The “Redox Couple” of Lipoic Acid and Dihydrolipoic Acid
Oxidation reduction (redox reactions) involves the transfer of an electron from a donor to an acceptor. When the donor loses an electron, it is transformed from its reduced form to its oxidized form; when an acceptor gains an electron, it changes from its oxidized form to its reduced form. Together, the oxidized and reduced forms of a redox component are called a redox couple.
Alpha-Lipoic Acid occurs in two forms in the body: R-Lipoic Acid (RLA) and R-Dihydrolipoic Acid (R-DHLA). The two make up a “redox couple.”
R-Dihydrolipoic Acid is the reduced (has electrons added) form of R-Lipoic Acid. When R-DHLA is oxidized (has electrons removed) R-Lipoic Acid is produced.
R-Lipoic Acid donates an electron to R-DHLA, and the R-DHLA reacts with a free radical and is then oxidized back into R-Lipoic Acid, and the R-Lipoic Acid is then reduced using cellular reducing equivalents (NADH or NADPH) back into R-DHLA thus continuing the redox cycle. As the two forms swap electrons, they rapidly convert. Many of the properties of Lipoic Acid depend on this ability to rapidly swap electrons.
Unique Properties of R-Dihydrolipoic Acid
R-DHLA regenerates the antioxidants vitamin C, thioredoxin and glutathione which in turn can recycle vitamin E.1 Many of the properties generally attributed to R-Lipoic Acid are in fact due to its “redox” partner R-DHLA.
- R-DHLA reacts with a wider variety of free radicals and is therefore considered to be the more “powerful” anti-oxidant of the redox couple RLA/R-DHLA.2
- R-DHLA scavenges hypochlorous acid, peroxyl radicals and hydroxyl radicals.2
- R-DHLA is believed to prevent lipid peroxidation by reducing oxidized glutathione, thus altering the glutathione/glutathione disulphide (GSH/GSSG) ratio which decreases steadily after 45 years of age.
- Both R-DHLA and R-Lipoic Acid have metal-chelating capacity and scavenge reactive oxygen species (ROS), whereas only R-DHLA is able to regenerate endogenous antioxidants and to repair oxidative damage.*3
- R-DHLA inhibits COX-2 activity.4
- R-DHLA is the most effective antioxidant among sulfur-containing antioxidant compounds. Sulfur is an essential element for the entire biological kingdom because of its incorporation into amino acids, proteins and other bio-molecules. Sulfur-containing compounds are found in all body cells and are indispensable for life.5
- R-DHLA enhances glucose transport via the insulin signaling pathway.6
- R-DHLA but not R-Lipoic Acid, was shown to prevent ischemia-reperfusion induced damage in the heart and reduced the amount of tissue which dies due to a lack of oxygen resulting from a blood clot or blocking of an artery.7,8
- R-DHLA protects against single strand DNA breaks induced by singlet oxygen, although it does not do so directly and several steps might be involved in the process.9
However, in some cases, R-Dihydrolipoic Acid can also exert pro-oxidant properties, both by its iron ion-reducing ability and probably by its ability to generate reactive sulphur-containing radicals that can damage certain proteins. It may also act to regenerate ascorbate, which is known to reduce iron.
Combining R-Lipoic Acid and R-DHLA
The redox pair RLA/R-DHLA may provide more antioxidant protection than either alone. As a nutritional supplement, R-DHLA is best combined with R-Lipoic Acid as in GeroNova’s R-PLUS gelcaps.
RLA/R-DHLA act as antioxidants not only directly, through free radical quenching and metal chelation, but indirectly as well, through recycling of other antioxidants and possibly through increasing intracellular levels of glutathione.
Using the combination of RLA/R-DHLA can maintain the plasma redox status and may be one of the most effective means of controlling age-related increases in oxidative stress.
*An excessive production of ROS can overwhelm the endogenous antioxidant defense system resulting in lipid peroxidation, DNA strand breaks, protein denaturation and cross-linking. The brain is particularly vulnerable to oxidative injury, because it contains high concentrations of readily oxidized poly-unsaturated fatty acids, has a high rate of oxygen consumption per unit mass and has only a relatively modest antioxidant defense system.
- Molecular aspects of Lipoic Acid in the prevention of diabetes complications. Packer L, Kraemer K, Rimbach G. Nutrition. 2001 Oct;17(10):888-95
- The pharmacology of the antioxidant Lipoic Acid. Biewenga GP, Haenen GR, Bast A. Gen Pharmacol. 1997 Sep;29(3):315-31. 1.
- In vitro neuroprotection against oxidative stress by pre-treatment with a combination of Dihydrolipoic Acid and phenyl-butyl nitrones. Koenig ML, Meyerhoff JL. Neurotox Res. 2003;5(4):265-72.
- Alpha-Lipoic Acid inhibits inflammatory bone resorption by suppressing prostaglandin E2 synthesis.Ha H, Lee JH, Kim HN, et al., J Immunol. 2006 Jan 1;176(1):111-7.
- Antioxidant effects of sulfur-containing amino acids. Atmaca G. Yonsei Med J. 2004 Oct 31;45(5):776-88.
- Stimulation of glucose uptake by the natural coenzyme alpha-Lipoic Acid/thioctic acid: participation of elements of the insulin signaling pathway. Estrada DE, Ewart HS, Tsakiridis T, et al. Diabetes. 1996 Dec;45(12):1798-804.
- Cardioprotective efficiency of Dihydrolipoic Acid in working rat hearts during hypoxia and reoxygenation. 31P nuclear magnetic resonance investigations. Assadnazari H, Zimmer G, Freisleben HJ, Werk W, Leibfritz D. Arzneimittelforschung. 1993 Apr;43(4):425-32.
- Dihydrolipoate reduces neuronal injury after cerebral ischemia. Prehn JH, Karkoutly C, Nuglisch J, et al. J Cereb Blood Flow Metab. 1992 Jan;12(1):78-87.
- Prevention of singlet oxygen-induced DNA damage by lipoate. Devasagayam TP, Subramanian M, Pradhan DS, et al., Chem Biol Interact. 1993 Jan;86(1):79-92.
- Lipoic and Dihydrolipoic Acids as antioxidants. A critical evaluation. Scott BC, Aruoma OI, Evans PJ, et al. Free Radic Res. 1994 Feb;20(2):119-33.