title: Sildenafil attenuates LPS-induced pro-inflammatory responses through down-regulation of intracellular ROS-related MAPK/NF-κB signaling pathways in N9 microglia.
abstract: Excessive activation of microglial cells has been implicated in various neuroinflammation. The present study showed that sildenafil, a PDE5 inhibitor, significantly suppressed NO, interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α) production induced by LPS in microglial cells through decreasing the protein and/or mRNA expressions of inducible NO synthase (iNOS), IL-1β and TNF-α in a concentration-dependent manner. Sildenafil also blocked IκBα phosphorylation and degradation, inhibited the phosphorylation of mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinases 1 and 2 (ERK1/2), p38 MAPK, and c-Jun N-terminal kinase (JNK). Moreover, the increase of the expression of gp91phox, a critical and catalytic subunit of NADPH oxidase, and the levels of intracellular reactive oxygen species (iROS) induced by LPS were markedly inhibited by sildenafil. In summary, these data suggest that sildenafil exerts its in vitro anti-inflammatory effect in LPS-activated N9 microglial cells by blocking nuclear factor-κB (NF-κB) and MAPKs activation, which may be partly due to its potent down-regulation of the NADPH-derived iROS production.
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, 110016 Shenyang, PR China.
authors.forename: Siqi
authors.initials: S
authors.lastname: Zhao
authors.forename: Lijia
authors.initials: L
authors.lastname: Zhang
authors.forename: Guoning
authors.initials: G
authors.lastname: Lian
authors.forename: Xiaoxiao
authors.initials: X
authors.lastname: Wang
authors.forename: Haotian
authors.initials: H
authors.lastname: Zhang
authors.forename: Xuechun
authors.initials: X
authors.lastname: Yao
authors.forename: Jingyu
authors.initials: J
authors.lastname: Yang
authors.forename: Chunfu
authors.initials: C
authors.lastname: Wu
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D018929:Cell Culture Techniques; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D051550:I-kappa B Kinase / Q000378:metabolism; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D020928:Mitogen-Activated Protein Kinases / Q000096:biosynthesis*; D016328:NF-kappa B / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology*; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology
chemical_list: D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D016328:NF-kappa B; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D017382:Reactive Oxygen Species; D013450:Sulfones; D014409:Tumor Necrosis Factor-alpha; D000068677:Sildenafil Citrate; D052247:Nitric Oxide Synthase Type II; D051550:I-kappa B Kinase; D020928:Mitogen-Activated Protein Kinases