Saphenous Sensory Nerve Conduction Velocity Research Articles

Effects of proinsulin C-peptide in experimental diabetic neuropathy: vascular actions and modulation by nitric oxide synthase inhibition.

Proinsulin C-peptide treatment can partially prevent nerve dysfunction in type 1 diabetic rats and patients. This could be due to a direct action on nerve fibers or via vascular mechanisms as C-peptide stimulates the nitric oxide (NO) system and NO-mediated vasodilation could potentially account for any beneficial C-peptide effects. To assess this further, we examined neurovascular function in streptozotocin-induced diabetic rats. After 6 weeks of diabetes, rats were treated for 2 weeks with C-peptide to restore circulating levels to those of nondiabetic controls. Additional diabetic groups were given C-peptide with NO synthase inhibitor N(G)-nitro-L-arginine (L-NNA) co-treatment or scrambled C-peptide. Diabetes caused 20 and 16% reductions in sciatic motor and saphenous sensory nerve conduction velocity, which were 62 and 78% corrected, respectively, by C-peptide. L-NNA abolished C-peptide effects on nerve conduction. Sciatic blood flow and vascular conductance were 52 and 41%, respectively, reduced by diabetes (P < 0.001). C-peptide partially (57-66%) corrected these defects, an effect markedly attenuated by L-NNA co-treatment. Scrambled C-peptide was without effect on nerve conduction or perfusion. Thus, C-peptide replacement improves nerve function in experimental diabetes, and the data are compatible with the notion that this is mediated by a NO-sensitive vascular mechanism.

Looking to the future: diabetic neuropathy and effects of rosuvastatin on neurovascular function in diabetes models

Vascular defects contribute substantially to neuropathic changes associated with metabolic abnormalities in diabetes. Statins appear to exert beneficial effects on vascular function independent of cholesterol lowering. In studies of the streptozotocin-induced diabetes rat model, rosuvastatin treatment was shown to correct sciatic motor and saphenous sensory nerve conduction velocity deficits (large fiber defects), thermal hyperalgesia (small fiber defects) and deficits in sciatic nerve and superior cervical ganglion blood flow. Rosuvastatin reversed deficits in nitrergic nerve–mediated vasodilation in the corpus cavernosum and corrected deficits in endothelium-derived hyperpolarising factor–mediated vasodilation in mesenteric vessels. Rosuvastatin did not alter plasma cholesterol in diabetic animals (a characteristic effect in this model), but significantly lowered triglycerides at high doses. Treatment with mevalonate reversed the beneficial effects of rosuvastatin on nerve function and blood flow, suggesting that the effects are mediated by inhibition of the cholesterol biosynthesis pathway in the absence of cholesterol reduction. Thus, rosuvastatin has wide-ranging neurovascular actions in diabetic rats that may be independent of lipid-lowering activity.

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

Elevated protein kinase C (PKC) activity is thought to play a substantial role in the aetiology of diabetic microvascular complications, the PKCbeta 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. Diabetes was induced by streptozotocin; duration was 8 weeks. NCV was monitored and blood flow was assessed by hydrogen clearance microelectrode polarography. 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 ( approximately 20% 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. LY333531, alone or combined with antioxidants or GLA, could form the basis for therapeutic intervention in neuropathy, which requires assessment in clinical trials.

Pentoxifylline effects on nerve conduction velocity and blood flow in diabetic rats.

Pentoxifylline has several actions that improve blood rheology and tissue perfusion and may therefore potentially be applicable to diabetic neuropathy. The aims of this study were to ascertain whether 2 weeks of treatment with pentoxifylline could correct nerve conduction velocity and blood flow deficits in 6-week streptozotocin-diabetic rats and to examine whether the effects were blocked by co-treatment with the cyclooxygenase inhibitor, flurbiprofen, or the nitric oxide synthase inhibitor, NG-nitro-ʟ-arginine. Diabetic deficits in sciatic motor and saphenous sensory nerve conduction velocity were 56.5% and 69.8% corrected, respectively, with pentoxifylline treatment. Sciatic endoneurial blood flow was approximately halved by diabetes and this deficit was 50.4% corrected by pentoxifylline. Flurbiprofen co-treatment markedly attenuated these actions of pentoxifylline on nerve conduction and blood flow whereas NG-nitro-ʟ-arginine was without effect. Thus, pentoxifylline treatment confers neurovascular benefits in experimental diabetic neuropathy, which are linked at least in part to cyclooxygenasemediated metabolism.

