The variation of the phase-separation temperature (Td) was studied in lenses during formation of cataracts induced by a subcutaneous ihfection of sodium selenite. In normal control animals, the Tc decreased monotonically with increasing age. Approximately 2 days after administration of the selenite the T, decreased sharply to a minimum, and then at day 4 the Tc increased dramatically toward body temperature. Mature irreversible cataracts formed -6 days after injection of the selenite. (18)(19)(20)(21). The effect of WR-77913 on x-ray cataract was not entirely unexpected because the amino phosphorothioates are believed to behave as free-radical scavengers (17). The inhibition of the x-ray cataract could be explained as protection against oxidative damage to lens cells caused by free radicals as well as an effect on T, (17,22).It was not anticipated that WR-77913 would prevent cataract produced by selenite. In contrast to the x-ray cataract, T, was reported to decrease rather than increase in the selenite cataract (23). Selenite-induced opacity was associated with lenticular accumulation of calcium (24, 25) rather than free-radical formation. Oxidation of protein sulfhydryls was observed in the late stages of cataract formation (24,26,27), although oxidation of epithelial cells may be important at earlier stages of cataract formation. The differences between the x-ray and selenite mechanisms make the selenite model an interesting test for the effectiveness of WR-77913 as a PSI in vivo. In this report we show a remarkable observation: the chemical inhibition of abnormal changes in Tc, in vivo, is sufficient for the effective prevention of selenite cataract in rats. While it is possible that the properties of WR-77913 as a PSI may have nothing to do with its mode of action in preventing selenite cataract, we present direct evidence that reagents acting in vivo on a cytoplasmic phase separation have the potential to control and prevent formation of cataract. was administered by intraperitoneal injection at a dose of 820 mg/kg 15 min prior to the injection ofPBS only (control group B) or sodium selenite (group D). At various times, upl to 9 days after treatments, animals from each group were euthanized. Lenses were removed and placed in silicone oil in the temperature-controlled sample chamber (see Fig. 2). The T" was measured immediately.
MATERIALS AND METHODS