title: Anti-Neuroinflammatory Effect of MC13, a Novel Coumarin Compound From Condiment Murraya, Through Inhibiting Lipopolysaccharide-Induced TRAF6-TAK1-NF-κB, P38/ERK MAPKS and Jak2-Stat1/Stat3 Pathways.
abstract: MC13 is a novel coumarin compound found in Murraya, an economic crop whose leaves are widely used as condiment (curry) in cuisine. The aims of the present study were to investigate the neuroprotective effects of MC13 on microglia-mediated inflammatory injury model as well as potential molecular mechanism. Cell viability and apoptosis assay demonstrated that MC13 was not toxic to neurons and significantly protected neurons from microglia-mediated inflammatory injury upon lipopolysaccharide (LPS) stimulation. Results showed that MC13 markedly inhibited LPS-induced production of various inflammatory mediators, including nitrite oxide (Griess method), TNF-α and IL-6 (ELISA assay) in a concentration-dependent manner. Mechanism study showed that MC13 could suppress the activation of NF-κB, which was the central regulator for inflammatory response, and also decreased the interaction of TGF-β-activated kinase 1 (TAK1)-binding protein (TAB2) with TAK1 and TNF receptor associated factor (TRAF6), leading to the decreased phosphorylation levels of NF-κB upstream regulators such as IκB and IκB kinase (IKK). MC13 also significantly down-regulated the phosphorylation levels of ERK and p38 MAPKs, which played key roles in microglia-mediated inflammatory response. Furthermore, MC13 inhibited Jak2-dependent Stat1/3 signaling pathway activation by blocking Jak2 phosphorylation, Stat1/3 phosphorylation, and nuclear translocation. Taken together, our results demonstrated that MC13 protected neurons from microglia-mediated neuroinflammatory injury by inhibiting TRAF6-TAK1-NF-κB, p38/ERK MAPKs, and Jak2-Stat1/3 pathways. Finally, MC13 might interact with LPS and interfere LPS-binding to cell membrane surface. These findings suggested that coumarin might act as a potential medicinal agent for treating neuroinflammation as well as inflammation-related neurodegenerative diseases.
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
authors: Ke-Wu
authors: KW
authors: Zeng
authors: Research Studio of Integration of Traditional and Western Medicine, First Hospital, Peking University, Beijing, 100034, China.
authors: Qian
authors: Q
authors: Yu
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
authors: Li-Xi
authors: LX
authors: Liao
authors: Research Studio of Integration of Traditional and Western Medicine, First Hospital, Peking University, Beijing, 100034, China.
authors: Fang-Jiao
authors: FJ
authors: Song
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
authors: Hai-Ning
authors: HN
authors: Lv
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
authors: Yong
authors: Y
authors: Jiang
authors: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China.
authors: Peng-Fei
authors: PF
authors: Tu
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D017209:Apoptosis; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003374:Coumarins / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D008070:Lipopolysaccharides; D051379:Mice; D017628:Microglia / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D032101:Murraya / Q000737:chemistry*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000893:Anti-Inflammatory Agents; D003374:Coumarins; D008070:Lipopolysaccharides; D018696:Neuroprotective Agents; D010936:Plant Extracts
keywords: COUMARIN; JAK/STAT; MAPK; MICROGLIA; NEUROINFLAMMATION; NF-κB