Macrolide derivatives reduce proinflammatory macrophage activation and macrophage‐mediated neurotoxicity

Abstract

Summary 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.

Delayed Azithromycin Treatment Improves Recovery After Mouse Spinal Cord Injury

“…AZM administration significantly reduced the mean rostral-caudal lesion length when given 30 min after injury ( p = 0.03; Figures 5A,B); the 3-h delivery timepoint was not statistically significant ( p = 0.55; Figure 5). Given that pro-inflammatory macrophages are neurotoxic and that AZM limits this activation in vitro we sought to quantify whether post-SCI AZM treatment improved the number of surviving neurons at 28 dpi (Zhang et al, 2015, 2019). However, AZM treatment did not affect neuron sparing throughout the rostral-caudal extent of the lesion (ANOVA main effect of treatment p = 0.26; Figures 6A,B) or total neuron sparing according to area under the neuron by distance curve (ANOVA p = 0.98; Figure 6C).…”

“…More recently, we established that delaying treatment for 30 min post-injury substantially decreases markers associated with pro-inflammatory (M1) macrophage activation while significantly increasing anti-inflammatory (M2) macrophage markers (Gensel et al, 2017). Further, we recently found that AZM decreases neurotoxic, pro-inflammatory macrophage activation independent of its antibiotic properties (Zhang et al, 2019). Collectively, these findings highlight AZM as a promising SCI immunomodulatory therapeutic; however, the long-term effects of delayed AZM treatment are unknown.…”

Targeted analysis of six emerging derivatives or metabolites together with 25 common macrolides in milk using Quick, Easy, Cheap, Effective, Rugged and Safe extraction and ultra‐performance liquid chromatography quadrupole/electrostaticfield orbitrap mass spectrometry

“…The European Union stipulates the residue limits of erythromycin, spiramycin, tilmicosin, and tylosin in milk were 40,200,50, and 50 µg/kg, respectively [7]. Currently, a report that six derivatives or metabolites of macrolides had been found in domestic and industrial wastewater for the first time, and their concentration can up to 20.1 µg/L, which may indirectly pollute crops and foods [8]. Telithromycin, kirromycin, meleumycin, N-demethyl-roxithromycin, N-demethyl-clarithromycin, and erythromycin A oxime were included and their structures are shown in Fig.…”

“…However, the peak width of neo spiramycin I became broader with the addition of ammonium acetate, and there were also two chromatographic peaks existed in oleandomycin. Therefore, in this experiment, a series of pH (3,4,5,6,7,8,9, and 10) gradients were selected to optimize the peak shapes of neo spiramycin I and oleandomycin. The results showed that the peak shape and peak resolution of each target were relatively good at pH ≤ 3 and pH ≥ 9.…”

Immunization with neural‐derived peptides increases neurogenesis in rats with chronic spinal cord injury

“…A91 modulates the inflammatory and autoreactive response observed following SCI. These effects are carried out by inducing a Th2 response, thus promoting an M2 macrophage phenotype and providing a permissive microenvironment for functional recovery 14‐16 …”