A Selective Aldose Reductase Inhibitor of a New Structural Class Prevents or Reverses Early Retinal Abnormalities in Experimental Diabetic Retinopathy

  1. Wei Sun1,
  2. Peter J. Oates2,
  3. James B. Coutcher2,
  4. Chiara Gerhardinger1 and
  5. Mara Lorenzi1
  1. 1Schepens Eye Research Institute and Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts
  2. 2Department of Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, Groton, Connecticut
  1. Address correspondence and reprint requests to Mara Lorenzi, MD, Schepens Eye Research Institute, Harvard Medical School, 20 Staniford St., Boston, MA 02114. E-mail: lorenzi{at}vision.eri.harvard.edu

Abstract

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.

Footnotes

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted July 5, 2006.
    • Received January 31, 2006.
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