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S. Samtani, J. Amaral, M.D., S. P. Becerra Ph.D., R. N. Fariss Ph.D.; Doxycycline-Mediated Inhibition of Matrix Metalloproteinase Types 2 and 9, and Choroidal Neovascularization. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5415.
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Doxycycline is a broad spectrum antibiotic and has been shown to have certain anti-angiogenic properties. Matrix metalloproteinases (MMPs) are extracellular matrix endopeptidases that act as pro-angiogenic factors, degrading substrates such as collagens and gelatin. We investigated the effect of doxycycline on choroidal neovascularization (CNV), and its regulation of MMP-2 and MMP-9 and anti-angiogenic pigment epithelium derived factor (PEDF).
Doxycycline was orally administered to Brown Norway rats at 500, 50, 5, and 0.5 mg/kg/day, and non treated animals were used as controls. After 7 days of doxycycline treatment, experimental CNV was induced with laser. Seven days post-induction, animals were euthanized, blood samples collected and serum separated. Eyes were collected from experimental and control animals for confocal analysis. The RPE/choroid was flat-mounted, labeled with isolectin IB4 and CNV volumes were determined using confocal microscopy and VolocityTM software. Protein levels of MMP-2, MMP-9, and PEDF in serum were determined using Enzyme Linked ImmunoSorbent (ELISA) assays. MMP catalytic activity was determined in solution assays using a fluorogenic MMP peptide substrate, and in in situ assays using gelatin as substrate embedded in polyacrylamide zymography gels.
CNV volumes decreased logarithmically with doxycycline treatment. A dosage of 500 mg/kg/day showed a 70 % inhibition of CNV, compared to control animals. Doxycycline elevated the levels of PEDF in the serum. ELISA assays show that the pro- and active forms of MMP-2 and MMP-9 in serum did not change significantly with doxycycline. Doxycycline inhibited the activity of MMP-2 and MMP-9 in solution assays and zymography.
Doxycycline inhibited the progression of experimental CNV, elevated the serum levels of PEDF protein and inhibited the catalytic activity of MMP-2 and MMP-9 without affecting their protein levels. These results suggest a potential therapeutic role for doxycycline as an anti-angiogenic agent.
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