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
R. Kuruvilla et J. Eichberg, 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, Journal of neurochemistry, 71(2), 1998, pp. 775-783
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.