Effects of the protein kinase Cβ inhibitor LY333531 on neural and vascular function in rats with streptozotocin-induced diabetes

Abstract

Elevated protein kinase C activity has been linked to the vascular and neural complications of diabetes. The aim of the present study was to examine the involvement of the beta-isoform of protein kinase C in abnormalities of neuronal function, neural tissue perfusion and endothelium-dependent vasodilation in diabetes, by treatment with the selective inhibitor LY333531 (10 mg.kg(-1).day(-1)). Diabetes was induced in rats by streptozotocin; the duration of diabetes was 8 weeks. Nerve conduction velocity was monitored, and responses to noxious mechanical and thermal stimuli were estimated by the Randall-Sellito and Hargreaves tests respectively. Sciatic nerve and superior cervical ganglion blood flow were measured by microelectrode polarography and hydrogen clearance. Vascular responses were examined using the in vitro mesenteric bed preparation. An 8-week period of diabetes caused deficits in sciatic motor (20%) and saphenous nerve sensory (16%) conduction velocity, which were reversed by LY333531. Diabetic rats had mechanical and thermal hyperalgesia. LY333531 treatment did not affect mechanical thresholds, but corrected thermal hyperalgesia. Sciatic nerve and superior cervical ganglion blood flow were both reduced by 50% by diabetes; this was almost completely corrected by 2 weeks of LY333531 treatment. Diabetes caused a 32% reduction in vasodilation of the mesenteric vascular bed in response to acetylcholine, mediated by nitric oxide and endothelium-derived hyperpolarizing factor. When the former was abolished during nitric oxide synthase inhibition, an 80% diabetic deficit in the remaining relaxation was noted. LY333531 treatment attenuated the development of these defects by 64% and 53% respectively. Thus protein kinase C beta contributes to the neural and vascular complications of experimental diabetes; LY333531 is a candidate for further study in clinical trials of diabetic neuropathy and vasculopathy.

Sural nerve pathology in diabetic patients with minimal but progressive neuropathy

“…Animal models of diabetic neuropathy demonstrate a reduction in nerve conduction velocity and blood flow [16] yet they do not show structural changes observed in human diabetic neuropathy and there is controversy as to whether the changes they do show are due to maturational delay induced by hyperglycaemia, or due to diabetes itself [17,18]. Experimental studies demonstrate progressive molecular alterations leading to nodal and paranodal degeneration with axo-glial dysjunction and axonal atrophy [19].…”

New hope for the treatment of diabetic complications

“…These investigations show for the first time that this beneficial effect relates to its ability to reverse endothelium-dependent vasodilator responses and correct deficits in neural blood flow [15]. The observation that LY333531 can successfully reverse established abnormalities in these experiments gives considerable hope that a new treatment for diabetic microvascular complications is a realistic prospect in the not too distant future.…”

“…In this issue of Clinical Science, Cotter et al [15] show that LY333531 also reverses neuronal dysfunction in diabetic rats. These investigations show for the first time that this beneficial effect relates to its ability to reverse endothelium-dependent vasodilator responses and correct deficits in neural blood flow [15].…”

Novel Therapeutics for Diabetic Micro- and Macrovascular Complications

“…Ishii et al first showed that oral administration of highly selective PKC-β inhibitor ruboxistaurin mesylate (LY333531) inhibits the phosphorylation of PKC-β 2 and PKC-α in diabetic rats thereby decreasing the glomerular filtration, albumin excretion and retinal circulation in a dose-responsive manner [86]. Subsequent studies with ruboxistaurin proved that it delays the progression of diabetic retinopathy, nephropathy, and neuropathy in animal models [83,[87][88][89][90]. Ruboxistaurin has been successfully tested in clinical studies.…”