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Effects of protein kinase Cβ inhibition on neurovascular dysfunction in diabetic rats: interaction with oxidative stress and essential fatty acid dysmetabolism
Author(s) -
Cameron Norman E.,
Cotter Mary A.
Publication year - 2002
Publication title -
diabetes/metabolism research and reviews
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.307
H-Index - 110
eISSN - 1520-7560
pISSN - 1520-7552
DOI - 10.1002/dmrr.307
Subject(s) - endocrinology , medicine , diabetes mellitus , oxidative stress , diabetic neuropathy , protein kinase c , streptozotocin , kinase , chemistry , biochemistry
Background Elevated protein kinase C (PKC) activity is thought to play a substantial role in the aetiology of diabetic microvascular complications, the PKCβ isoform being identified as particularly important. Neuropathy has a vascular component; therefore, one aim was to assess whether the PKCβ inhibitor, LY333531, could correct nerve conduction velocity (NCV) and perfusion deficits in diabetic rats. Neurovascular dysfunction also depends on oxidant stress and impaired ω‐6 essential fatty acid metabolism; correctable by antioxidant and γ‐linolenic acid (GLA) treatments, respectively. A second aim was to assess whether there were interactions between these mechanisms and PKCβ‐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 (∼20% correction) on NCV and sciatic perfusion. However, when combined with equi‐effective doses of the antioxidants vitamin E or α‐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 PKCβ, oxidative stress and essential fatty acid mechanisms. Conclusions LY333531, alone or combined with antioxidants or GLA, could form the basis for therapeutic intervention in neuropathy, which requires assessment in clinical trials. Copyright © 2002 John Wiley & Sons, Ltd.