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.
Document Type
Article
Publication Date
5-2019
Digital Object Identifier (DOI)
https://doi.org/10.1111/cns.13092
Funding Information
This work was supported by the University of Kentucky Igniting Research Collaborations Pilot Grant Program to JCG and SGVL.
Related Content
Additional supporting information may be found online in the Supporting Information section at the end of the article.
Repository Citation
Zhang, Bei; Kopper, Timothy J.; Liu, Xiaodong; Cui, Zheng; Van Lanen, Steven G.; and Gensel, John C., "Macrolide Derivatives Reduce Proinflammatory Macrophage Activation and Macrophage‐Mediated Neurotoxicity" (2019). Physiology Faculty Publications. 152.
https://uknowledge.uky.edu/physiology_facpub/152
Supporting Information
Notes/Citation Information
Published in CNS Neuroscience & Therapeutics, v. 25, issue 5, p. 591-600.
© 2018 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.