title: TUDCA: An Agonist of the Bile Acid Receptor GPBAR1/TGR5 With Anti-Inflammatory Effects in Microglial Cells.
abstract: Bile acids are steroid acids found in the bile of mammals. The bile acid conjugate tauroursodeoxycholic acid (TUDCA) is neuroprotective in different animal models of stroke and neurological diseases. We have previously shown that TUDCA has anti-inflammatory effects on glial cell cultures and in a mouse model of acute neuroinflammation. We show now that microglial cells (central nervous system resident macrophages) express the G protein-coupled bile acid receptor 1/Takeda G protein-coupled receptor 5 (GPBAR1/TGR5) in vivo and in vitro. TUDCA binding to GPBAR1/TGR5 caused an increase in intracellular cAMP levels in microglia that induced anti-inflammatory markers, while reducing pro-inflammatory ones. This anti-inflammatory effect of TUDCA was inhibited by small interference RNA for GPBAR1/TGR5 receptor, as well as by treatment with a protein kinase A (PKA) inhibitor. In the mouse model of acute neuroinflammation, treating the animals with TUDCA was clearly anti-inflammatory. TUDCA biased the microglial phenotype in vivo and in vitro toward the anti-inflammatory. The bile acid receptor GPBAR1/TGR5 could be a new therapeutic target for pathologies coursing with neuroinflammation and microglia activation, such as traumatic brain injuries, stroke, or neurodegenerative diseases. TUDCA and other GPBAR1/TGR5 agonists need to be further investigated, to determine their potential in attenuating the neuropathologies associated with microglia activation. J. Cell. Physiol. 232: 2231-2245, 2017. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Departamento de Neurobiología Funcional y de Sistemas Instituto Cajal (CSIC), Madrid, Spain.
authors.forename: Natalia
authors.initials: N
authors.lastname: Yanguas-Casás
authors.affiliation: Departamento de Neurobiología Funcional y de Sistemas Instituto Cajal (CSIC), Madrid, Spain.|Unidad de Neurología Experimental, Hospital Nacional de Parapléjicos (SESCAM), Toledo, Spain.
authors.forename: M Asunción
authors.initials: MA
authors.lastname: Barreda-Manso
authors.affiliation: Departamento de Neurobiología Funcional y de Sistemas Instituto Cajal (CSIC), Madrid, Spain.|Unidad de Neurología Experimental, Hospital Nacional de Parapléjicos (SESCAM), Toledo, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Nieto-Sampedro
authors.affiliation: Unidad de Neurología Experimental, Hospital Nacional de Parapléjicos (SESCAM), Toledo, Spain.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Romero-Ramírez
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004195:Disease Models, Animal; D004660:Encephalitis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016548:Prosencephalon / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology*; D013997:Time Factors; D014162:Transfection
chemical_list: D000893:Anti-Inflammatory Agents; C513561:Gpbar1 protein, mouse; C518268:Gpbar1 protein, rat; D018836:Inflammation Mediators; D018696:Neuroprotective Agents; D047428:Protein Kinase Inhibitors; D043562:Receptors, G-Protein-Coupled; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases