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S. Kachi, N. Umeda, H. Akiyama, M. Kachi, S. F. Hackett, A. P. Mazar, P. A. Campochiaro; ATN-224.021 and ATN-427.021 Suppress Choroidal Neovascularization. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3426.
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ATN-224.021 (ammonium tetrathiomolybdate) and its tungstate analog, ATN-427.021 (ammonium tetrathiotungstate) are copper chelators that have several effects in vitro including inhibition of superoxide dysmutase 1, inhibition of NF-ΚB, and down-regulation of several pro-angiogenic growth factors. We investigated the effects of ATN-224.021 and ATN-427.02 in a murine model of laser-induced choroidal neovascularization (CNV).
Five week old female C57BL/6 mice had rupture of Bruch’s membrane at 3 locations in each eye and were treated orally by gavage every morning with 50 mg/kg of ATN-224.021 (14 mice), 100 mg/kg of ATN-427.021 (10 mice) or phosphate buffered saline (PBS; 10 mice). After 2 weeks, 4 of the mice treated with ATN-224.021 were euthanized and the retinas and RPE/choroid was dissected to measure the concentration of the molybdenum. The remainder of the mice were perfused with fluorescein-labeled dextran and the area of CNV at Bruch’s membrane rupture sites was measured by image analysis.
Compared to the average area of CNV in the PBS control group (6.176 ± 0.567 mm2x10-3) the area of CNV was significantly smaller in mice treated with ATN-427.021 (3.563 ± 0.356 mm2x10-3 , p=0.002 by linear mixed model) and in mice treated with ATN-224.021 (3.083 ± 0.356 mm2x10-3, p=0.0001). In mice treated with ATN-224.021, the concentration of molybdenum in the retina was 0.3503 ± 0.0990 ng/mg protein and 12.3417 ± 2.5627 ng/mg protein in RPE/choroid and was below the level of detection in the ocular tissues of control mice.
ATN-224.021 and ATN-427.021 suppress CNV. Additional work is needed to determine which of their in vitro activities are responsible for the inhibition of CNV.
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