Effects of the Diacylglycerol Complexing Agent, Cremophor, on Nerve-Conduction Velocity and Perfusion in Diabetic Rats

The contribution of diacylglycerol (DAG) and protein kinase C (PKC) to diabetic complications has been the subject of debate. In vascular tissues, diabetes increases DAG content, which activates PKC and causes abnormal tissue perfusion. Reduced nerve blood flow has been implicated in the development of neuropathy. However, nerve DAG/PKC activity is not increased and may even be reduced by diabetes, which has also been implicated in neuropathy. The aim was to test whether 2 weeks of treatment with cremophor, an agent that complexes DAG and prevents PKC activation, could correct nerve-conduction velocity (NCV) deficits in rats with 6 weeks of untreated diabetes, as predicted on a vascular hypothesis, or whether this worsened the deficits, as predicted for a direct effect on nerve fibers. Diabetes caused 17.9 ± 0.9% (± SEM) and 15.5 ± 1.6% reductions in sciatic motor and saphenous sensory NCV, respectively, that were largely (79.6 ± 6.3% and 57.8 ± 11.5%) corrected by 100 mg · kg −1 · day −1 cremophor treatment. The effects of cremophor on motor and sensory NCV were completely attenuated by co-treatment with the nitric oxide synthase inhibitor, N G-nitro- l -arginine. In contrast, co-treatment with the cyclooxygenase inhibitor, flurbiprofen, had no effect on NCV. Sciatic nutritive and total endoneurial perfusion were 49.7 ± 3.4% and 51.8 ± 4.2% reduced by diabetes, respectively, and these deficits were 69.5 ± 7.4% and 79.0 ± 11.6% corrected by cremophor treatment. Thus the data suggest that an increased DAG/PKC vascular mechanism, perhaps linked to the nitric oxide system, contributes to the etiology of diabetic nerve dysfunction.

Nerve conduction velocity, laser Doppler flow, and axonal caliber in galactose and streptozotocin diabetes

In an initial study, the effects of galactose intoxication on nerve laser Doppler blood flow (NLDF) and nerve conduction velocity (NCV) were assessed after 1–16 weeks of galactose feeding in pentobarbital-anesthetized rats. NLDF was not significantly changed at any time point. NCV was significantly reduced after 16, but not 1 or 4, weeks of galactose feeding. In a second study, NLDF was not significantly changed by 4 weeks of galactose intoxication, but streptozotocin-diabetic NLDF was significantly reduced compared to both control ( P<0.001) and galactose-intoxicated rats ( P<0.05). Compared to control animals, sciatic motor NCV was significantly ( P<0.001) reduced in the galactose group, while sciatic and saphenous sensory NCVs were not significantly changed. In the streptozotocin-diabetic rats, motor and sensory NCVs were all significantly reduced ( P<0.001). In contrast to the NCV findings, mean caliber of myelinated axons in both the saphenous and sciatic nerves was reduced in galactose-intoxicated, but not streptozotocin-diabetic rats. The observed sequence of changes associated with these two models of diabetic neuropathy is not consistent with the proposed roles of ischemia and axonal dwindling in the reported nerve conduction deficits.

NT-3 attenuates functional and structural disorders in sensory nerves of galactose-fed rats.

The present study investigated the effect of NT-3, a neurotrophin expressed in nerve and skeletal muscle, on myelinated fiber disorders of galactose-fed rats. Adult, female Sprague-Dawley rats were fed diets containing complete micronutrient supplements and either 0% D-galactose (control) or 40% D-galactose. Treated controls received 20 mg/kg NT-3 and treated galactose-fed rats received 1, 5, or 20 mg/kg NT-3 three times per week by subcutaneous injections. After 2 months, sciatic and saphenous sensory nerve conduction velocity (SNCV) and sciatic motor nerve conduction velocity (MNCV) were measured and the sciatic, sural, peroneal and saphenous nerves and dorsal and ventral roots processed for light microscopy. Treatment of control animals with NT-3 had no effect on any functional or structural parameter. Compared to control values, galactose feeding induced a sensory and motor nerve conduction deficit and a reduction in axonal caliber. Treatment with 5 and 20 mg/kg NT-3 ameliorated deficits in sciatic and saphenous SNCV in galactose-fed rats but had no effect on the MNCV deficit. NT-3 treatment also attenuated the decrease in mean axonal caliber in the dorsal root and sural nerve but not in the saphenous nerve, ventral root and peroneal nerve. These observations show that NT-3 can selectively attenuate the sensory conduction deficit of galactose neuropathy in a dose-dependent manner that depends only in part on restoration of axonal caliber of large-fiber sensory neurons.

