Doxycycline's Effect on Ocular Angiogenesis: An In Vivo Analysis

Abstract

Purpose To determine the in vivo effect of doxycycline (doxy) on choroidal angiogenesis and pterygium growth by using a choroidal neovascular murine model (CNV), a directed in vivo angiogenesis assay (DIVAA) and a pterygium murine model. Design Experimental Study Participants 3 murine models were investigated with 4 mice minimum per group and 22 maximum per group. Methods Mice received water with or without doxycycline (Leiter's Pharmacy, San Jose, CA). For the CNV, the neovascular lesion volume was determined in choroid-retinal pigment epithelial (RPE) flat mounts using confocal microscopy seven days after laser induction. For DIVAA, silicone capsules containing 10,000 human pterygium epithelial cells were implanted in the flanks of mice subcutaneously. After eleven days, neovascularization (NV) was quantified using spectrofluorimetry after murine tail-vein injection of fluorescein isothiocyanate (FITC)-labeled dextran. A pterygium epithelial cell model was developed by injecting 10,000 human pterygium epithelial cells in the nasal subconjunctival space in athymic nude mice. Doxy was started on day six at 50 mg/kg/day; corneal lesions that resulted from the injections were compared at days six and fifteen. Main outcome measures Student's t-test was used to evaluate the data for the CNV and DIVAA models and histologic preparations were used to evaluate pterygia lesions. Results There was significantly less NV and lesion volume with doxy taken in drinking water versus plain water. With doxy treatment, the laser-induced CNV showed a maximal 66% decrease in choroidal blood vessel volume (p≤0.008) and the DIVAA showed a 30% reduction of blood vessel growth and migration (p<0.004). Histologic preparations demonstrated that pterygium cell lesions regressed when mice were administered doxy for 9 days. Conclusions Doxycycline significantly inhibited angiogenesis in three murine models. The most dramatic effect was found in the choroidal neovascularization model followed by the pterygia epithelial cell DIVAA model. The anterior segment pterygium model also showed regression histologically. This suggests that doxycycline may be successful as an adjunctive treatment for choroidal neovascularization and pterygia in humans; clinical trials would be necessary to determine if there is a benefit.

Doxycycline Inhibits Polarization of Macrophages to the Proangiogenic M2-type and Subsequent Neovascularization

“…Doxycycline has also been reported to dose-dependently reduce laser-induced CNV lesions in mice, as shown in this study as well (9,11,12), and preliminary observations suggest a beneficial effect of doxycycline in treating neovascular AMD. One study suggests that this effect may be mediated by increased FasL expression by RPE cells after doxycycline treatment (11).…”

“…4B). Importantly, several studies have shown that doxycycline dose-dependently inhibits CNV lesion formation in this model, demonstrating a potent antiangiogenic activity of doxycycline (9,11,12). Thus, we hypothesized that inhibition of M2-type macrophage polarization by doxycycline results in reduced proangiogenic cytokine expression and subsequent neovascularization in this model.…”

Corneal Neovascularization and Treatment: Review

“…tarafından yapılan bir çalışmada, oral doksisiklin verilmiş olan tavşanlarda lazer ile indüklenmiş korneal NV'nin gerilediği gösteril-miştir. 73 …”

“…Adenovirüs taşıyıcı ile sağlanan çVEGFR-1 ve çVEGFR-3 salınımındaki artışın hayvan korneasında NV'yi engellediği gösterilmiştir. 73 Nonviral yöntemler daha güvenlidir, ancak daha kısa etki süreleri vardır. Çift sarmallı small interfering RNA (siRNA), plazmidlerden daha küçük olup, subkonjonktival enjeksiyon sonrası korneal hücrelerin içine girerek mRNA'lara spesifik olarak bağlanır.…”

Are We There Yet? A Story About Cardiac Stem Cells

“…However, when tet-on system is used, DOX must be administered in the drinking water of mice, which can be rather expensive. In addition, DOX inhibits angiogenesis in mouse (Cox et al, 2010;Fainaru et al, 2008). In our lab, the DOX-treated murine hearts (1mg/ml in the drinking water) tend to be ~30% smaller compared to the age-matched untreated hearts (data not shown).…”