title: Similarities and differences between primary and secondary degeneration of the optic nerve and the effect of minocycline.
abstract: OBJECTIVE
  To investigate the mechanism of secondary degeneration of the optic nerve, and to evaluate the neuroprotective effect of minocycline in this process.
  
  
  METHODS
  A partial transection model that morphologically separates primary and secondary degeneration was applied unilaterally in 152 Wistar rat eyes. The involvement of pro-apoptotic, pro-survival and inflammatory pathways was analyzed by quantitative real-time PCR and immunohistochemistry at multiple time points. The neuroprotective effect of daily intraperitoneal injections of minocycline 22 mg/kg/day was evaluated at 7, 11 and 21 days post-injury. Retrograde labeling of retinal ganglion cells (RGCs) with fluorogold was via the superior colliculus, and surviving RGCs were counted using retinal whole mounts.
  
  
  RESULTS
  Both primary and secondary degeneration led to a significant up-regulation of the pro-apoptotic genes, GADD45α, ei24 and CDK2, and the pro-survival gene, IAP-1. These processes differed, however, in their reaction to minocycline. Minocycline protected RGC death from secondary degeneration at 11 days (6 ± 8% loss compared to 37 ± 7% in the saline-treated group, n = 15, P = 0.012), and at 21 days (42 ± 7% versus 64 ± 7% respectively, n = 15, P = 0.06) after partial transection. In contrast, its effect on primary degeneration was not significant.
  
  
  CONCLUSIONS
  While the genetic profile supported similarities between primary and secondary degeneration of the optic nerve, the specific effect of minocycline on secondary degeneration revealed a potential difference between the two. The mechanism underlying secondary degeneration, and its role in optic neuropathies such as glaucoma, awaits further studies.
authors.affiliation: Sam Rothberg Ophthalmic Molecular Biology Laboratory, Goldschleger Eye Institute, Sheba Medical Center, Tel-Hashomer, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Tel-Hashomer, 52621, Israel. halevko@hotmail.com
authors.forename: Hani
authors.initials: H
authors.lastname: Levkovitch-Verbin
authors.forename: Oriel
authors.initials: O
authors.lastname: Spierer
authors.forename: Shelly
authors.initials: S
authors.lastname: Vander
authors.forename: Rima
authors.initials: R
authors.lastname: Dardik
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000502:physiology; D007150:Immunohistochemistry; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D007274:Injections, Intraperitoneal; D008911:Minocycline / Q000494:pharmacology*; D009409:Nerve Crush; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D009901:Optic Nerve Diseases / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D051381:Rats; D017208:Rats, Wistar; D012165:Retinal Ganglion Cells / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000097642:GADD45 Proteins
chemical_list: D051017:Apoptosis Regulatory Proteins; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D018797:Cell Cycle Proteins; D051357:Cyclin-Dependent Kinase 2; D051034:Inhibitor of Apoptosis Proteins; D008911:Minocycline; D018696:Neuroprotective Agents; D009687:Nuclear Proteins; C499073:Gadd45a protein, rat; D000097642:GADD45 Proteins; C494836:Birc3 protein, rat