Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0086543 (cataract)
 29,165 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two new potent aldose reductase inhibitors, AL-1567 (DL-spiro(2-fluoro-9H-fluoren-9,4'-imidazolidine)-2',5'-dione) and AL-1576 (spiro-(2,7-difluoro-9H-fluoren-9,4'-imidazolidine)2',5'-dione), have been characterized with respect to in vitro activity toward rat lens and human placental aldose reductase and in vivo activity in uncontrolled, severely diabetic rats dosed acutely with the compounds. The IC50 values for inhibition of rat lens aldose reductase are 2.7 X 10(-8) mol/L for AL-1567 and 8.5 X 10(-9) mol/L for AL-1576; very similar IC50 values were measured for each compound with the human placental enzyme. When the compounds were administered orally once per day to 3-week diabetic rats for a period of eight days, the ED50 values for normalization of lens sorbitol levels were 0.60 mg/kg for AL-1567 and 0.05 mg/kg for AL-1576, and for normalization of sciatic nerve sorbitol levels; 0.22 mg/kg for AL-1567 and 0.04 mg/kg for AL-1576. Compared with published data on other aldose reductase inhibitors evaluated in very similar diabetic rat models, both compounds have unusually high activity in lens, and AL-1576 appears to be the most active such compound in both lens and sciatic nerve reported thus far. The evidence linking increased sorbitol pathway activity to diabetic complications, such as cataract and neuropathy in animal models, suggests that aldose reductase inhibitors will be useful therapeutic agents in human diabetics.
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PMID:Effects of two new aldose reductase inhibitors, AL-1567 and AL-1576, in diabetic rats. 310 57

The effect of an aldose reductase inhibitor, AL-1576, on the development of UV-B and X-ray-induced cataract was studied with 100 female Brown-Norway rats. Histological studies were made with 32 eyes. A new histological procedure enabled detailed information on UV or X-ray-induced impairment on the lens, as well as on the potential efficiency of anticataract drugs. No definite effect of the aldose reductase inhibitor, AL-1576, on the development of UV or X-ray-induced cataract could be found. It may be concluded that AL-1576 cannot prevent damage caused by irradiation, like that of other oxidative influences. Disadvantageous effects of AL-1576 on the lens could be excluded.
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PMID:Effect of an aldose reductase inhibitor, AL-1576, on the development of UV-B and X-ray cataract. 314 4

Accumulation of sorbitol or galactitol and depletion of myo-inositol in hyperglycemic conditions such as diabetes and galactosemia involve the activity of aldose reductase and are implicated in hyperglycemia-induced complications such as cataract and neuropathy. A high-performance liquid chromatographic method has been developed for the measurement of polyols in the lens and sciatic nerve of rats. This method comprises polyol extraction from tissues, lyophilization of extracts, derivatization of polyols by the reaction with phenylisocyanate, and HPLC of derivatives with detection at 240 nm. The time needed for each run is less than 25 min, which allows the testing of a large number of samples per day. Sensitivity is very high: as low as 0.5 nmol each of sorbitol, galactitol, and myo-inositol in lyophilized extracts of tissues can be determined. The present method offers a reliable tool to evaluate the in vivo activities of aldose reductase and its inhibitors.
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PMID:Analysis of sorbitol, galactitol, and myo-inositol in lens and sciatic nerve by high-performance liquid chromatography. 318

Polyhydric alcohols (polyols) are widely distributed in nature, and the enzymes of the polyol pathway (aldose reductase and sorbitol dehydrogenase) are present in many mammalian tissues. The function of this pathway remains a mystery. A primary role for the pathway in the pathogenesis of 'sugar cataract' was provided by a number of experimental observations and in the 1960s the 'osmotic hypothesis' was propounded. This hypothesis also had implications for the pathogenesis of diabetic neuropathy. However, in the 1970s doubts were raised about the validity of the hypothesis, culminating in experiments which suggested that abnormalities in myo-inositol metabolism in nerve and lens were more closely related to the glucose-induced functional changes in these tissues than was the polyol pathway. Nevertheless, increased activity of the polyol pathway must still be regarded as an instigator of the biochemical abnormalities that lead to damage of lens and nerve in diabetes mellitus.
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PMID:The polyol pathway. A historical review. 379 30

Heretofore, the intracellular accumulation of sorbitol has been associated exclusively with deleterious (cataractogenic) changes in the lens. This study demonstrates a beneficial role for the sorbitol pathway in the rabbit lens, namely that of counteracting extracellular, glucose-derived, osmotic stress with the intracellular production of osmotically active sorbitol. Large and sudden increases in the extracellular glucose concentration lead to dehydration of the lens, a response that can be diminished by intracellular sorbitol and fructose production. These results are discussed in light of the impact (beneficial/detrimental) of aldose reductase inhibitors on the lens. Sugar cataract formation appears to result from continuous, rather than cyclical, activity of a pathway which normally may have a protective function in the lens.
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PMID:Sorbitol production in the lens: a means of counteracting glucose-derived osmotic stress. 380 97

