Comparison of the effects of inhibitors of aldose reductase and sorbitol dehydrogenase on neurovascular function, nerve conduction and tissue polyol pathway metabolites in streptozotocin-diabetic rats

Abstract

Elevated polyol pathway activity has been implicated in the development of diabetic complications, including neuropathy [1]. In diabetic models, inhibitors of the first enzyme in the pathway, aldose reductase, prevent or correct nerve conduction velocity (NCV) and regeneration deficits [2][3][4][5][6][7][8][9][10][11][12][13]. Clinical trials of aldose reductase inhibitors (ARIs) have shown modest improvements in neurological symptoms, NCV, sensory measures, and an increase in nerve fibre regeneration [14-17] despite a less effective polyol pathway blockade than was found necessary for functional effects in animal studies [6,10,18].Several hypotheses have been advanced to explain the action of ARI. Some putative mechanisms are primarily dependent on the first half of the polyol pathway, conversion of glucose to sorbitol by aldose Diabetologia (1997) 40: 271-281 Comparison of the effects of inhibitors of aldose reductase and sorbitol dehydrogenase on neurovascular function, nerve conduction and tissue polyol pathway metabolites in streptozotocin-diabetic rats Summary Aldose reductase inhibitors (ARIs) attenuate diabetic complications in several tissues, including lens, retina, kidney, blood vessels, striated muscle and peripheral nerve. However, it is unclear whether their action in diabetes mellitus depends directly on inhibiting the conversion of glucose to sorbitol by aldose reductase or indirectly by reducing the sorbitol available for subsequent metabolism to fructose by sorbitol dehydrogenase. To identify the polyol pathway step most relevant to complications, particularly neuropathy, we compared the biochemical effects of a sorbitol dehydrogenase inhibitor, WAY-135 706, (250 mg ⋅ kg −1 ⋅ day −1 ) and an ARI, WAY-121 509, (10 mg ⋅ kg −1 ⋅ day −1 ) on a variety of tissues, and their effects on nerve perfusion and conduction velocity. After 6 weeks of untreated streptozotocin diabetes, rats were treated for 2 weeks. Sorbitol was elevated 2.1-32.6-fold by diabetes in lens, retina, kidney, aorta, diaphragm, erythrocytes and sciatic nerve; this was further increased (1.6-8.2-fold) by WAY-135 706 whereas WAY-121 509 caused a marked reduction. Fructose 1.6-8.0-fold elevated by diabetes in tissues other than diaphragm, was reduced by WAY-135 706 and WAY-121 509, except in the kidney. Motor and sensory nerve conduction velocities were decreased by 20.2 and 13.9 %, respectively with diabetes. These deficits were corrected by WAY-121 509, but WAY-135 706 was completely ineffective. A 48.6 % diabetes-induced deficit in sciatic nutritive endoneurial blood flow was corrected by WAY-121 509, but was unaltered by WAY-135 706. Thus, despite profound sorbitol dehydrogenase inhibition, WAY-135 706 had no beneficial effect on nerve function. The data demonstrate that aldose reductase activity, the first step in the polyol pathway, makes a markedly greater contribution to the aetiology of diabetic neurovascular and neurological dysfunction than does the second step involving sorbitol dehydrogenase. [Diabetologia (1997) 40: ...

Effect of Treating Streptozotocin‐Induced Diabetic Rats With Sorbinil, Myo‐Inositol or Aminoguanidine on Endoneurial Blood Flow, Motor Nerve Conduction Velocity and Vascular Function of Epineurial Arterioles of the Sciatic Nerve

“…Immediately after determination of MNCV, sciatic nerve endoneurial nutritive blood flow was determined as described by Cameron et al [33,50]. The trachea was intubated for mechanical ventilation and a carotid cannula inserted to monitor mean arterial blood pressure.…”

Evaluation of a sorbitol dehydrogenase inhibitor on diabetic peripheral nerve metabolism: a prevention study

“…Some groups [29±31] have reported that SDIs reduce nerve conduction deficit induced by diabetes. Others failed to find improved nerve conduction in diabetic rats treated with SDI compared with an untreated diabetic group [4] or in SDH-deficient diabetic mice compared with diabetic mice with normal SDH levels [32].…”

“…[Diabetologia (1999) 42: 1187±1194] pletely understood. A number of reports [1,2,4, 10±14] link vascular [4, 15±20], metabolic [21±24] and neurotrophic [25±27] imbalances that are induced by diabetes to the activity of the first half of the sorbitol pathway, aldose reductase. Some investigators [28,29] have hypothesized that adverse consequences of increased sorbitol pathway activity in the diabetic nerve are not due to aldose reductase activation itself, but are related to the second half of the sorbitol pathway, sorbitol dehydrogenase (SDH).…”

“…According to the concept of ªdiabetic pseudohypoxiaº [28], the increased flux through SDH accounts for NAD-redox imbalances (increase in NADH:NAD + ratio) related to diabetes and constitutes a universal mechanism for development of diabetic complications including neuropathy, retinopathy and nephropathy. Studies of the role for SDH in diabetic complications using SDH inhibitors (SDIs) [4,30,31] as well as a SDH-deficient mouse model [32] resulted in contradictory findings. Some groups [29±31] have reported that SDIs reduce nerve conduction deficit induced by diabetes.…”

“…These abnormalities which develop gradually and become manifest in long-standing diabetes [38,39] exacerbate nerve functional deficits acquired in the initial phase of diabetic neuropathy. The importance of sorbitol pathway-linked metabolic imbalances in neural structures is illustrated by findings [41] of a large increase in neuroaxonal dystrophy with SDH inhibition by the dose of SDI not affecting nerve blood flow in the diabetic model of lesser duration [4]. Out of a variety of metabolic variables, we have selected nerve energy status and indices of oxidative stress.…”