title: Tauroursodeoxycholic acid reduces glial cell activation in an animal model of acute neuroinflammation.
abstract: BACKGROUND
  Bile acids are steroid acids found predominantly in the bile of mammals. The bile acid conjugate tauroursodeoxycholic acid (TUDCA) is a neuroprotective agent in different animal models of stroke and neurological diseases. However, the anti-inflammatory properties of TUDCA in the central nervous system (CNS) remain unknown.
  
  
  METHODS
  The acute neuroinflammation model of intracerebroventricular (icv) injection with bacterial lipopolysaccharide (LPS) in C57BL/6 adult mice was used herein. Immunoreactivity against Iba-1, GFAP, and VCAM-1 was measured in coronal sections in the mice hippocampus. Primary cultures of microglial cells and astrocytes were obtained from neonatal Wistar rats. Glial cells were treated with proinflammatory stimuli to determine the effect of TUDCA on nitrite production and activation of inducible enzyme nitric oxide synthase (iNOS) and NFκB luciferase reporters. We studied the effect of TUDCA on transcriptional induction of iNOS and monocyte chemotactic protein-1 (MCP-1) mRNA as well as induction of protein expression and phosphorylation of different proteins from the NFκB pathway.
  
  
  RESULTS
  TUDCA specifically reduces microglial reactivity in the hippocampus of mice treated by icv injection of LPS. TUDCA treatment reduced the production of nitrites by microglial cells and astrocytes induced by proinflammatory stimuli that led to transcriptional and translational diminution of the iNOS. This effect might be due to inhibition of the NFκB pathway, activated by proinflammatory stimuli. TUDCA decreased in vitro microglial migration induced by both IFN-γ and astrocytes treated with LPS plus IFN-γ. TUDCA inhibition of MCP-1 expression induced by proinflammatory stimuli could be in part responsible for this effect. VCAM-1 inmunoreactivity in the hippocampus of animals treated by icv LPS was reduced by TUDCA treatment, compared to animals treated with LPS alone.
  
  
  CONCLUSIONS
  We show a triple anti-inflammatory effect of TUDCA on glial cells: i) reduced glial cell activation, ii) reduced microglial cell migratory capacity, and iii) reduced expression of chemoattractants (e.g., MCP-1) and vascular adhesion proteins (e.g., VCAM-1) required for microglial migration and blood monocyte invasion to the CNS inflammation site. Our results present a novel TUDCA anti-inflammatory mechanism, with therapeutic implications for inflammatory CNS diseases.
authors.forename: Natalia
authors.initials: N
authors.lastname: Yanguas-Casás
authors.forename: M Asunción
authors.initials: MA
authors.lastname: Barreda-Manso
authors.affiliation: Laboratorio de Plasticidad Neural, Instituto Cajal (CSIC), Avenida Doctor Arce 37, 28002 Madrid, Spain. mns@cajal.csic.es.
authors.forename: Manuel
authors.initials: M
authors.lastname: Nieto-Sampedro
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Romero-Ramírez
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002756:Cholagogues and Choleretics / Q000494:pharmacology*; D004195:Disease Models, Animal; D004660:Encephalitis / Q000139:chemically induced / Q000473:pathology*; D005786:Gene Expression Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000473:pathology*; D007276:Injections, Intraventricular; D008070:Lipopolysaccharides / Q000633:toxicity; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects*; D009573:Nitrites / Q000378:metabolism; D017208:Rats, Wistar; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D002756:Cholagogues and Choleretics; D005904:Glial Fibrillary Acidic Protein; D008070:Lipopolysaccharides; D008840:Microfilament Proteins; D009573:Nitrites; D019010:Vascular Cell Adhesion Molecule-1; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine