title: Minocycline mechanism of neuroprotection involves the Bcl-2 gene family in optic nerve transection.
abstract: The second-generation tetracycline, minocycline, has been shown to exhibit neuroprotective therapeutic benefits in many neurodegenerative diseases including experimental glaucoma and optic nerve transection (ONT). This study investigated the mechanism underlying minocycline neuroprotection in a model of ONT. ONT was applied unilaterally in 36 Wistar rat eyes. The rats were randomly divided into a minocycline (22 mg/kg/d) treatment group and a saline treatment group (control). Treatment (minocycline or saline) was given by intraperitoneal injections initiated 3 d before ONT and continued daily until the end of the experiment. The involvement of pro-apoptotic, pro-survival and inflammatory pathways was analyzed by quantitative Real-Time Polymerase Chain Reaction at 4 h and 3 d after the transection in both treatment groups. The involvement of Bcl-2 protein was evaluated by immunohistochemistry. We found that Minocycline significantly increased the expression of the antiapoptotic gene bcl-2 4 h after transection (n = 8, p = 0.008) and decreased the expression of Bax at the same time point (n = 8, p = 0.03). Tumor Necrosis Factor α (TNFα), Inhibitor of Apoptosis Protein (IAP1) and Gadd45α were significantly upregulated in the retinas of eyes with ONTs compared to control (n = 10 for each gene, p = 0.02, p = 0.03, p = 0.04, respectively) but this effect was unaffected by minocycline. This study further support that the mechanism underlying minocycline neuroprotection involves the Bcl-2 gene family, suggesting that minocycline has antiapoptotic properties that support its value as a promising neuroprotective drug.
authors.affiliation: From the Sam Rothberg Ophthalmic Molecular Biology Laboratory, Goldschleger Eye Institute, Sheba Medical Center , Tel-Hashomer, Sackler Faculty of Medicine, Tel-Aviv University , Israel.
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: Piven
authors.initials: P
authors.lastname: Ilia
mesh_terms: D000818:Animals; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects*; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D008911:Minocycline / Q000494:pharmacology* / Q000627:therapeutic use*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D009901:Optic Nerve Diseases / Q000188:drug therapy* / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012160:Retina / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018800:Thy-1 Antigens / Q000378:metabolism; D013997:Time Factors; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism; D000097642:GADD45 Proteins
chemical_list: D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D018797:Cell Cycle Proteins; D016207:Cytokines; D051034:Inhibitor of Apoptosis Proteins; D008911:Minocycline; D018696:Neuroprotective Agents; D052247:Nitric Oxide Synthase Type II; D009687:Nuclear Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D018800:Thy-1 Antigens; D051028:bcl-2-Associated X Protein; C499073:Gadd45a protein, rat; D000097642:GADD45 Proteins; C494836:Birc3 protein, rat
keywords: axotomy; minocycline; retinal ganglion cells