title: Doxycycline Suppresses Microglial Activation by Inhibiting the p38 MAPK and NF-kB Signaling Pathways.
abstract: In neurodegenerative diseases, the inflammatory response is mediated by activated glial cells, mainly microglia, which are the resident immune cells of the central nervous system. Activated microglial cells release proinflammatory mediators and neurotoxic factors that are suspected to cause or exacerbate these diseases. We recently demonstrated that doxycycline protects substantia nigra dopaminergic neurons in an animal model of Parkinson's disease. This effect was associated with a reduction of microglial cell activation, which suggests that doxycycline may operate primarily as an anti-inflammatory drug. In the present study, we assessed the anti-inflammatory potential of doxycycline using lipopolysaccharide (LPS)-activated primary microglial cells in culture as a model of neuroinflammation. Doxycycline attenuated the expression of key activation markers in LPS-treated microglial cultures in a concentration-dependent manner. More specifically, doxycycline treatment lowered the expression of the microglial activation marker IBA-1 as well as the production of ROS, NO, and proinflammatory cytokines (TNF-α and IL-1β). In primary microglial cells, we also found that doxycycline inhibits LPS-induced p38 MAP kinase phosphorylation and NF-kB nuclear translocation. The present results indicate that the effect of doxycycline on LPS-induced microglial activation probably occurs via the modulation of p38 MAP kinase and NF-kB signaling pathways. These results support the idea that doxycycline may be useful in preventing or slowing the progression of PD and other neurodegenerative diseases that exhibit altered glia function.
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, UM75, U1127, UMR 7225, Institut du Cerveau et de la Moelle Epinière, Paris, France.|Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo (USP), Av. Bandeirantes 3900, CEP 14049-900, Ribeirão Preto, SP, Brazil.
authors.forename: Flávia V
authors.initials: FV
authors.lastname: Santa-Cecília
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, UM75, U1127, UMR 7225, Institut du Cerveau et de la Moelle Epinière, Paris, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Socias
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, UM75, U1127, UMR 7225, Institut du Cerveau et de la Moelle Epinière, Paris, France.
authors.forename: Mohand O
authors.initials: MO
authors.lastname: Ouidja
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, UM75, U1127, UMR 7225, Institut du Cerveau et de la Moelle Epinière, Paris, France.
authors.forename: Julia E
authors.initials: JE
authors.lastname: Sepulveda-Diaz
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, UM75, U1127, UMR 7225, Institut du Cerveau et de la Moelle Epinière, Paris, France.|Instituto Superior de Investigaciones Biológicas, INSIBIO (CONICET-UNT) and Instituto de Química Biológica "Dr Bernabé Bloj", Facultad de Bioquímica, Química y Farmacia (UNT), San Miguel de Tucumán, Tucumán, Argentina.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Acuña
authors.affiliation: Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo (USP), Av. Bandeirantes 3900, CEP 14049-900, Ribeirão Preto, SP, Brazil.
authors.forename: Rangel L
authors.initials: RL
authors.lastname: Silva
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, UM75, U1127, UMR 7225, Institut du Cerveau et de la Moelle Epinière, Paris, France.
authors.forename: Patrick P
authors.initials: PP
authors.lastname: Michel
authors.affiliation: Department of Morphology, Physiology and Pathology, School of Odontology of Ribeirão Preto (FORP), University of São Paulo (USP), Ribeirão Preto, SP, Brazil.
authors.forename: Elaine
authors.initials: E
authors.lastname: Del-Bel
authors.affiliation: Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo (USP), Av. Bandeirantes 3900, CEP 14049-900, Ribeirão Preto, SP, Brazil. thicunha@fmrp.usp.br.
authors.forename: Thiago M
authors.identifier: http://orcid.org/0000-0002-7855-3700
authors.initials: TM
authors.lastname: Cunha
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, UM75, U1127, UMR 7225, Institut du Cerveau et de la Moelle Epinière, Paris, France. ritaraisman@gmail.com.
authors.forename: Rita
authors.initials: R
authors.lastname: Raisman-Vozari
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001921:Brain / Q000166:cytology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004318:Doxycycline / Q000494:pharmacology*; D004347:Drug Interactions; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D016177:Macrophage-1 Antigen / Q000378:metabolism; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000187:drug effects*; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D000090243:Nucleophosmin; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: C491049:Aif1 protein, mouse; D000900:Anti-Bacterial Agents; D002135:Calcium-Binding Proteins; D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; D008070:Lipopolysaccharides; D016177:Macrophage-1 Antigen; D008840:Microfilament Proteins; D016328:NF-kappa B; D009687:Nuclear Proteins; D017382:Reactive Oxygen Species; D000090243:Nucleophosmin; D009569:Nitric Oxide; D048051:p38 Mitogen-Activated Protein Kinases; D004318:Doxycycline
keywords: Cytokines; Doxycycline; Microglia; Parkinson’s disease