The effect of aldose reductase inhibition on motor nerve conduction velocity in diabetic rats

Summary. This study examined the effects of an aldose reductase inhibitor, Sorbinil, on neuropathy over a 6-month period in streptozotocin-diabetic rats. Sorbinil treatment prevented the 10-fold increase in nerve sorbitol found with diabetes. It produced a 60% improvement in tibial nerve motor conduction velocity after 6 months. Morphometric profiles of nerves were also normalised. Axon area was reduced by 14% in untreated diabetic rats compared to age-matched controls, whereas Sorbinil-treated animals showed normal age-related axon growth. Myelin area was increased by 28% in untreated diabetic animals, but was the same as age-matched controls with Sorbinil treatment. Nerve myo-inositol levels were reduced by 45% after three months of untreated diabetes, but were normal after six months. Sorbinil treatmend tended to restore myo-inositol levels toward normal over the shorter time period. It was concluded that axon growth retardation is the most likely cause of the conduction deficit seen in longterm experimental diabetes.

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“…Yue et al [7] demonstrated a similar effect starting with younger animals over a 9-month period. However, they did not control nerve temperature.…”

Section: Discussionmentioning

confidence: 80%

“…In diabetic rats, aldose reductase inhibitor treatment has been found to improve conduction velocity [7], reduce polyol and restore myo-inositol levels [8], and to enhance axonal transport [9]. However, there is disagreement in the literature; treatments that increase diabetic nerve myoinositol content do not necessarily improve conduction velocity [10].…”

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confidence: 99%

The effects of Sorbinil on peripheral nerve conduction velocity, polyol concentrations and morphology in the streptozotocin-diabetic rat

et al. 1986

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“…Hyperglycaemiainduced mitochondrial production of ROS has been shown to induce activation of the polyol pathway [20]. Inhibition of aldose reductase activity has previously been used to inhibit glucose metabolism through the polyol pathway [21,22,23]. In the present study we used AL-1576, which in comparative studies with other aldose reductase inhibitors has been shown to be both highly potent and selective and to lack antioxidant effects [24,25].…”

Section: Discussionmentioning

confidence: 99%

Polyol-pathway-dependent disturbances in renal medullary metabolism in experimental insulin-deficient diabetes mellitus in rats

et al. 2004

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Aims/hypothesis. The renal medullary region is particularly vulnerable to reduced oxygen concentration because of its low blood perfusion and high basal oxygen consumption. This study investigated renal metabolic changes in relation to the previously observed decreased oxygen tension in streptozotocin-induced diabetic rats. Methods. Blood perfusion, oxygen tension and consumption, interstitial pH, and glycolytic and purinebased metabolites were determined in the renal cortex and the medulla of non-diabetic and diabetic animals by, respectively, laser Doppler flowmetry, oxygen and pH microelectrodes, and microdialysis. The importance of increased polyol pathway activity for the observed alterations was investigated by daily treatment with the aldose reductase inhibitor AL-1576 throughout the course of diabetes.Results. The diabetes-induced decrease in renal oxygen tension, due to augmented oxygen consumption, did not result in manifest hypoxia in either the cortical or the medullary region, as evaluated by microdialysis measurements of purine-based metabolites. The profound alterations in medullary oxygen metabolism were, however, associated with an increased lactate : pyruvate ratio and a concomitantly decreased pH. Notably, the renal medullary changes in oxygen tension, oxygen consumption, lactate : pyruvate ratio and pH were preventable by inhibition of aldose reductase. Conclusions/interpretation. Substantial metabolic changes were observed in the renal medulla in diabetic animals. These disturbances seemed to be mediated by increased polyol pathway activity and could be prevented by inhibition of aldose reductase.

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“…In the diabetic rat these complications can be ameliorated by aldose reductase inhibition [10,17], thus demonstrating a reversible component, at least over a relatively short period in this species. In man, elevated sorbitol and fructose concentrations are found in the nerves of diabetic patients [18] and the reduction of erythrocyte sorbitol levels by sorbinil in diabetic patients [19] suggests a possible role for this agent in the treatment of diabetic neuropathy.…”

Section: Discussionmentioning

confidence: 99%

Clinical and neurophysiological studies with the aldose reductase inhibitor, sorbinil, in symptomatic diabetic neuropathy

et al. 1984

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Summary. The effect of sorbinil (200 mg daily for 4 weeks) was examined in 13patients, mean age 59.7years (range 42-72 years), with symptomatic diabetic neuropathy of mean duration 6years (range 1-18years). In this double-blind, placebo-controlled crossover trial, studies were made of motor, sensory and autonomic nerve function, severity of painful symptoms and duration of sleep. One patient was withdrawn because of an adverse reaction to sorbinil. In the other 12, constant mean values for glycosylated haemoglobin A1 between 11% and 12% indicated stable though not ideal diabetic control throughout the study. Example values for nerve conduction velocity on placebo and active treatment were: 44.3 +_ 5.9 and 44.8 + 5.1 metres/s (mean + SD) for median motor nerve, 38.4+8.2 and 37.2+7.7metres/s for median sensory nerve. Thus there was no significant effect of sorbinil on conduction velocity in these or any other of the motor and sensory nerves tested. Abnormal autonomic function was not improved by sorbinil. Subjective pain scores on a 10 cm visual analogue scale were 4.2 + 2.4 on placebo and 4.3 + 2.4 after sorbinil. Duration of sleep on placebo and active treatment was 6.1 _+ 1.6 and 6.2 + 1.7 h/night, respectively. We were not able to detect any beneficial effect of sorbinil on painful diabetic neuropathy in our patients.Key words: Aldose reductase inhibitor, sorbinil, diabetic neuropathy.Peripheral neuropathy is a common complication of diabetes mellitus and in some patients severe pain may be experienced which is refractory to conventional treatments. Impaired nerve function may be related to inadequate control of blood glucose levels [1,2]. Recently, improvement in glycaemic control using continuous subcutaneous insulin infusion [3,4] and intensive intermittent subcutaneous insulin injections [5] have been associated with an observed improvements in neurophysiological function. Unfortunately, there are many difficulties in implementing such regimens so that normal or near normal blood glucose levels cannot be achieved in many patients. Effective alternative treatments for symptomatic diabetic neuropathy would therefore be valuable.Sorbitol and fructose accumulate in the nerves of diabetic animals and man in proportion to the degree of hyperglycaemia [6,7] and have been implicated in the impaired nerve conduction [8,9]. Inhibition of aldose reductase, the first and rate-limiting enzyme in the polyol pathway, has a beneficial effect on nerve conduction in rats with spontaneous galactosaemia and with streptozotocin-induced diabetes [6,/0]. Sorbinil, a non-competitive inhibitor of aldose reductase, has recently become available for use in man. Initial reports have suggested that treatment with this inhibitor may improve motor and sensory nerve conduction velocities [11] and reduce painful symptoms and weakness [12] in patients with diabetic neuropathy. In the present study we have examined the effects of this drug in patients with symptomatic diabetic neuropathy. Subjects and methods Subjects and study designA ran...

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The effect of aldose reductase inhibition on motor nerve conduction velocity in diabetic rats

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The effects of Sorbinil on peripheral nerve conduction velocity, polyol concentrations and morphology in the streptozotocin-diabetic rat

The effects of Sorbinil on peripheral nerve conduction velocity, polyol concentrations and morphology in the streptozotocin-diabetic rat

Polyol-pathway-dependent disturbances in renal medullary metabolism in experimental insulin-deficient diabetes mellitus in rats

Clinical and neurophysiological studies with the aldose reductase inhibitor, sorbinil, in symptomatic diabetic neuropathy

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