Effect of aldose reductase inhibition on nerve conduction and morphometry in diabetic neuropathy. Zenarestat Study Group

Neurology. 1999 Aug 11;53(3):580-91. doi: 10.1212/wnl.53.3.580.


Objective: To determine whether the aldose reductase inhibitor (ARI) zenarestat improves nerve conduction velocity (NCV) and nerve morphology in diabetic peripheral polyneuropathy (DPN).

Methods: A 52-week, randomized, placebo-controlled, double-blinded, multiple-dose, clinical trial with the ARI zenarestat was conducted in patients with mild to moderate DPN. NCV was measured at baseline and study end. Contralateral sural nerve biopsies were obtained at 6 weeks and at the study's end for nerve sorbitol measurement and computer-assisted light morphometry to determine myelinated nerve fiber density (number of fibers/mm2 cross-sectional area) in serial bilateral sural nerve biopsies.

Results: Dose-dependent increments in sural nerve zenarestat level and sorbitol suppression were accompanied by significant improvement in NCV. In a secondary analysis, zenarestat doses producing >80% sorbitol suppression were associated with a significant increase in the density of small-diameter (<5 microm) sural nerve myelinated fibers.

Conclusions: Aldose reductase pathway inhibition improves NCV slowing and small myelinated nerve fiber loss in DPN in humans, but >80% suppression of nerve sorbitol content is required. Thus, even low residual levels of aldose reductase activity may be neurotoxic in diabetes, and potent ARIs such as zenarestat may be required to stop or reverse progression of DPN.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / physiology
  • Aldehyde Reductase / antagonists & inhibitors
  • Biopsy
  • Diabetic Neuropathies / drug therapy*
  • Diabetic Neuropathies / pathology*
  • Diabetic Neuropathies / physiopathology
  • Double-Blind Method
  • Female
  • Humans
  • Male
  • Middle Aged
  • Neural Conduction / drug effects*
  • Quinazolines / adverse effects
  • Quinazolines / therapeutic use*


  • Quinazolines
  • FR 74366
  • Aldehyde Reductase