Macrolide derivatives reduce proinflammatory macrophage activation and macrophage-mediated neurotoxicity

Bei Zhang, Timothy J. Kopper, Xiaodong Liu, Zheng Cui, Steven G. Van Lanen, John C. Gensel

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

Introduction: Azithromycin (AZM) and other macrolide antibiotics are applied as immunomodulatory treatments for CNS disorders. The immunomodulatory and antibiotic properties of AZM are purportedly independent. Aims: To improve the efficacy and reduce antibiotic resistance risk of AZM-based therapies, we evaluated the immunomodulatory and neuroprotective properties of novel AZM derivatives. We semisynthetically prepared derivatives by altering sugar moieties established as important for inhibiting bacterial protein synthesis. Bone marrow-derived macrophages (BMDMs) were stimulated in vitro with proinflammatory, M1, stimuli (LPS + INF-gamma) with and without derivative costimulation. Pro- and anti-inflammatory cytokine production, IL-12 and IL-10, respectively, was quantified using ELISA. Neuron culture treatment with BMDM supernatant was used to assess derivative neuroprotective potential. Results: Azithromycin and some derivatives increased IL-10 and reduced IL-12 production of M1 macrophages. IL-10/IL-12 cytokine shifts closely correlated with the ability of AZM and derivatives to mitigate macrophage neurotoxicity. Conclusions: Sugar moieties that bind bacterial ribosomal complexes can be modified in a manner that retains AZM immunomodulation and neuroprotection. Since the effects of BMDMs in vitro are predictive of CNS macrophage responses, our results open new therapeutic avenues for managing maladaptive CNS inflammation and support utilization of IL-10/12 cytokine profiles as indicators of macrophage polarization and neurotoxicity.

Original languageEnglish
Pages (from-to)591-600
Number of pages10
JournalCNS Neuroscience and Therapeutics
Volume25
Issue number5
DOIs
StatePublished - May 2019

Bibliographical note

Funding Information:
This work was supported by the University of Kentucky Igniting Research Collaborations Pilot Grant Program to JCG and SGVL.

Publisher Copyright:
© 2018 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.

Keywords

  • M2
  • brain
  • erythromycin
  • microglia
  • spinal cord injury
  • stroke

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health
  • Physiology (medical)
  • Pharmacology (medical)

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