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.

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Acknowledgments

Our study received funding from the MINCyT-ECOS Program, A12S02; from the São Paulo Research Foundation (FAPESP) under Grant Agreements No. 2011/19670-0 (Thematic Project); 2013/08216-2 (Center for Research in Inflammatory Disease); from CNPq; and from the Program Investissements d’avenir “ANR-10-IAIHU-06” and the Translational Research Infrastructure for Biotherapies in Neurosciences ANR-11-INBS-0011-NeurATRIS. EDB and RRV are coordinators of Science without Borders-Special Visitor Research (CNPQ). FVSC received a fellowship from the Science Without Borders CNPq Program. BS and LA are recipients of a fellowship from the Bernardo Houssay Program, MINCyT-CONICET-CAMPUS FRANCE.

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Correspondence to Thiago M. Cunha or Rita Raisman-Vozari.

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Flávia V. Santa-Cecília and Benjamin Socias have contributed equally to this work.

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Santa-Cecília, F.V., Socias, B., Ouidja, M.O. et al. Doxycycline Suppresses Microglial Activation by Inhibiting the p38 MAPK and NF-kB Signaling Pathways. Neurotox Res 29, 447–459 (2016). https://doi.org/10.1007/s12640-015-9592-2

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Keywords

  • Parkinson’s disease
  • Doxycycline
  • Microglia
  • Cytokines