Treatment with the xanthine oxidase inhibitor, allopurinol, improves nerve and vascular function in diabetic rats

Melanie E. Inkster, Mary A. Cotter, Norman E Cameron

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Abstract

Several putative sources of reactive oxygen species could potentially contribute to diabetic neuropathy and vasculopathy. The aim was to assess the involvement of elevated xanthine oxidase activity. After 6 weeks of streptozotocin-diabetes, groups of rats were given 2 weeks of high-dose allopurinol treatment (50 and 250 mg/kg) to gauge the effect of maximal blockade of xanthine oxidase. In the final experiments, rats were subjected to sensory testing and, under butabarbital anaesthesia, measurements were made on nerve conduction velocities and neural tissue blood flow estimated by hydrogen clearance microelectrode polarography. Further groups were used to study detailed responses of the isolated mesenteric vascular bed after 4 weeks of diabetes and allopurinol (150 mg/kg) treatment. Diabetes caused 20% and 14% reduction in motor and sensory conduction velocity, which were 78% and 81% corrected by allopurinol treatment respectively, both doses giving similar results. Diabetic rats showed tactile allodynia and thermal hyperalgesia, which were completely corrected by allopurinol, whereas mechanical hyperalgesia was only 45% ameliorated. Sciatic nerve and superior cervical ganglion blood flow was halved by diabetes and allopurinol corrected this by approximately 63%. Mesenteric endothelium-dependent vascular responses to acetylcholine, which depend upon nitric oxide and endothelium derived hyperpolarizing factor, were attenuated by diabetes. Allopurinol treatment gave approximately 50% protection for both components. Thus, xanthine oxidase is an important source of reactive oxygen species that contributes to neurovascular dysfunction in experimental diabetes. Inhibition of xanthine oxidase could be a potential therapeutic approach to diabetic neuropathy and vasculopathy.

Original languageEnglish
Pages (from-to)63-71
Number of pages9
JournalEuropean Journal of Pharmacology
Volume561
Issue number1-3
Early online date19 Jan 2007
DOIs
Publication statusPublished - 30 Apr 2007

Keywords

  • diabetic neuropathy
  • xanthine oxidase
  • allopurinol
  • blood flow
  • vascular endothelium
  • nitric oxide
  • EDHF
  • aldose reductase inhibition
  • endothelium-dependent relaxation
  • endoneurial blood-flow
  • Alpha-Lipoic acid
  • conduction-velocity
  • peripheral-nerve
  • neurovascular function
  • tactile allodynia
  • oxidative stress
  • oxygen-tension

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