fps-zm1 and fasudil

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.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Benzamides; Calcium-Binding Proteins; Cardiac Myosins; Cell Line, Transformed; Cell Polarity; Cyclooxygenase 2; Cytokines; Dose-Response Relationship, Drug; Glycation End Products, Advanced; Mice; Microfilament Proteins; Microglia; Myosin Light Chains; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Phosphorylation; Protein Kinase Inhibitors; Reactive Oxygen Species; rho-Associated Kinases; Signal Transduction