title: A dopamine-alpha-lipoic acid hybridization compound and its acetylated form inhibit LPS-mediated inflammation.
abstract: In the present study, we synthesized and evaluated the anti-inflammatory effects of dopamine and alpha-lipoic acid (ALA) hybrid compounds, ALA-dopamine (HBU-199) and its acetylated derivative, ALA-acetyl dopamine (HBU-200), in BV2 microglia and RAW264.7 macrophage cells. HBU-199 and HBU-200 both significantly and dose-dependently inhibited LPS-induced nitric oxide (NO) productions, NO synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-6 and interleukin-1β mRNA expressions and iNOS and COX-2 protein expressions. Furthermore, HBU-199 and HBU-200 protected RAW264.7 cells from activation-induced cell death. However, at same concentrations, dopamine or ALA did not inhibit LPS-mediated production of inflammatory molecules and activation-induced cell death. HBU-199 and HBU-200 inhibited LPS-induced inhibition of inhibitory kappa-B-alpha (IκB-α) phosphorylation and nuclear factor-kappa B (NF-κB) activation. Furthermore, LPS-mediated DNA binding of p65 and p50 to the NF-κB binding site of the iNOS promoter was inhibited by HBU-199 and HBU-200, whereas dopamine and ALA did not inhibit LPS-induced NF-κB activation and IκB-α phosphorylation. Moreover, HBU-199 and HBU-200 suppressed LPS-stimulated phosphorylation of Akt, but not glycogen synthase kinase 3 beta. Overall, our data suggest that the ALA-dopamine hybrid compounds down-regulate inflammatory responses via inhibition of NF-κB and NF-κB-dependent gene expression, suggesting that it is a promising therapeutic agent for both systemic inflammatory diseases and inflammatory diseases of central nervous system.
authors.affiliation: Departmentof Physiology and Biophysics, College of Medicine, Inha University, Incheon, Republic of Korea.
authors.forename: Ji-Sun
authors.initials: JS
authors.lastname: Hwang
authors.affiliation: Departmentof Physiology and Biophysics, College of Medicine, Inha University, Incheon, Republic of Korea.
authors.forename: Jeong-Mi
authors.initials: JM
authors.lastname: An
authors.affiliation: Department of Chemistry, Inha University, Incheon, Republic of Korea.
authors.forename: Hyeongjin
authors.initials: H
authors.lastname: Cho
authors.affiliation: Department of Chemical & Biological Engineering, Hanbat National University, Daejeon, Republic of Korea.
authors.forename: Seung Hwan
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Chemical & Biological Engineering, Hanbat National University, Daejeon, Republic of Korea.
authors.forename: Jeong-Ho
authors.initials: JH
authors.lastname: Park
authors.affiliation: Departmentof Physiology and Biophysics, College of Medicine, Inha University, Incheon, Republic of Korea. Electronic address: iohan@inha.ac.kr.
authors.forename: Inn-Oc
authors.initials: IO
authors.lastname: Han
mesh_terms: D000107:Acetylation; D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004298:Dopamine / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D007249:Inflammation / Q000188:drug therapy; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D008063:Thioctic Acid / Q000737:chemistry*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D008070:Lipopolysaccharides; D016328:NF-kappa B; D009573:Nitrites; D012333:RNA, Messenger; D008063:Thioctic Acid; D051057:Proto-Oncogene Proteins c-akt; D004298:Dopamine
keywords: Alpha-lipoic acid; Dopamine; Inflammation