Post-ischemic treatment with azithromycin protects ganglion cells against retinal ischemia/reperfusion injury in the rat

Mol Vis. 2017 Dec 11;23:911-921. eCollection 2017.

Abstract

Purpose: Retinal ischemic phenomena occur in several ocular diseases that share the degeneration and death of retinal ganglion cells (RGCs) as the final event. We tested the neuroprotective effect of azithromycin, a widely used semisynthetic macrolide antibiotic endowed with anti-inflammatory and immunomodulatory properties, in a model of retinal ischemic injury induced by transient elevation of intraocular pressure in the rat.

Methods: Retinal ischemia was induced in adult rats with transient elevation of intraocular pressure. RGCs were retrogradely labeled with Fluoro-Gold, and survival was assessed following a single dose of azithromycin given systemically at the end of the ischemia. The expression of death-associated proteins and extracellular signal-regulated kinase (ERK) activation was studied with western blotting. Expression and activity of matrix metalloproteinase-2 (MMP-2) and -9 were analyzed with gelatin zymography.

Results: Acute post-injury administration of azithromycin significantly prevented RGC death. This effect was accompanied by reduced calpain activity and prevention of Bcl-2-associated death promoter (Bad) upregulation. The observed neuroprotection was associated with a significant inhibition of MMP-2/-9 gelatinolytic activity and ERK1/2 phosphorylation.

Conclusions: Azithromycin provides neuroprotection by modifying the inflammatory state of the retina following ischemia/reperfusion injury suggesting potential for repurposing as a drug capable of limiting or preventing retinal neuronal damage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / therapeutic use*
  • Apoptosis / drug effects
  • Azithromycin / therapeutic use*
  • Blotting, Western
  • Calpain / metabolism
  • Cell Survival / drug effects
  • Cytoprotection
  • Disease Models, Animal*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Male
  • Matrix Metalloproteinase 2 / metabolism
  • Matrix Metalloproteinase 9 / metabolism
  • Neuroprotective Agents / therapeutic use
  • Phosphorylation
  • Rats
  • Rats, Wistar
  • Reperfusion Injury / metabolism
  • Reperfusion Injury / prevention & control*
  • Retinal Diseases / metabolism
  • Retinal Diseases / prevention & control*
  • Retinal Ganglion Cells / drug effects*
  • Retinal Ganglion Cells / metabolism
  • bcl-Associated Death Protein / metabolism

Substances

  • Anti-Bacterial Agents
  • Bad protein, rat
  • Neuroprotective Agents
  • bcl-Associated Death Protein
  • Azithromycin
  • Extracellular Signal-Regulated MAP Kinases
  • Calpain
  • Matrix Metalloproteinase 2
  • Mmp2 protein, rat
  • Matrix Metalloproteinase 9
  • Mmp9 protein, rat