Prevention of sensory disorders in diabetic Sprague-Dawley rats by aldose reductase inhibition or treatment with ciliary neurotrophic factor

Diabetologia. 2004 Apr;47(4):718-24. doi: 10.1007/s00125-004-1354-2.


Aims/hypothesis: Sensory neuropathy in diabetic patients frequently presents itself as progressive loss of thermal perception, while some patients describe concurrent spontaneous pain, allodynia or hyperalgesia. Diabetic rats develop thermal hypoalgesia and tactile allodynia by unknown mechanisms. We investigated whether sensory disorders in rats were related to glucose metabolism by aldose reductase. We also explored the therapeutic potential of exogenous neurotrophic factors.

Methods: Behavioural assessments of thermal and tactile sensitivity were performed in normal rats and in rats with streptozotocin-induced diabetes. Some of the rats were treated with insulin, aldose reductase inhibitors, ciliary neurotrophic factor or brain-derived neurotrophic factor.

Results: Thermal hypoalgesia was present after 8 weeks of diabetes and was prevented by insulin treatment, which maintained normoglycaemia, by the aldose reductase inhibitor Statil or by ciliary neurotrophic factor. Brain-derived neurotrophic factor did not have an effect. When diabetic rats were tested after shorter durations of diabetes, they showed transient thermal hyperalgesia after 4 weeks which progressed to thermal hypoalgesia after 8 weeks. The aldose reductase inhibitor IDD 676 (Lidorestat), given from the onset of diabetes, prevented the development of thermal hyperalgesia and also stopped progression to thermal hypoalgesia when delivered in the last 4 weeks of an 8-week period of diabetes. Tactile allodynia was not prevented by neurotrophic factor or aldose reductase inhibitor treatment.

Conclusions/interpretation: Transient thermal hyperalgesia and subsequent progressive thermal hypoalgesia occur in diabetic rats secondary to exaggerated flux through the polyol pathway. A depletion of ciliary neurotrophic factor mediated by the polyol pathway may be involved in the aetiology of thermal hypoalgesia.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aldehyde Reductase / antagonists & inhibitors*
  • Animals
  • Body Weight / drug effects
  • Brain-Derived Neurotrophic Factor / therapeutic use
  • Ciliary Neurotrophic Factor / therapeutic use*
  • Diabetes Mellitus, Experimental / complications*
  • Diabetic Neuropathies / prevention & control*
  • Enzyme Inhibitors / therapeutic use*
  • Female
  • Hot Temperature
  • Hypoglycemic Agents / therapeutic use
  • Insulin / therapeutic use
  • Pain Measurement / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Sensation Disorders / etiology
  • Sensation Disorders / prevention & control*
  • Sensory Thresholds / drug effects


  • Brain-Derived Neurotrophic Factor
  • Ciliary Neurotrophic Factor
  • Enzyme Inhibitors
  • Hypoglycemic Agents
  • Insulin
  • Aldehyde Reductase