MODULATION OF CELLULAR REDUCING EQUIVALENT HOMEOSTASIS BY ALPHA-LIPOIC ACID - MECHANISMS AND IMPLICATIONS FOR DIABETES AND ISCHEMIC-INJURY

The therapeutic potential of alpha-lipoic acid (thioctic acid) was eva luated with respect to its influence on cellular reducing equivalent h omeostasis. The requirement of NADH and NADPH as cofactors in the cell ular reduction of alpha-lipoic acid to dihydrolipoate has been reporte d in various cells and tissues. However, there is no direct evidence d escribing the influence of such reduction of alpha-lipoate on the leve ls of cellular reducing equivalents and homeostasis of the NAD(P)H/NAD (P) ratio. Treatment of the human Wurzburg T-cell line with 0.5 mM alp ha-lipoate for 24 hr resulted in a 30% decrease in cellular NADH level s. alpha-Lipoate treatment also decreased cellular NADPH, bur this eff ect was relatively less and slower compared with that of NADH. A conce ntration-dependent increase in glucose uptake was observed in Wurzburg cells treated with alpha-lipoate. Parallel decreases (30%) in cellula r NADH/NAD(+) and in lactate/pyruvate ratios were observed in alpha-li poate-treated cells. Such a decrease in the NADH/NAD(+) ratio followin g treatment with alpha-lipoate may have direct implications in diabete s, ischemia-reperfusion injury, and other pathologies where reductive (high NADH/NAD(+) ratio) and oxidant (excess reactive oxygen species) imbalances are considered as major factors contributing to metabolic d isorders. Under conditions of reductive stress, alpha-lipoate decrease s high NADH levels in the cell by utilizing it as a co-factor for its own reduction process, whereas in oxidative stress both alpha-lipoate and its reduced form, dihydrolipoate, may protect by direct scavenging of free radicals and recycling other antioxidants from their oxidized forms. Copyright (C) 1997 Elsevier Science Inc.