title: Inhibition of AGEs/RAGE/Rho/ROCK pathway suppresses non-specific neuroinflammation by regulating BV2 microglial M1/M2 polarization through the NF-κB pathway.
abstract: The microglia-mediated neuroinflammation plays an important role in the pathogenesis of Alzheimer's disease (AD). Advanced glycation end products (AGEs)/receptor for advanced glycation end products (RAGE) or Rho/Rho kinase (ROCK) are both involved in the development of non-specific inflammation. However, there are few reports about their effects on neuroinflammation. Here, we explored the mechanism of AGEs/RAGE/Rho/ROCK pathway underlying the non-specific inflammation and microglial polarization in BV2 cells. AGEs could activate ROCK pathway in a concentration-dependent manner. ROCK inhibitor fasudil and RAGE-specific blocker FPS-ZM1 significantly inhibited AGEs-mediated activation of BV2 cells and induction of reactive oxygen species (ROS). FPS-ZM1 and fasudil exerted their anti-inflammatory effects by downregulating inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), NLRP3 and nuclear translocation of nuclear factor kappa B (NF-κB) p65. In addition, AGEs induced both M1 (CD16/32, M1 marker) and M2 (CD206, M2 marker) phenotype in BV2 cells. Fasudil and FPS-ZM1 led to a decreased M1 and increased M2 phenotype. Together, these results indicate that the AGEs/RAGE/Rho/ROCK pathway in BV2 cells could intensify the non-specific inflammation of AD, which will provide novel strategies for the development of anti-AD drugs.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China; International Joint Laboratory (SYSU-PolyU HK) of Novel Anti-dementia Drugs of Guangdong, Guangzhou 510006, China; National and Local United Engineering Lab of Drug ability and New Drugs Evaluation, Sun Yat-sen University, Guangzhou 510080, China; Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Jingkao
authors.initials: J
authors.lastname: Chen
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China; International Joint Laboratory (SYSU-PolyU HK) of Novel Anti-dementia Drugs of Guangdong, Guangzhou 510006, China; National and Local United Engineering Lab of Drug ability and New Drugs Evaluation, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Zhaowei
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Department of TCM, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China.
authors.forename: Minghua
authors.initials: M
authors.lastname: Jin
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China; International Joint Laboratory (SYSU-PolyU HK) of Novel Anti-dementia Drugs of Guangdong, Guangzhou 510006, China; National and Local United Engineering Lab of Drug ability and New Drugs Evaluation, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Yalin
authors.initials: Y
authors.lastname: Tu
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China; International Joint Laboratory (SYSU-PolyU HK) of Novel Anti-dementia Drugs of Guangdong, Guangzhou 510006, China; National and Local United Engineering Lab of Drug ability and New Drugs Evaluation, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Shengnan
authors.initials: S
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China; International Joint Laboratory (SYSU-PolyU HK) of Novel Anti-dementia Drugs of Guangdong, Guangzhou 510006, China; National and Local United Engineering Lab of Drug ability and New Drugs Evaluation, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Yang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China; International Joint Laboratory (SYSU-PolyU HK) of Novel Anti-dementia Drugs of Guangdong, Guangzhou 510006, China; National and Local United Engineering Lab of Drug ability and New Drugs Evaluation, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Qiuhe
authors.initials: Q
authors.lastname: Chen
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China; International Joint Laboratory (SYSU-PolyU HK) of Novel Anti-dementia Drugs of Guangdong, Guangzhou 510006, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhang
authors.affiliation: International Joint Laboratory (SYSU-PolyU HK) of Novel Anti-dementia Drugs of Guangdong, Guangzhou 510006, China; Department of Applied Biology and Chemical Technology, Hong Kong Polytechnic University, Hong Kong, China.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Han
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China; International Joint Laboratory (SYSU-PolyU HK) of Novel Anti-dementia Drugs of Guangdong, Guangzhou 510006, China; National and Local United Engineering Lab of Drug ability and New Drugs Evaluation, Sun Yat-sen University, Guangzhou 510080, China; Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China. Electronic address: pirb@mail.sysu.edu.cn.
authors.forename: Rongbiao
authors.initials: R
authors.lastname: Pi
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D024722:Cardiac Myosins / Q000378:metabolism; D002461:Cell Line, Transformed; D016764:Cell Polarity / Q000187:drug effects / Q000502:physiology*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism*; D017628:Microglia / Q000145:classification / Q000187:drug effects / Q000502:physiology*; D018994:Myosin Light Chains / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: C491049:Aif1 protein, mouse; D001549:Benzamides; D002135:Calcium-Binding Proteins; D016207:Cytokines; C572629:FPS-ZM1; D017127:Glycation End Products, Advanced; D008840:Microfilament Proteins; D018994:Myosin Light Chains; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; C107184:myosin light chain 2; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D051546:Cyclooxygenase 2; D054460:rho-Associated Kinases; D024722:Cardiac Myosins; C049347:fasudil
keywords: Advanced glycation end products; Alzheimer's disease; BV2 cells; Neuroinflammation; Rho kinase