An aldose reductase inhibitor reverses early diabetes-induced changes in peripheral nerve function, metabolism, and antioxidative defense

FASEB J. 2002 Jan;16(1):123-5. doi: 10.1096/fj.01-0603fje. Epub 2001 Nov 14.


Aldose reductase inhibitors (ARIs) prevent peripheral nerve dysfunction and morphological abnormalities in diabetic animal models. However, some experimental intervention studies and clinical trials of ARIs on diabetic neuropathy appeared disappointing because of either 1) their inadequate design and, in particular, insufficient correction of the sorbitol pathway activity or 2) the inability to reverse established functional and metabolic deficits of diabetic neuropathy by AR inhibition in general. We evaluated whether diabetes-induced changes in nerve function, metabolism, and antioxidative defense are corrected by the dose of ARI (sorbinil, 65 mg/kg/d in the diet), resulting in complete inhibition of increased sorbitol pathway activity. The groups included control rats and streptozotocin-diabetic rats treated with/without ARI for 2 weeks after 4 weeks of untreated diabetes. ARI treatment corrected diabetes-induced nerve functional changes; that is, decrease in endoneurial nutritive blood flow, motor and sensory nerve conduction velocities, and metabolic abnormalities (i.e., mitochondrial and cytosolic NAD+/NADH redox imbalances and energy deficiency). ARI restored nerve concentrations of two major non-enzymatic antioxidants, reduced glutathione (GSH) and ascorbate, and completely arrested diabetes-induced lipid peroxidation. In conclusion, treatment with adequate doses of ARIs (that is, doses that completely inhibit increased sorbitol pathway activity) is an effective approach for reversal of, at least, early diabetic neuropathy.

MeSH terms

  • Aldehyde Reductase / antagonists & inhibitors*
  • Animals
  • Antioxidants / metabolism
  • Cytosol / drug effects
  • Cytosol / metabolism
  • Diabetes Mellitus, Experimental / drug therapy*
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / physiopathology
  • Diabetic Neuropathies / drug therapy*
  • Diabetic Neuropathies / metabolism
  • Diabetic Neuropathies / physiopathology
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / pharmacology*
  • Imidazoles / administration & dosage
  • Imidazoles / pharmacology*
  • Imidazolidines*
  • Lipid Peroxidation / drug effects
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Models, Biological
  • NAD / metabolism
  • Neural Conduction / drug effects
  • Oxidation-Reduction / drug effects
  • Oxidative Stress
  • Peripheral Nerves / drug effects
  • Peripheral Nerves / metabolism
  • Peripheral Nerves / physiopathology
  • Rats


  • Antioxidants
  • Enzyme Inhibitors
  • Imidazoles
  • Imidazolidines
  • NAD
  • Aldehyde Reductase
  • sorbinil