Effects of protein kinase Cbeta inhibition on neurovascular dysfunction in diabetic rats: interaction with oxidative stress and essential fatty acid dysmetabolism

Norman E Cameron, Mary Anne Cotter

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81 Citations (Scopus)

Abstract

Background Elevated protein kinase C (PKC) activity is thought to play a substantial role in the aetiology of diabetic microvascular complications, the PKC isoform being identified as particularly important. Neuropathy has a vascular component; therefore, one aim was to assess whether the PKCbeta inhibitor, LY333531, could correct nerve conduction velocity (NCV) and perfusion deficits in diabetic rats. Neurovascular dysfunction also depends on oxidant stress and impaired (omega-6 essential fatty acid metabolism; correctable by antioxidant and gamma-linolenic acid (GLA) treatments, respectively. A second aim was to assess whether there were interactions between these mechanisms and PKCbeta-mediated effects.

Methods Diabetes was induced by streptozotocin; duration was 8 weeks. NCV was monitored and blood flow was assessed by hydrogen clearance microelectrode polarography.

Results Diabetes caused 19.7% and 13.9% reductions in sciatic motor and saphenous sensory NCV, respectively. Two weeks of LY333531 treatment dose-dependently corrected these deficits. A dose of 10 mg kg(-1) day(-1) gave non-diabetic NCV values and also completely corrected a 50% diabetic reduction in sciatic endoneurial blood flow. Low-dose (0.25 mg kg(-1) day(-1)) LY333531 had modest effects (similar to20% correction) on NCV and sciatic perfusion. However, when combined with equi-effective doses of the antioxidants vitamin E or alpha-lipoic acid, or GLA, motor and sensory NCV and sciatic nerve perfusion were in the non-diabetic range. The joint effect was equivalent to that of the 10 mg kg(-1) day(-1) LY333531 dose, demonstrating synergism between PKCbeta, oxidative stress and essential fatty acid mechanisms.

Conclusion LY333531, alone or combined with antioxidants or GLA, could form the basis for therapeutic intervention in neuropathy, which requires assessment in clinical trials. Copyright (C) 2002 John Wiley Sons, Ltd.

Original languageEnglish
Pages (from-to)315-323
Number of pages8
JournalDIABETES-METABOLISM RESEARCH AND REVIEWS
Volume18
Issue number4
DOIs
Publication statusPublished - 2002

Keywords

  • protein kinase C
  • neuropathy
  • oxidative stress
  • blood flow
  • essential fatty acid
  • diabetes
  • rat
  • ALPHA-LIPOIC ACID
  • NERVE BLOOD-FLOW
  • ALDOSE REDUCTASE INHIBITION
  • NITRIC-OXIDE SYNTHASE
  • GAMMA-LINOLENIC ACID
  • VASCULAR ENDOTHELIUM
  • CONDUCTION DEFICITS
  • PERIPHERAL-NERVE
  • POLYOL PATHWAY
  • SCIATIC-NERVES

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