title: Minocycline upregulates pro-survival genes and downregulates pro-apoptotic genes in experimental glaucoma.
abstract: OBJECTIVE
  Minocycline, a second-generation tetracycline with anti-inflammatory and anti-apoptotic properties, was reported to be neuroprotective in experimental glaucoma and optic nerve transection as well as in other neurodegenerative diseases. The purpose of this study was to investigate the mechanism underlying that neuroprotective effect in murine glaucoma.
  
  
  METHODS
  Elevated intraocular pressure was induced in 159 rats by the translimbal photocoagulation laser model. Minocycline 22 mg/kg or saline was injected intraperitoneally starting 3 days before the induction of glaucoma, and continued daily until the animals were sacrificed. The effect of minocycline on gene expression was evaluated using a quantitative polymerase chain reaction (PCR) array for apoptosis. The involvement of selected pro-apoptotic, pro-survival, and inflammatory genes was further analyzed by quantitative real-time PCR at multiple time points. Immunohistochemistry was used to study the effect of minocycline on microglial activation and to localize Bcl-2 changes.
  
  
  RESULTS
  Minocycline significantly increased the anti-apoptotic gene Bcl-2 expression at day 8 and day 14 after the induction of glaucoma (p = 0.04 and p = 0.03 respectively), and decreased IL-18 expression in the retina at day 14 and day 30 (p = 0.04 and p < 0.001 respectively). PCR arrays suggested that additional genes were affected by minocycline, including Tp53bp2, TRAF4, osteoprotegerin, caspase 1 and 4, and members of the tumor necrosis factor superfamily. Additionally, minocycline decreased the amount of activated microglia in glaucomatous eyes.
  
  
  CONCLUSIONS
  These results suggest that minocycline upregulates pro-survival genes and downregulates apoptotic genes, thus shifting the balance toward the anti-apoptotic side in experimental glaucoma.
authors.affiliation: Goldschleger Eye Institute, Sheba Medical Center, Tel-Hashomer, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel, halevko@hotmail.com.
authors.forename: Hani
authors.initials: H
authors.lastname: Levkovitch-Verbin
authors.forename: Yael
authors.initials: Y
authors.lastname: Waserzoog
authors.forename: Shelly
authors.initials: S
authors.lastname: Vander
authors.forename: Daria
authors.initials: D
authors.lastname: Makarovsky
authors.forename: Ilia
authors.initials: I
authors.lastname: Piven
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects*; D005901:Glaucoma / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D007274:Injections, Intraperitoneal; D020382:Interleukin-18 / Q000235:genetics / Q000378:metabolism; D017628:Microglia / Q000187:drug effects; D008911:Minocycline / Q000627:therapeutic use*; D009901:Optic Nerve Diseases / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D012165:Retinal Ganglion Cells / Q000378:metabolism; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism; D051025:bcl-Associated Death Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D051017:Apoptosis Regulatory Proteins; C494821:Bad protein, rat; D020382:Interleukin-18; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D008911:Minocycline