A selective aldose reductase inhibitor of a new structural class prevents or reverses early retinal abnormalities in experimental diabetic retinopathy.
Previously studied inhibitors of aldose reductase were largely from two chemical classes, spirosuccinamide/hydantoins and carboxylic acids. Each class has its own drawbacks regarding selectivity, in vivo potency, and human safety; as a result, the pathogenic role of aldose reductase in diabetic retinopathy remains controversial. ARI-809 is a recently discovered aldose reductase inhibitor (ARI) of a new structural class, pyridazinones, and has high selectivity for aldose versus aldehyde reductase. To further test the possible pathogenic role of aldose reductase in the development of diabetic retinopathy, we examined the retinal effects of this structurally novel and highly selective ARI in insulinized streptozotocin-induced diabetic rats. ARI-809 treatment was initiated 1 month after diabetes induction and continued for 3 months at a dose that inhibited the polyol pathway in the retina of diabetic rats to a similar extent as sorbinil, a poorly selective hydantoin ARI previously shown to prevent retinopathy in this model. ARI-809 improved survival, inhibited cataract development, normalized retinal sorbitol and fructose, and protected the retina from abnormalities that also occur in human diabetes: neuronal apoptosis, glial reactivity, and complement deposition. Because ARI-809 is a novel chemotype highly selective for aldose reductase, these results support the notion that aldose reductase is the key relay that converts hyperglycemia into glucose toxicity in neural and glial cell types in the retina.
Sun
Wei
W
Schepens Eye Research Institute, Harvard Medical School, 20 Staniford St., Boston, MA 02114, USA.
Oates
Peter J
PJ
Coutcher
James B
JB
Gerhardinger
Chiara
C
Lorenzi
Mara
M
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000473:pathology; D003930:Diabetic Retinopathy / Q000188:drug therapy / Q000517:prevention & control*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D008297:Male; D011108:Polymers / Q000378:metabolism; D011724:Pyridazines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation
C514725:CP-744809; D004791:Enzyme Inhibitors; D011108:Polymers; D011724:Pyridazines; C024617:polyol; D018799:Intercellular Adhesion Molecule-1; D000449:Aldehyde Reductase