Recent advances in the therapy of diabetic peripheral neuropathy by means of an aldose reductase inhibitor.
Nerve conduction slowing, a hallmark of both experimental and human diabetic neuropathy, is improved or corrected by administration of aldose reductase inhibitors such as sorbinil. Recent experiments in animals attribute acutely reversible nerve conduction slowing in diabetes to a myo-inositol-related defect in nerve sodium-potassium adenosinetriphosphatase, which generates the transmembrane sodium and potassium potentials necessary for nerve impulse conduction and the sodium gradient necessary for sodium-dependent uptake of substrates. This myo-inositol-related abnormality in sodium-potassium adenosinetriphosphatase function is currently viewed as a cyclic metabolic defect involving sequential alteration of sodium-dependent myo-inositol uptake, myo-inositol content, myo-inositol incorporation into membrane phospholipids, and phospholipid-dependent sodium-potassium adenosinetriphosphatase function in peripheral nerve. Aldose reductase inhibitors have been shown to normalize both nerve myo-inositol content and nerve sodium-potassium adenosinetriphosphatase activity. These observations suggest that the acute effects of aldose reductase inhibitors on nerve conduction in both animals and humans with diabetes may be mediated by correction of an underlying myo-inositol-related nerve sodium-potassium adenosinetriphosphatase defect. Furthermore, this sorbinil-corrected sodium-potassium adenosinetriphosphatase defect in diabetic nerve may contribute to other biochemical, functional, and structural abnormalities present in diabetic peripheral neuropathy.
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D001692:Biological Transport; D003929:Diabetic Neuropathies / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D048289:Imidazolidines; D007294:Inositol / Q000172:deficiency; D009431:Neural Conduction / Q000187:drug effects; D010525:Peripheral Nerves / Q000378:metabolism; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013012:Sorbitol / Q000378:metabolism; D013401:Sugar Alcohol Dehydrogenases / Q000037:antagonists & inhibitors*
D007093:Imidazoles; D048289:Imidazolidines; D007294:Inositol; D013012:Sorbitol; D013401:Sugar Alcohol Dehydrogenases; D000449:Aldehyde Reductase; D000254:Sodium-Potassium-Exchanging ATPase; C026411:sorbinil