Poly(ADP-ribose) polymerase is not involved in the neuroprotection exerted by azithromycin against ischemic stroke in mice.
Repurposing azithromycin has recently emerged as a promising strategy for the acute treatment of ischemic stroke. The mechanism of neuroprotection depends on the ability of this macrolide to promote polarization of microglia/macrophages towards beneficial M2 phenotypes. The immunomodulatory and anti-inflammatory effects of azithromycin, well documented in chronic inflammatory airway diseases, have been ascribed to the inhibition of the transcription factors nuclear factor (NF)-κB and activator protein (AP)-1. Since these inflammatory transcription factors are positively regulated by poly(ADP-ribose) polymerase (PARP)-1, an enzyme actively involved in ischemic brain injury, we have investigated whether the neuroprotective properties of azithromycin in ischemic stroke involve upstream modulation of PARP-1. Administration of a single dose of this macrolide antibiotic upon reperfusion reduced, to a similar extent in wild type and PARP-1 knockout mice, infarct brain damage produced by transient occlusion of the middle cerebral artery. Moreover, we demonstrated the lack of effects of azithromycin on PARP-dependent death of HeLa cells, as well as on activity of purified PARP-1 and PARP-2. Thus, azithromycin protects mice against ischemic stroke injury through a mechanism independent of PARP activation.
Section of Preclinical and Translational Pharmacology, Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy.
Francesco
F
Petrelli
Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Italy.
Mirko
M
Muzzi
Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Italy.
Alberto
A
Chiarugi
Section of Preclinical and Translational Pharmacology, Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy.
Giacinto
G
Bagetta
Section of Preclinical and Translational Pharmacology, Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy. Electronic address: amantea@unical.it.
Diana
D
Amantea
D000818:Animals; D017963:Azithromycin / Q000494:pharmacology* / Q000627:therapeutic use; D002545:Brain Ischemia / Q000150:complications*; D016923:Cell Death / Q000187:drug effects; D055786:Gene Knockout Techniques; D056747:Immunomodulation / Q000187:drug effects; D008297:Male; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D020521:Stroke / Q000150:complications* / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology
D018696:Neuroprotective Agents; D017963:Azithromycin; D000071137:Poly (ADP-Ribose) Polymerase-1
Azithromycin; PARP; drug repurposing; ischemic stroke; neuroprotection