title: Protosappanin A inhibits oxidative and nitrative stress via interfering the interaction of transmembrane protein CD14 with Toll-like receptor-4 in lipopolysaccharide-induced BV-2 microglia.
abstract: Oxidative and nitrative stresses have been established to play a pivotal role in neuroinflammation. During inflammation-mediated neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease, reactive oxygen species (ROS) and nitric oxide (NO) are produced by activated microglia, further inducing increased neuronal injury in the brain. Protosappanin A (PTA) is a bioactive compound isolated from a traditional Chinese medicine, Caesalpinia sappan L. (Lignum Sappan), showing immunosuppressive effects. However, the molecular mechanisms responsible for the anti-oxidative and nitrative activity of PTA have not been elucidated, particularly in central nervous system. In this study, we found that PTA significantly inhibited ROS and NO production by suppression of NADPH oxidase and inducible nitric oxide synthase (iNOS) activity on lipopolysaccharide (LPS)-stimulated BV-2 microglia. Moreover, PTA modulated IKK/IκB/NF-κB inflammation signal pathway to inhibit the activity and expressions of NADPH oxidase and iNOS. A further study indicated that PTA didn't inhibit LPS interaction with transmembrane protein CD14, which is a receptor for LPS binding. However, PTA interfered with the interaction of CD14 with Toll-like receptor (TLR4), an early cell event of IKK/IκB/NF-κB inflammation signal activation, resulting in a block on LPS translocation from CD14 to TLR4. Therefore, CD14/TLR4 interaction may be a potential drug target in neuroinflammation-related oxidative and nitrative stress. Taken together, these results suggest that PTA has anti-oxidative/nitrative activities on brain immune and neuroinflammation through regulation of CD14/TLR4-dependent IKK/IκB/NF-κB inflammation signal pathway.
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Ke-Wu
authors.initials: KW
authors.lastname: Zeng
authors.forename: Ming-Bo
authors.initials: MB
authors.lastname: Zhao
authors.forename: Zhi-Zhong
authors.initials: ZZ
authors.lastname: Ma
authors.forename: Yong
authors.initials: Y
authors.lastname: Jiang
authors.forename: Peng-Fei
authors.initials: PF
authors.lastname: Tu
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D018920:Coculture Techniques; D005786:Gene Expression Regulation; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000633:toxicity*; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D015394:Molecular Structure; D009249:NADP; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015538:Nitrosation; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010636:Phenols / Q000494:pharmacology*; D051381:Rats; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D016328:NF-kappa B; D010636:Phenols; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; C090723:protosappanin A; D009249:NADP; D052247:Nitric Oxide Synthase Type II; D051550:I-kappa B Kinase