Aldose reductase is implicated in the pathogenesis of diabetic cataracts; therefore, inhibition of this enzyme subsequent to cataractogenesis may represent a therapeutic approach for restoration of lens physiology. In the present study, the effect of aldose reductase inhibition subsequent to stage I cataract formation was investigated in the streptozocin-induced diabetic rat. Our results indicated that the aldose reductase inhibitor sorbinil, a spirohydantoin, arrested further progression and promoted a reparative process despite continuation of hyperglycemia and elevated lens glucose. Quantitative analysis of scanning electron micrographs indicated that the afflicted lens regions were contained and their cellular components stabilized with regard to fiber hydration and interdigitation. The reparative process included: normalization of lens sorbitol, gradual recovery of existing fiber contour and interdigitation, production of new fibers, and partial restoration of lens myo-inositol content.
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PMID:Reversal of diabetic cataract by sorbinil, an aldose reductase inhibitor. 391 57

Previous cytochemical and biochemical studies have shown an increase in the activity of acid phosphatase and arylsulfatase during the induction of galactose cataracts in rat lenses. It was postulated that these enzymes may be involved in lens fiber degradation observed during cataractogenesis, however, the role of these enzymes in the repair process was not ruled out. The present investigation has evaluated the level of acid phosphatase activity in lenses in which the induction of opacity is inhibited with the aldose reductase inhibitor sorbinil and during the recovery of galactose induced opacity. Sprague-Dawley rats received 50% galactose diet, or galactose diet with sorbinil, or laboratory chow diet. Following 20 days on this diet all rats received lab chow plus 50 mg kg-1 sorbinil (recovery diet). The lenses were removed at desired intervals following the initiation of the above three diets and following the transfer of animals to the recovery diet. Cytochemical localization and biochemical quantitation of acid phosphatase activity were performed with methods previously reported. Most of the enzyme activity was localized within the epithelial cells and superficial cortical fibers. In the epithelial cell layer, the enzyme activity was primarily localized in lysosomes and at extracellular sites near the epithelial cell membrane which abut each other and cortical fibers. In cortical fibers the enzyme activity was observed at various extracellular sites between the cell membranes of neighboring fibers. The effect of sorbinil, if any, and the possible role of acid hydrolases in the repair process during cataract reversal is discussed.
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PMID:Acid phosphatase II. Cytochemical localization in lenses of normal and galactose-fed rats. 392 63

We tried to counteract the appearance of galactosemic cataracts in weaned rats by high doses of vitamin E. Rats were fed a diet containing 33% galactose. Cataract development was monitored by biomicroscopy and by several biochemical parameters: K+/Na+ ratio, aldose reductase activity, level of protein and non-protein sulfhydryl (SH) groups. Vitamin E was given parenterally at a dose of 100 mg/kg/day. The K+/Na+ ratio drops after 15 days of galactosemia, while the level of the aldose reductase rises after only 5 days of treatment. The non-protein SH groups lens contents fall from the 5th day of treatment onwards, while protein SH groups are not affected. In short-term experiments vitamin E does not prevent biochemical changes caused by galactosemia. The oxidative insult does not seem to be primarily involved in galactose cataract.
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PMID:Changes of some biochemical parameters of the lens in galactose-treated weaned rats with and without vitamin E therapy. 392 May 97

The protein aldose reductase has been implicated in cataract in diabetes and galactosaemia. Recently it has been suggested that a number of non-steroidal anti-inflammatory agents have inhibitory activity against aldose reductase activity, and therefore might be used to prevent diabetic complications including cataract. Steady state kinetic experiments show that Clinoril (Sulindac sulphoxide) acts as a non-competitive inhibitor of NADPH oxidation with purified bovine lens aldose reductase, with an action that may involve binding to more than one site on the protein. As a preliminary to studying the effect on human lens and cataract, a double-masked, placebo-controlled study using random allocation into parallel groups was conducted on 20 volunteers to determine the penetration of Clinoril (Sulindac) and its metabolites into normal human red cells, and the effect of the drug on red cell NADPH-oxidising activity. It was found that while Clinoril, the sulphoxide form of the drug, and its metabolites the sulphone and the sulphide could be detected in the appropriate plasma samples (up to 36 micrograms of the sulphone/ml of plasma), very little could be detected in the red cells. There was no significant effect on red cell NADPH-oxidising activity.
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PMID:The inhibition of bovine lens aldose reductase by Clinoril, its absorption into the human red cell and its effect on human red cell aldose reductase activity. 392 May 99

Aldose reductase is implicated in the pathogenesis of sugar cataracts; therefore, inhibition of this enzyme subsequent to cataractogenesis may represent a therapeutic approach for the restoration of lens physiology despite the persistence of diabetes or galactosemia. In the present study, the effect of aldose reductase inhibition subsequent to stage-I cataract formation was investigated in the galactose-maintained rat. Our results indicated that despite continuation of galactose feeding the aldose reductase inhibitor, Sorbinil, a spirohydantoin, arrested further progression and promoted a reparative process. Quantitative analysis of scanning electron micrographs indicated that the afflicted lens regions were contained and their cellular components stabilized with regard to fiber hydration and interdigitation. The reparative process involved: decrease in lens dulcitol, gradual recovery of fiber thickness and partial restoration of lens myo-inositol content. At this stage of cataractogenesis, despite continuance of galactose feeding, the effects of Sorbinil treatment were comparable to the reparative process achieved by restoration of a normal diet.
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PMID:Reversal of stage-I sugar cataract by Sorbinil, an aldose reductase inhibitor. 392 28


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