| In cultured Schwann cells, elevated glucose induces alterations in arachidonic acid metabolism that causes a decrease in the content of glycerophospholipid arachidonoyl-containing molecular species (ACMS). This could result from decreased de novo arachidonic acid biosynthesis. Incorporation of radioactive 8,11,14-eicosatrienoic acid into ACMS was lower for cells grown in 30 mM vs. 5 mM glucose, consistent with a decrease in Δ5 desaturase activity. Free cytosolic NAD+/NADH decreased whereas NADP +/NADPH remained unchanged for cells grown in elevated glucose, implying that decreased desaturase activity is a result of metabolic changes other than reduced cofactor availability. Schwann cells in elevated glucose were susceptible to oxidative stress, as shown by increased malonaldehyde, depleted glutathione levels, and reduced cytosolic superoxide dismutase activity. In addition, oxygen consumption was not affected by varying glucose concentration, suggesting that weakened antioxidant protection mechanisms are especially important in glucose-induced oxidative stress. Glutathionealtering compounds had no effect on ACMS levels, in contrast to N-acetyl cysteine, and α-lipoic acid, which partly corrected ACMS depletion in phosphatidylcholine. Zopolrestat, an aldose reductase inhibitor, known to partly correct ACMS depletion, also improved incorporation of eicosatrienoic acid into ACMS.; These findings suggest that in the Schwann cell cultures, a high glucose level elicits oxidative stress, stimulates polyol pathway activity, and weakens antioxidant protection mechanisms that could decrease arachidonic acid biosynthesis and that this deficit can be partly corrected by treatment with exogenous antioxidants.; We attempted to extrapolate these observations to experimentally diabetic animals, namely STZ-diabetic rats, as a model for type I diabetes, and Zucker diabetic fatty (ZDF) rats, for type II diabetes. Preventive administration of the aldose reductase inhibitor, sorbinil, or the antioxidants, vitamin E and α-lipoic acid, did not restore ACMS or glutathione levels in diabetic sciatic nerves to the extent observed in cultured Schwann cells. In ZDF rats, high fat intake, age, and gender are all contributing factors to increased oxidative stress in diabetic animals, and have a limited, but visible influence on ACMS depletion.; These results suggest that altered arachidonic acid metabolism is influenced by biochemical factors like increased oxidative stress and heightened polyol pathway activity. |
