Prevention and reversal of defective axonal transport and motor nerve conduction velocity in rats with experimental diabetes by treatment with the aldose reductase inhibitor sorbinil

• Published in: Diabetes (New York, N.Y.) Vol. 33; no. 5; pp. 470 - 476
• Main Authors: TOMLINSON, D. R, MORIARTY, R. J, MAYER, J. H
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01-05-1984
• Subjects: Aldehyde Reductase - antagonists & inhibitors; Animals; Axonal Transport; Biological and medical sciences; Choline O-Acetyltransferase - metabolism; Diabetes Mellitus, Experimental - physiopathology; Diabetes. Impaired glucose tolerance; Diabetic Neuropathies - drug therapy; Diabetic Neuropathies - physiopathology; Diabetic Neuropathies - prevention & control; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Imidazoles - therapeutic use; Imidazolidines; Inositol - metabolism; Male; Medical sciences; Neural Conduction; Rats; Rats, Inbred Strains; Sciatic Nerve - physiopathology; Sorbitol - metabolism; Endocrinopathy; Conduction; Nervous system diseases; Rat; Diabetes mellitus; Rodentia; Enzyme inhibitor; Prevention; Vertebrata; Experimental disease; Mammalia; Aldose reductase; Axoplasmic transport; Motor nerve; Streptozotocin
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diab.33.5.470

This investigation was designed to determine whether the aldose reductase inhibitor Sorbinil prevented the development of or reversed defects of nerve conduction and axonal transport in streptozotocin-diabetic rats. Untreated diabetes of either 3 or 6 wk duration caused a fall in sciatic motor nerve conduction velocity (MNCV) of 6-9 m/s (P less than 0.001) and significantly reduced the accumulation of axonally transported choline acetyltransferase activity against a 24-h sciatic nerve crush. These functional defects were associated with accumulation of sorbitol and depletion of myo-inositol in the sciatic nerve. Treatment with Sorbinil (25 mg/kg/day, p.o.) throughout the period of diabetes prevented the development of all these abnormalities in both 3- and 6-wk diabetic groups. In a second study, three groups of rats were subject to 3 wk untreated diabetes followed by Sorbinil treatment (as above) for 1, 2, or 3 wk to determine whether the abnormalities expected from 3 wk of untreated diabetes could be reversed. One week of treatment significantly elevated both MNCV and choline acetyltransferase accumulation (P less than 0.05). The longer treatments progressively ameliorated these defects such that the group that received Sorbinil for the second 3 wk of a 6-wk diabetic period gave values that were similar to controls and to diabetic rats that had been given Sorbinil throughout their diabetes. Sorbitol accumulation was markedly reduced by only 1 wk of Sorbinil treatment, but the normalization of myo-inositol levels required 2 wk of treatment. These findings indicate that Sorbinil treatment in diabetic rats prevented and reversed both Sorbitol accumulation and depletion of nerve myo-inositol in the sciatic nerve.