Azithromycin protects mice against ischemic stroke injury by promoting macrophage transition towards M2 phenotype

Exp Neurol. 2016 Jan:275 Pt 1:116-25. doi: 10.1016/j.expneurol.2015.10.012. Epub 2015 Oct 27.

Abstract

To develop novel and effective treatments for ischemic stroke, we investigated the neuroprotective effects of the macrolide antibiotic azithromycin in a mouse model system of transient middle cerebral artery occlusion. Intraperitoneal administration of azithromycin significantly reduced blood-brain barrier damage and cerebral infiltration of myeloid cells, including neutrophils and inflammatory macrophages. These effects resulted in a dose-dependent reduction of cerebral ischemic damage, and in a remarkable amelioration of neurological deficits up to 7 days after the insult. Neuroprotection was associated with increased arginase activity in peritoneal exudate cells, which was followed by the detection of Ym1- and arginase I-immunopositive M2 macrophages in the ischemic area at 24-48 h of reperfusion. Pharmacological inhibition of peritoneal arginase activity counteracted azithromycin-induced neuroprotection, pointing to a major role for drug-induced polarization of migratory macrophages towards a protective, non-inflammatory M2 phenotype.

Keywords: Azithromycin; Drug repurposing; Immune system; Macrophage polarization; Stroke.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Anti-Bacterial Agents / therapeutic use*
  • Azithromycin / pharmacology
  • Azithromycin / therapeutic use*
  • Brain Ischemia / drug therapy*
  • Brain Ischemia / metabolism
  • Brain Ischemia / pathology
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Macrophage Activation / drug effects*
  • Macrophages / drug effects*
  • Macrophages / metabolism
  • Macrophages / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neuroprotective Agents / pharmacology
  • Neuroprotective Agents / therapeutic use*
  • Stroke / drug therapy*
  • Stroke / metabolism
  • Stroke / pathology

Substances

  • Anti-Bacterial Agents
  • Neuroprotective Agents
  • Azithromycin