Effect of sorbitol dehydrogenase inhibition on sugar cataract formation in galactose-fed and diabetic rats.

Abstract

Several recent studies with the sorbitol dehydrogenase inhibitors 4-[4-(N,N-dimethylsulfamoyl)-piperazino]-2-methylpyrimidine, SDH-1, and its active metabolite 4-[4-(N, N-dimethylsulfamoyl)piperazino]-2-hydroxymethylpyrimidine , SDH-2, suggest that inhibition of sorbitol dehydrogenase may be beneficial in delaying the onset of diabetic complications due to their ability to ameliorate redox changes associated with polyol metabolism. To compare the relative importance of sorbitol dehydrogenase versus aldose reductase inhibition on sugar cataract formation, cataract formation was monitored in 50% galactose-fed and diabetic rats treated with/without the sorbitol dehydrogenase inhibitors SDH-1 or SDH-2 or the aldose reductase inhibitors AL 1576 or Ponalrestat. For these studies, diabetes was induced in young 50 g rats with streptozotocin while galactosemia was produced by feeding a diet containing 50% galactose. Inhibitors were administered in the diet with the diet containing 0.06% (w/w) of the sorbitol dehydrogenase inhibitors or Ponalrestat, and 0.0125% (w/w) of AL 1576. Cataract formation was monitored by hand-held slit lamp and polyol levels were measured by gas chromatography. Sugar cataract formation was accelerated in diabetic rats treated with sorbitol dehydrogenase inhibitors while no difference in cataract formation was observed in galactose-fed rats treated with/without SDH inhibitors. Cataract formation was inhibited in both diabetic and galactosemic rats by either Ponalrestat or AL 1576. These results support the concept that sugar cataract formation is initiated by the aldose reductase catalysed intracellular accumulation of polyols and that these sugar cataracts can be prevented through inhibition of aldose reductase.

• Authors: P F Kador, J Inoue, E F Secchi, M J Lizak, L Rodriguez, K Mori, W Greentree, K Blessing, P A Lackner, S Sato
• Journal: Experimental eye research (Exp Eye Res) Vol. 67 Issue 2 Pg. 203-8 (Aug 1998) ISSN: 0014-4835 [Print] England
• PMID: 9733586 (Publication Type: Journal Article)
• Copyright: Copyright 1998 Academic Press.

Chemical References

• Enzyme Inhibitors
• Fluorenes
• Hydantoins
• Phthalazines
• Piperazines
• Pyrimidines
• S 0773
• imirestat
• 2-hydroxymethyl-4-(4-(N,N-dimethylaminosulfonyl)-1-piperazino)pyrimidine
• ponalrestat
• L-Iditol 2-Dehydrogenase
• Aldehyde Reductase
• Galactose

Topics

• Aldehyde Reductase (antagonists & inhibitors)
• Animals
• Cataract (enzymology, etiology, prevention & control)
• Diabetes Mellitus, Experimental (complications)
• Enzyme Inhibitors (pharmacology)
• Fluorenes (therapeutic use)
• Galactose
• Hydantoins (therapeutic use)
• L-Iditol 2-Dehydrogenase (antagonists & inhibitors)
• Phthalazines (therapeutic use)
• Piperazines (pharmacology)
• Pyrimidines (pharmacology)
• Rats
• Rats, Sprague-Dawley