title: Azithromycin protects mice against ischemic stroke injury by promoting macrophage transition towards M2 phenotype.
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.
authors.affiliation: Section of Preclinical and Translational Pharmacology, Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy. Electronic address: amantea@unical.it.
authors.forename: Diana
authors.initials: D
authors.lastname: Amantea
authors.affiliation: Section of Preclinical and Translational Pharmacology, Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy.
authors.forename: Michelangelo
authors.initials: M
authors.lastname: Certo
authors.affiliation: Section of Preclinical and Translational Pharmacology, Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Petrelli
authors.affiliation: C. Mondino National Neurological Institute, Pavia, Italy; Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Tassorelli
authors.affiliation: C. Mondino National Neurological Institute, Pavia, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Micieli
authors.affiliation: Department of Health Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy.
authors.forename: Maria Tiziana
authors.initials: MT
authors.lastname: Corasaniti
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Puccetti
authors.affiliation: Department of Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Fallarino
authors.affiliation: Section of Preclinical and Translational Pharmacology, Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy.
authors.forename: Giacinto
authors.initials: G
authors.lastname: Bagetta
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017963:Azithromycin / Q000494:pharmacology / Q000627:therapeutic use*; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D020521:Stroke / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D000900:Anti-Bacterial Agents; D018696:Neuroprotective Agents; D017963:Azithromycin
keywords: Azithromycin; Drug repurposing; Immune system; Macrophage polarization; Stroke