EVALUATION OF METALLOPROTEINASE INHIBITORS IN THE TREATMENT OF INTRAOCULAR ANGIOGENESIS AND PROLIFERATION

Abstract

Choroidal neovascularization (CNV) is a common feature of many ocular disorders, including ocular histoplasmosis, angioid streaks, and myopia and is the major cause of severe visual loss in patients with age related macular degeneration. Choroidal neovascularization shares many of the same pathological steps with other angiogenesis. The process is initiated by the release of angiogenic factors, which stimulate the endothelial cells to secrete proteolytic enzymes (MMPs). These enzymes facilitate endothelial cell migration to form new blood vessels. Thus, inhibition of the angiogenic process at this level might be an effective treatment modality for this devastating disease. AG3340 is a non-peptidic, small molecular weight, synthetic MMPI with selective inhibitory action ofMMP-2, MMP-9, MMP-3, and MT-MMPl.

Aim of the work: The aim of the work was to evaluate the efficacy and toxicity of AG3340, a potent matrix metalloproteinase inhibitor, as a preventive treatment in an animal model of choroidal neovascularization.

Materials and methods:

This experiment was carried out on 41 female Brown Norway rats. Choroidal neovascularization was induced in 35 rats bilaterally using diode laser photocoagulation. One day after laser, 7 f.LI of AG3340 was injected intravitreally in the right eye of the all-35 rats. The left eyes, served as controls, received equal amount of the drug vehicle. The other 6 rats (12 eyes) had no experimental procedure and were only used as a normal control for histological sections and toxicity study. All the rats were examined clinically using slit lamp and indirect ophthalmoscope one day, three days, five days, and then weekly after drug injection up to the time of sacrifice. Simultaneous fluorescein and indocyanine green angiography was performed using scanning laser ophthalmoscope (SLO) to all 35 rats at 2 and 4 weeks after drug injection. After 4 weeks, 17 rats were sacrificed and their eyes were processed for histological studies. Another set of FA and ICG was done to the remaining 18 rats at 8 weeks. Then, 9 of these 18 rats were sacrificed and their eyes were processed for histological studies.