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We reported that in utero galactose-induced cataracts could be inhibited if aldose reductase inhibitors (ARIs) were included in the galactose diet of pregnant rats. These studies involved morphological and cytochemical approaches. We undertook this investigation to evaluate the effects of ARIs in preventing the formation, accumulation and depletion of dulcitol in lenses of in utero galactose exposed neonates and in mothers during and following pregnancy. Sprague Dawley rats were fed Purina Rat Chow with 50% galactose either with or without 15mg Sorbinil or 1mg Eisai compound E-0722/day/Kg body weight during and following pregnancy. The lenses of neonates and mothers were processed to determine dulcitol concentrations. At parturition there was a significant amount of dulcitol in the lenses of pups and their mothers, which reduced rapidly in the lenses of pups regardless of the diet fed to the nursing mother. While galactose had a cross-placental but not a milk-mediated effect, the ARIs had both cross-placental and milk-mediated effects on dulcitol accumulation and depletion, respectively. The galactose feeding of mothers post-parturition maintained the high lenticular dulcitol concentration and the absence of galactose led to a reduction in lenticular dulcitol. The correlation between dulcitol accumulation and cataract development is discussed.

We have shown that galactose cataract development is delayed or inhibited with the administration of aldose reductase inhibitors (ARIs). Dulcitol forms and accumulates in the lens of rats fed galactose. We undertook investigations to study the effectiveness of ARIs in preventing the formation and accumulation of dulcitol in the lens. Young Sprague Dawley rats were fed Purina Rat Chow with 50% galactose either with or without 15 mg sorbinil, 0.15, 0.5, or 1.0 mg E-0722/day/Kg body weight. At desired intervals following the initiation of diets, the lenses were processed for the determination of galactose and dulcitol levels. The lenticular dulcitol increased significantly in all animals fed galactose reaching a maximum level by approximately 15 days with comparatively lower levels in the groups fed ARIs with galactose; this increase was dose dependent in the groups fed E-0722. There was a subsequent, rapid drop in lenticular dulcitol by 18 days in all dietary groups. Interestingly, a second peak of increased lenticular dulcitol was observed in all groups. The correlation between dulcitol accumulation and cataract development is discussed.

Lens ultrastructure and Na- K-ATPase activity in the lenses of rats fed galactose and a galactose + sorbinil diet (aldose reductase inhibitor) were studied. Lenses of rats on the galactose diet exhibited development of peripheral opacity within 3-4 days. This opacity progressed with the continuation of the galactose feeding, and by 20 days mature cataracts were observed in these animals. The formation of vacuoles, cysts, membrane disruption in the epithelium and fibers, and swelling of fibers accompanied the development of opacity. With the progression of opacity there was a considerable drop in lens Na- K-ATPase activity in the galactose-fed animals. However, the lenses of rats that were treated with sorbinil did not show any of the alterations in the ultrastructure of the epithelium and fibers that accompany galactose cataractogenesis. The level of Na-K-ATPase activity in the sorbinil-treated animals was similar to that found in lenses from the laboratory chow-fed group of rats. These observations further substantiate the role of aldose reductase in sugar-cataract development.

We have demonstrated an increase in activity of arylsulfatase A and B during galactose induced cataract development in rats. Our recent investigation shows that acid phosphatase activity, which increases substantially during galactose cataract development in rats, could be contained to near normal level if Sorbinil, an aldose reductase inhibitor, was fed along with galactose to the rat. We have observed that the activity of other lysosomal enzymes, arylsulfatase A and/or B, also increases during galactose cataractogenesis. In the present report, we provide information with regards to the effect of Sorbinil on the activity of these enzymes during cataractogenesis. A modified Hopsu-Havu and Helminen method (1974) with p-nitrocatecholsulfate as substrate was used for localization of both arylsulfatase A and B; and the method of Hara et al. (1979) was utilized to obtain quantitative data on the level of arylsulfatase A and B activity. Ultrastructural cytochemistry shows that arylsulfatase activity in all lenses was primarily localized in epithelial cells in lysosomes with very little or no activity in cortical fibers. The number of arylsulfatase positive lysosomes and the activity level of these enzymes increased with the progression of cataract development. Galactose induced damage to lens morphology and increase in activity of arylsulfatase A and B was inhibited by inclusion of 50mg/Kg (diet) Sorbinil in the galactose containing cataractogenic diet. However, Sorbinil had no significant effect on the enzyme activity following the establishment of mature cataracts.

Our recent investigations have shown that the Eisai compound, E-0722, (2R-4S-6-fluoro-1-2-methylspirochroman 4,4'-imidazolidine 2,5'-dione) is a more potent aldose reductase inhibitor than Sorbinil (D-6-fluorospirochroman 4,4'-imidazolidine 2,5'-dione). In the previous studies these aldose reductase inhibitors were added to the 50% galactose diet fed to rats to determine their effect on galactose-induced alterations in the lens and the development of cataract. In this report we present our results on the effect of prefeeding the aldose reductase inhibitor, E-0722, on the alterations in rat lens following subsequent feeding of galactose. For this study, young Sprague Dawley rats were prefed either rat chow or rat chow plus 50% galactose containing 1mg/day/Kg body weight of E-0722 for 1 or 2 weeks. After this dietary regimen, the animals were transferred to diets containing 50% galactose for different periods. For controls, rats were fed either rat chow or 50% galactose without the prefeeding of E-0722. Our results obtained through gross observation of the lenses, light microscopic studies of lens sections and assay of Na+-K+-ATPase (NPPase) activity show that the prefeeding of E-0722 prior to galactose feeding delays galactose-induced alterations and the development of mature cataract.