A protein kinase C-beta-selective inhibitor ameliorates neural dysfunctionin streptozotocin-induced diabetic rats

Increased protein kinase C (PKC) activity has been implicated in the pathog enesis of diabetic retinopathy and nephropathy. However the role of PHC in diabetic neuropaths remains unclear The present study was conducted to comp are the effect of PHC inhibition by a PKC-beta-selective inhibitor LY333531 (LY), on diabetic nerve dysfunction with that of an aldose reductase inhib itor, NZ-314 (NZ). Streptozotocin-induced diabetic rats were treated with o r without LY and/or NZ for 4 weeks, and motor nerve conduction velocity (MN CV), coefficient of variation of R-R interval (C VR-R), sciatic nerve blood flow (SNBF), peak latencies of oscillatory potentials on electroretinogram , PKC activities in membranous and cytosolic fractions of sciatic nerves, a nd polyol contents in the tail nerves were measured. Untreated diabetic rat s demonstrated delayed MNCV decreased CVR-R, reduced SNBF, and prolonged pe ak latencies of oscillatory potentials. Treatment with LP as well as NZ pre vented all these deficits in diabetic rats. There were no significant diffe rences in PKC activities in membranous or cytosolic fractions of sciatic ne rves between normal and diabetic rats. Treatment with neither LY nor NZ alt ered PKC activities. Nerve myo-inositol depletion in diabetic rats was amel iorated not only by NZ, but also by LY These observations suggest that inhi bition of PBC-beta by LY may hare a beneficial effect in preventing the dev elopment of diabetic nerve dysfunction, and that this effect may be mediate d through its action on the endoneurial micro-vasculature.