Dissociation between biochemical and functional effects of the aldose reductase inhibitor, ponalrestat, on peripheral nerve in diabetic rats

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Abstract
1 The aim of the study was to examine the effects in rats of two different doses of the aldose reductase inhibitor, ponalrestat, on functional measures of nerve conduction and sciatic nerve biochemistry. 2 After 1 month, streptozotocin-induced diabetes produced 22%, 23% and 15% deficits in conduction velocity of sciatic nerves supplying gastrocnemius and tibialis anterior muscles and saphenous sensory nerve respectively compared to controls. These deficits were maintained over 2 months diabetes. 3 Slower-conducting motor fibres supplying the interosseus muscles of the foot did not show a diabetic deficit compared to onset controls, however, there was a 13% reduction in conduction velocity after 2 months diabetes relative to age-matched controls, indicating a maturation deficit. 4 Resistance to hypoxic conduction failure was investigated for sciatic nerve trunks in vitro. There was an increase in the duration of hypoxia necessary for an 80% reduction in compound action potential amplitude with diabetes. This was progressive; after 1 month, hypoxia time was increased by 22% and after 2 months by 57%. 5 The effect of 1-month treatment with the aldose reductase inhibitor, ponalrestat, on the abnormalities caused by an initial month of untreated diabetes was examined. Two doses of ponalrestat were employed, 8 mg kg−1 day−1 (which is equivalent to, or greater than, the blockade employed in clinical trials), and 100 mg kg−1 day−1. 6 Sciatic nerve sorbitol content was increased 7 fold by diabetes. Both doses were effective in reducing this 70% for 8 mg kg−1 day−1, and to within the control range for 100 mg kg−1 day−1. However, 8 mg kg−1 day−1 produced only a modest lowering (44%) of the 8 fold increase in fructose content, indicating that flux through the polyol pathway remained substantially elevated. For 100 mg kg−1 day−1 ponalrestat, fructose content was within the normal range, indicating a profound inhibition of flux through the pathway. 7 Conduction velocity abnormalities in sciatic motor branches supplying gastrocnemius and tibialis anterior muscles, and sensory saphenous nerve were completely restored by treatment with ponalrestat at 100 mg kg−1 day−1, whereas 8 mg kg−1 day−1 was completely ineffective. The maturation deficit for interosseus motor nerve was unaffected by treatment. 8 Neither 8 or 100 mg kg−1 day−1 ponalrestat reversed the increased resistance to hypoxic conduction failure resulting from the initial month of untreated diabetes. However, both doses prevented further increases in hypoxic resistance over the treatment period. 9 Three main conclusions were reached. First, substantial blockade of polyol pathway flux is necessary to reverse conduction velocity deficits and this degree of aldose reductase inhibition has not been achieved in clinical trials. Second, nerve content of fructose is a better biochemical indicator of likely functional benefit than that of sorbitol. Third, conduction velocity and hypoxic resistance were differentially affected by the two doses of ponalrestat, a finding that suggests differences in their aetiology.

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