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

Diabetologia. 1999 Sep;42(9):1120-30. doi: 10.1007/s001250051280.


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 WAY151 003 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 WAY151 003 (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 WAY151 003. 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 WAY151 003 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkaloids
  • Animals
  • Benzophenanthridines
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / physiopathology*
  • Diabetic Neuropathies / drug therapy
  • Diabetic Neuropathies / physiopathology*
  • Enzyme Inhibitors / pharmacology
  • Male
  • Neural Conduction / drug effects
  • Neural Conduction / physiology
  • Phenanthridines / pharmacology*
  • Piperidines / pharmacology*
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase C / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Regional Blood Flow / drug effects
  • Sciatic Nerve / blood supply
  • Sciatic Nerve / drug effects
  • Sciatic Nerve / physiopathology*
  • Sodium-Potassium-Exchanging ATPase / metabolism*


  • Alkaloids
  • Benzophenanthridines
  • Enzyme Inhibitors
  • Phenanthridines
  • Piperidines
  • NPC 15437
  • chelerythrine
  • Protein Kinase C
  • Sodium-Potassium-Exchanging ATPase