DEPLETION OF PHOSPHOLIPID ARACHIDONOYL-CONTAINING MOLECULAR-SPECIES IN A HUMAN SCHWANN-CELL LINE GROWN IN ELEVATED GLUCOSE AND THEIR RESTORATION BY AN ALDOSE REDUCTASE INHIBITOR

In experimental diabetic neuropathy, defective arachidonic acid metabo lism characterized by a decrease in the proportion of glycerophospholi pid arachidonoyl-containing molecular species (ACMS) occurs and has be en implicated in the pathogenesis of the disorder. In this study, we e valuated the suitability of a tumor-derived human Schwann cell line (N F1T) as a model to investigate the mechanism underlying the loss of AC MS. NF1T cells grown in 30 versus 5.5 mM glucose undergo a marked redu ction in ACMS in phosphatidylcholine, phosphatidylethanolamine, and ph osphatidylinositol, in a manner resembling that of diabetic nerve, The depletion of ACMS can be reversed on transferring the cells from 30 m M glucose to medium containing physiological levels of glucose. Cells maintained in 5.5 nM glucose plus 25 mM mannitol or sorbitol did not e xhibit decreased ACMS levels, indicating that osmotic effects were not responsible for ACMS depletion. However, growth in 25 mM fructose eli cited a reduction of ACMS similar to that produced by 30 mM glucose. E xcessive glucose flux through the polyol pathway has been implicated i n the neural and vascular abnormalities associated with diabetes. Ther efore, we examined the effects of polyol pathway inhibitors, including two aldose reductase inhibitors, zopolrestat and sorbinil, and a sorb itol dehydrogenase inhibitor (SDI), CP166,572, on ACMS levels in NF1T cells cultured in elevated glucose concentrations. At 200 mu M, zopolr estat fully and sorbinil partially corrected ACMS depletion. The SDI a t concentrations up to 100 mu M failed to affect diminished ACMS level s. Neither zopolrestat nor the SDI restored ACMS levels reduced in the presence of elevated fructose concentrations. These findings suggest that enhanced flux through the polyol pathway and, in particular, elev ated aldose reductase activity may play a significant role in the redu ction of ACMS levels in the cells brought about by elevated glucose le vels.