Vitamin E an lipoic acid (LA) can be considered metabolic antioxidants for a number of reasons:

1. Lipoamide in the E2 enzyme of mitochondria is an essential cofactor in oxidative metabolism.
2. Both substances are linked via recycling pathways to NADH and NADPH, allowing redox and antioxidant functions.
3. Both affect oxidant-induced transcription and signal transduction.
4. Vitamin E and LA inhibit activation of NF-kB by TNF-alpha and H₂O₂ in Jurkat and Wurzburg T-lymphocytes respectively.

Vitamin E and lipoate form an antioxidant network, rendering dihydrolipoate highly effective in a number of conditions of oxidative stress, e.g.,

1. Lipoate completely protects vitamin E-deficient animals from symptoms of E-deficiency.
2. 100% of GSH-depleted newborn rats (buthione suloximine-trated) develop cataracts. Lipoate protected against loss of GSH, vitamin C and vitamin E: in BSO-trated rat lenses glutathione, vitamin E and ascorbate decreased but in BSO+LA rats they were about 90% of normal.
3. In vitro diabetic cataractogenesis: Isolated rat lenses were incubated in 55mM glucose medium +/- LA (R,S, or racemic form)). Lenses in control medium remained clear and had no LDH leakage; those in glucose medium developed opacities and LDH leakage in 48 hours, and lenses incubated with glucose + LA exhibited stereospecific protection: R-LA completely protected from opacity, but the S form did not protect.
4. In rats subjected to reperfusion following ischemia induced by bilateral carotid artery occlusion, pretretment with LA (25 mg/kg intravenous) decreased mortality from 78% to 26%, almost completely abolished ischemia/reperfusion-induced losses of glutathione in the cortex, striatum and hippocampus, and reduced the average rise in TBARS in these brain regions from 225% to 60%. These are among the strongest therapeutic antioxidant effects yet observed in the protection against cerebral ischemia-reperfusion injury.