PMID- 30677254
OWN - NLM
STAT- MEDLINE
DCOM- 20200817
LR  - 20210109
IS  - 1755-5949 (Electronic)
IS  - 1755-5930 (Print)
IS  - 1755-5930 (Linking)
VI  - 25
IP  - 5
DP  - 2019 May
TI  - Macrolide derivatives reduce proinflammatory macrophage activation and 
      macrophage-mediated neurotoxicity.
PG  - 591-600
LID - 10.1111/cns.13092 [doi]
AB  - 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.
CI  - (c) 2018 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & 
      Sons Ltd.
FAU - Zhang, Bei
AU  - Zhang B
AD  - Department of Physiology, College of Medicine, Spinal Cord and Brain Injury 
      Research Center, University of Kentucky, Lexington, Kentucky.
FAU - Kopper, Timothy J
AU  - Kopper TJ
AD  - Department of Physiology, College of Medicine, Spinal Cord and Brain Injury 
      Research Center, University of Kentucky, Lexington, Kentucky.
FAU - Liu, Xiaodong
AU  - Liu X
AD  - Division of Bioorganic, Medicinal, & Computational Chemistry, College of 
      Pharmacy, University of Kentucky, Lexington, Kentucky.
FAU - Cui, Zheng
AU  - Cui Z
AD  - Division of Bioorganic, Medicinal, & Computational Chemistry, College of 
      Pharmacy, University of Kentucky, Lexington, Kentucky.
FAU - Van Lanen, Steven G
AU  - Van Lanen SG
AD  - Division of Bioorganic, Medicinal, & Computational Chemistry, College of 
      Pharmacy, University of Kentucky, Lexington, Kentucky.
FAU - Gensel, John C
AU  - Gensel JC
AUID- ORCID: 0000-0001-8980-108X
AD  - Department of Physiology, College of Medicine, Spinal Cord and Brain Injury 
      Research Center, University of Kentucky, Lexington, Kentucky.
LA  - eng
GR  - R01 NS091582/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190124
PL  - England
TA  - CNS Neurosci Ther
JT  - CNS neuroscience & therapeutics
JID - 101473265
RN  - 0 (Anti-Bacterial Agents)
RN  - 0 (Anti-Inflammatory Agents, Non-Steroidal)
RN  - 0 (IL10 protein, mouse)
RN  - 0 (Neuroprotective Agents)
RN  - 130068-27-8 (Interleukin-10)
RN  - 187348-17-0 (Interleukin-12)
RN  - 83905-01-5 (Azithromycin)
SB  - IM
MH  - Animals
MH  - Anti-Bacterial Agents/chemistry/pharmacology
MH  - Anti-Inflammatory Agents, Non-Steroidal/chemistry/pharmacology
MH  - Azithromycin/*analogs & derivatives/chemistry/pharmacology
MH  - Cell Line, Tumor
MH  - Inflammation/*drug therapy/immunology
MH  - Interleukin-10/metabolism
MH  - Interleukin-12/metabolism
MH  - Macrophage Activation/*drug effects
MH  - Macrophages/*drug effects/immunology
MH  - Mice, Inbred C57BL
MH  - Neurons/*drug effects/physiology
MH  - Neuroprotective Agents/*pharmacology
PMC - PMC6488883
OTO - NOTNLM
OT  - M2
OT  - brain
OT  - erythromycin
OT  - microglia
OT  - spinal cord injury
OT  - stroke
COIS- The authors declare no conflict of interest.
EDAT- 2019/01/25 06:00
MHDA- 2020/08/18 06:00
PMCR- 2019/01/24
CRDT- 2019/01/25 06:00
PHST- 2018/07/12 00:00 [received]
PHST- 2018/11/07 00:00 [revised]
PHST- 2018/11/15 00:00 [accepted]
PHST- 2019/01/25 06:00 [pubmed]
PHST- 2020/08/18 06:00 [medline]
PHST- 2019/01/25 06:00 [entrez]
PHST- 2019/01/24 00:00 [pmc-release]
AID - CNS13092 [pii]
AID - 10.1111/cns.13092 [doi]
PST - ppublish
SO  - CNS Neurosci Ther. 2019 May;25(5):591-600. doi: 10.1111/cns.13092. Epub 2019 Jan 
      24.