Inhibition of AGEs/RAGE/Rho/ROCK Pathway Suppresses Non-Specific Neuroinflammation by Regulating BV2 Microglial M1/M2 Polarization Through the NF-κB Pathway

J Neuroimmunol. 2017 Apr 15;305:108-114. doi: 10.1016/j.jneuroim.2017.02.010. Epub 2017 Feb 8.

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.

Keywords: Advanced glycation end products; Alzheimer's disease; BV2 cells; Neuroinflammation; Rho kinase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / analogs & derivatives
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / pharmacology
  • Animals
  • Benzamides / pharmacology
  • Calcium-Binding Proteins / metabolism*
  • Cardiac Myosins / metabolism
  • Cell Line, Transformed
  • Cell Polarity / drug effects
  • Cell Polarity / physiology*
  • Cyclooxygenase 2 / metabolism
  • Cytokines / metabolism
  • Dose-Response Relationship, Drug
  • Glycation End Products, Advanced / antagonists & inhibitors
  • Glycation End Products, Advanced / metabolism*
  • Glycation End Products, Advanced / pharmacology
  • Mice
  • Microfilament Proteins / metabolism*
  • Microglia / classification
  • Microglia / drug effects
  • Microglia / physiology*
  • Myosin Light Chains / metabolism
  • NF-kappa B / metabolism*
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
  • Phosphorylation / drug effects
  • Protein Kinase Inhibitors / pharmacology
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • rho-Associated Kinases / metabolism

Substances

  • Aif1 protein, mouse
  • Benzamides
  • Calcium-Binding Proteins
  • Cytokines
  • FPS-ZM1
  • Glycation End Products, Advanced
  • Microfilament Proteins
  • Myosin Light Chains
  • NF-kappa B
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Protein Kinase Inhibitors
  • Reactive Oxygen Species
  • myosin light chain 2
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
  • Cyclooxygenase 2
  • rho-Associated Kinases
  • Cardiac Myosins
  • fasudil