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      Diabetic-like corneal sensitivity loss in galactose-fed rats ameliorated with aldose reductase inhibitors.

      Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics

      Aldehyde Reductase, antagonists & inhibitors, Animals, Blinking, drug effects, Cataract, etiology, Cornea, physiopathology, Diabetes Mellitus, Experimental, complications, Diet, Enzyme Inhibitors, pharmacology, Fluorenes, Galactose, administration & dosage, Galactosemias, Hydantoins, Male, Physical Stimulation, Rats, Rats, Sprague-Dawley, Thiazoles, Thiazolidinediones

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          This study investigated whether diabetic-like corneal sensory deficits occur in the galactose-fed rat model of diabetic ocular complications and if such deficits could be prevented using either of two structurally different aldose reductase (AR) inhibitors, CT-112 or AL-1576. S-D rats were randomly grouped to receive a diet of Purina chow with either 50% starch (n=25) or 50% D-galactose (n=65). Some of the galactosemic rats received either 0.25% CT-112 topically 3x daily (n=15) or 28 mg/kg body wt/day AL-1576 systemically (n=10). The control and untreated galactosemic rats in the CT-112 portion of the study received equivalent topical doses of the vehicle. Sensitivity measurements were made with a Cochet-Bonnet Aesthesiometer mounted on a micromanipulator. The filament was applied to the central corneal surface (mean pressure of 0.96 g/mm2) and viewed using a slit-lamp biomicroscope. Ten consecutive stimuli were conducted on each cornea and the average number of blink-responses was expressed as a percent of total stimuli effected. Mean initial corneal sensitivities were similar in all groups. Corneal sensitivity in the galactosemic rat was reduced (p<0.01) at each monthly measurement compared to control. Animals treated with CT-112 or AL-1576 showed a significant increase in the mean blink-response compared to untreated galactose-fed rats and did not differ significantly from controls towards the completion of the 7 month study. Animals treated with AL-1576 did not develop cataracts, whereas those treated topically with CT-112 and untreated galactose-fed rats developed bilateral nuclear cataracts within 3 weeks. This is the first study to demonstrate decreased corneal sensitivity in the galactose-fed rat model and its amelioration with AR inhibitors. Thus, aldose reductase, the first enzyme of the polyol pathway, may have an important role in the pathogenesis of decreased corneal sensitivity. The model could be useful for investigating the pathogenic mechanism(s) involved in reduced corneal sensitivity associated with diabetic keratopathy in humans.

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