008315:Malondialdehyde; C077623:Ptgs2 protein, mouse; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496512:Ptgs1 protein, mouse; D013482:Superoxide Dismutase; D000218:Adamantane
keywords: COX-2; INOS; NF-κB; Neuroinflammation; Thiazole derivative