Protein kinase C effects on nerve function, perfusion, Na+,K+-ATPase activity and glutathione content in diabetic rats

Norman E Cameron, M A Cotter, A M Jack, M D Basso, T C Hohman

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114 Citations (Scopus)

Abstract

Aims/hypothesis. Increased protein kinase C activity has been linked to diabetic vascular complications in the retina and kidney, which were attenuated by protein kinase C antagonist treatment. Neuropathy has a vascular component, therefore, the aim was to assess whether treatment with WAY151003 or chelerythrine, inhibitors of protein kinase C regulatory and catalytic domains respectively, could correct nerve blood flow, conduction velocity, Na+,K+-ATPase, and glutathione deficits in diabetic rats.

Methods. Diabetes was induced by streptozotocin. Sciatic nerve conduction velocity was measured in vivo and sciatic endoneurial perfusion was monitored by microelectrode polarography and hydrogen clearance. Glutathione content and Na+,K+-ATPase activity were measured in extracts from homogenised sciatic nerves.

Results. After 8 weeks of diabetes, sciatic blood flow was 50% reduced. Two weeks of WAY151003 (3 or 100 mg/kg) treatment completely corrected this deficit and chelerythrine dose-dependently improved nerve perfusion. The inhibitors dose-dependently corrected a 20% diabetic motor conduction deficit, however, at high doses (> 3.0 mg/kg WAY151003; > 0.1 mg/kg chelerythrine) conduction velocity was reduced towards the diabetic level. Sciatic Na+,K+-ATPase activity, 42% reduced by diabetes, was partially corrected by low but not high dose WAY151003. In contrast, only a very high dose of chelerythrine partially restored Na+,K+-ATPase activity. A 30% diabetic deficit in sciatic glutathione content was unchanged by protein kinase C inhibition. The benefits of WAY151003 on blood flow and conduction velocity were blocked by nitric oxide synthase inhibitor co-treatment.

Conclusion/interpretation. Protein kinase C contributes to experimental diabetic neuropathy by a neurovascular mechanism rather than through Na+,K+-ATPase defects.

Original languageEnglish
Pages (from-to)1120-1130
Number of pages11
JournalDiabetologia
Volume42
Publication statusPublished - 1999

Keywords

  • neuropathy
  • nerve conduction
  • blood flow
  • protein kinase C
  • diacylglycerol
  • oxidative stress
  • diabetic rat
  • ALDOSE REDUCTASE INHIBITION
  • NITRIC-OXIDE SYNTHASE
  • ESSENTIAL FATTY-ACIDS
  • K+-ATPASE ACTIVITY
  • ACETYL-L-CARNITINE
  • PERIPHERAL-NERVE
  • SCIATIC-NERVE
  • NEUROVASCULAR FUNCTION
  • BLOOD-FLOW
  • VASCULAR ENDOTHELIUM

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