Abstract
After spinal cord injury (SCI), macrophages infiltrate into the lesion and can adopt a wide spectrum of activation states. However, the pro-inflammatory, pathological macrophage activation state predominates and contributes to progressive neurodegeneration. Azithromycin (AZM), an FDA approved macrolide antibiotic, has been demonstrated to have immunomodulatory properties in a variety of inflammatory conditions. Indeed, we previously observed that post-SCI AZM treatment reduces pro-inflammatory macrophage activation. Further, a combined pre- and post-injury treatment paradigm improved functional recovery from SCI. Therefore, for the current study, we hypothesize that post-injury AZM treatment will improve recovery from SCI. To test this hypothesis, we examined the therapeutic potential of delayed AZM treatment on locomotor, sensory, and anatomical recovery. We administered AZM beginning 30-min, 3-h, or 24-h following contusion SCI in female mice, and then daily for 7 days. AZM administration beginning 30-min and 3-h post-injury improved locomotor recovery with increased stepping function relative to vehicle controls. Further, delaying treatment for 30-min after SCI significantly reduced lesion pathology. Initiating AZM treatment 24-h post-injury was not therapeutically effective. Regardless of the timing of the initial treatment, AZM did not statistically reduce the development of neuropathic pain (mechanical allodynia) nor increase neuron survival. Collectively, these results add to a growing body of evidence supporting AZM’s translational potential as a therapeutic agent for SCI and other neuroinflammatory conditions in which patients currently have very few options.
Highlights
Spinal cord injury (SCI) induces a complex heterogeneous inflammatory response largely mediated by resident microglia and infiltrating monocyte-derived macrophages
Three mice were excluded based upon a prior exclusion criteria for abnormal impactor parameters reported by the Infinite Horizons (IH) spinal cord injury (SCI) device and abnormally high functioning locomotor behavior at 1 dpi (BMS >3) indicative of incomplete injury (n = 1)
As described previously, initiating AZM treatment 30 min after SCI, followed by repeated daily doses for 7 days, mediates an immunomodulatory shift in macrophage phenotype resulting in the downregulation of markers associated with pro-inflammatory M1 macrophage activation and upregulation of anti-inflammatory M2 markers (Gensel et al, 2017)
Summary
Spinal cord injury (SCI) induces a complex heterogeneous inflammatory response largely mediated by resident microglia and infiltrating monocyte-derived macrophages. While these cells are capable of adopting a wide spectrum of beneficial and detrimental functions, the acute SCI microenvironment promotes pro-inflammatory macrophage activation (Kigerl et al, 2009). Pro-inflammatory macrophages and microglia are widely believed to be major contributors to the continued neurodegeneration and tissue loss observed following the initial mechanical SCI. Targeting macrophage activation acutely is, a promising therapeutic approach to improve recovery. To date there are no FDA approved drugs to target these pathways after SCI.
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