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H. Levkovitch-Verbin, R. Dardik, Y. Nisgav, S. Vander, S. Melamed; Minocycline Is Neuroprotective in Glaucoma and Optic Nerve Transection by Affecting Inflammatory Genes and the Bcl-2 Family Expression. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5505.
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Minocycline, a second-generation tetracycline, is significantly neuroprotective in glaucoma and other models of optic nerve injury. In this study we investigated the mechanism of minocycline's neuroprotective effect on the survival of retinal ganglion cells (RGCs) in glaucomatous and in post optic nerve-transected rat eyes.
Experimental glaucoma was induced in 24 Wistar rats using the translimbal photocoagulation laser model. Optic nerve transection was performed in an additional 36 rats. Rats were randomized to treatment with intraperitoneal injections of 22mg/ml/day minocycline or saline. The rats with glaucoma were sacrificed on days 4, 8 and 14 post injury and the rats with optic nerve transection were sacrificed after 4 hours and 3 days. Retinas were excised and immediately frozen for reverse transcriptase-polymerase chain reaction. The expression of inflammatory genes like TNFα, IL-18, and FAS ligand were investigated. In addition, apoptotic related genes including Bax, Bcl-2, Gadd45α (p53 pathway), nNOS and the anti-apoptotic gene (caspase inhibitor) IAP1 were investigated too. Minocycline-treated and saline-treated eyes were compared in a masked way.
In both minocycline-treated and saline-treated retinas we found significant overexpression of the apoptotic related genes Bax, Gadd45 and nNOS and the inflammatory genes TNFα, Fas ligand, and IL-18 8 days after the induction of glaucoma (for each gene p<0.05). There was also significant down-regulation of bcl-2. Interestingly, minocycline significantly inhibited the downregulation of the pro-survival gene bcl-2 and the overexpression of Bax(p=0.04). This effect was not significant at 4 days. Minocycline also decreased the overexpression of the inflammatory genes but not significantly. In optic nerve transection, minocycline significantly decreased the level of the pro-apoptotic gene Bax (p=0.03)and increased the level of the pro-survival gene bcl-2(p=0.007) 4 hours after injury. This effect disappears at 3 days.
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