Nerve function and regeneration in diabetic and galactosaemic rats: antioxidant and metal chelator effects

Immature rats were made diabetic with streptozotocin or were fed a 40% galactose diet to stimulate the polyol pathway. Separate diabetic and galactosaemic groups were treated with butylated hydroxytoluene or trientine. After 4 weeks the sciatic nerve was freeze-lesioned. Two weeks later, the degree of myelinated fibre regeneration was assessed electrophysiologically and nerve conduction velocity was measured in the contralateral leg. Similar sciatic motor and saphenous sensory nerve conduction velocity deficits of approximately 18% and 19%, respectively, compared to age-matched control rats were found in both models. They were partially prevented by treatment (approximately 68% for butylated hydroxytoluene and 63% for trientine). There were 12% and 10% deficits in nerve regeneration distance with diabetes and galactosaemia respectively, which were markedly attenuated (approximately 80%) by both treatments. The data emphasise the importance of elevated free radical activity for the aetiology of neural/neurovascular deficits in experimental diabetes and galactosaemia.

Nerve function in galactosaemic rats: effects of evening primrose oil and doxazosin

Rats were fed for 6 weeks with a 40% galactose diet to chronically stimulate the polyol pathway. Sciatic motor and saphenous sensory nerve conduction velocity deficits of 22% and 14% respectively developed. Treatment with evening primrose oil or doxazosin from galactosaemia induction partially (approximately 60%) prevented the development of reduced motor and sensory conduction, the former treatment being more successful than the latter. Sciatic nerve resistance to hypoxic conduction failure was 49% increased by galactosaemia. This abnormality was 27% and 43% prevented by doxazosin and evening primrose oil respectively. Galactosaemic sciatic nerves had a 10% increase in water content and endoneurial capillary density was 24% reduced. While neither treatment affected water content, both caused angiogenesis, elevating capillary density by approximately 16%. The data support the hypothesis that, as in experimental diabetes mellitus, the main effect of polyol pathway activation on peripheral nerve function occurs indirectly via a neurovascular action.

Angiotensin II receptor blockade improves nerve function, modulates nerve blood flow and stimulates endoneurial angiogenesis in streptozotocin-diabetic rats and nerve function.

We examined the effect of the angiotensin II receptor blocker, ZD 8731, on nerve function, capillary density, and blood flow in streptozotocin-diabetic rats. Deficits in sciatic motor and saphenous sensory nerve conduction velocity of 21% and 15%, respectively, were observed after 1 month of diabetes mellitus (p < 0.001). These were completely ameliorated by a further month of ZD 8731 treatment (p < 0.001). Treatment of non-diabetic rats for 1 month with ZD 8731 had no effect on motor or sensory conduction velocity. Sciatic nerve capillary density was not significantly affected by 1- or 2-month untreated diabetes, however, there was a 15% increase in density with ZD 8731 treatment (p < 0.001). Treatment of non-diabetic rats for 1 month had no effect on capillary density. Diabetes prolonged the time taken for 80% conduction failure by 19% (p < 0.05) and 49% (p < 0.001) for 1 and 2 months of diabetes, respectively, when sciatic nerve was exposed to hypoxia in vitro. ZD 8731 treatment during the second month of diabetes limited the prolongation to 22%, not significantly different from 1 month of untreated diabetes but less than for the 2-month diabetic group (p < 0.001). Concentrations of sciatic nerve polyol pathway metabolites were elevated six-fold and myo-inositol was reduced 40% by diabetes; ZD 8731 treatment was without effect. Acute experiments examined the effect of ZD 8731 on sciatic nerve blood flow using laser-Doppler flowmetry. In non-diabetic rats, blood flow changes followed the dose-dependent reductions in systemic arterial pressure and there were no significant variations in sciatic vascular resistance.(ABSTRACT TRUNCATED AT 250 WORDS)