Lipoic Acid:
Overlooked No More
By A.S. Gissen
One of the least known nutritional supplements is alpha-lipoic acid (LA). This is surprising in light of the large amount of experimental and clinical research on the effects LA. First classified as a vitamin after its isolation, LA was subsequently found to be synthesized in both animals and humans. LA has an essential role in mitochondrial dehydrogenase reactions, and this metabolic role has been recognized for almost fifty years. In recent years LA has additionally gained significant attention as an antioxidant.
Now a comprehensive review article has been published that examines the mounting evidence that lipoic acid is not only a powerful antioxidant, but that the unique properties of this vitamin-like compound provide it with both preventive and therapeutic potential in numerous conditions and diseases.
LA and Oxidation
The authors of this review begin with an interesting evaluation of the criteria for considering the antioxidant potential of compounds. These criteria include specificity of
free radical quenching, metal chelating activity, interaction with other antioxidants, effects on gene expression, absorption and bioavailability, and concentration in tissues,
and solubility in aqueous (water) or membrane (lipid) domains. As they state, A substance need not excel in meeting all these criteria to be considered a good antioxidant. For example, vitamin E acts only in the membrane or lipid domains, its dominant action is to quench lipid peroxyl radicals, and it has little or no activity against radicals in the aqueous phase, yet it is considered one of the central antioxidants in the body. In other words, because vitamin E fulfills only some of these criteria, it would not be considered an ideal antioxidant. Instead, an ideal antioxidant would satisfy all of the above criteria.
According to the reviews authors, The lipoic acid/dihydrolipoic acid redox couple approaches the ideal; it has been called a universal antioxidant. The antioxidants normally responsible for this regeneration or recycling are vitamin C, ubiquinols (reduced coenzyme Q10), and thiols (including LA and glutathione). There is good experimental evidence that the DHLA formed from LA in the body can recycle vitamin E through its interaction with glutathione, vitamin C, and ubiquinol. LA administration has also been found to increase intracellular levels of glutathione, an important antioxidant, from 30 -70%. This increase has been found in organs such as the kidney, lung and liver. As the authors state, Thus, it appears that LA and DHLA act as antioxidants not only directly, through radical quenching and metal chelation, but indirectly as well, through recycling of other antioxidants and possibly through induction of increased intracellular levels of glutathione.
LA and Diabetes
LA supplementation has been shown to be effective in preventing damage in numerous models in which reactive oxygen species are implicated. The most widely studied of these conditions is diabetes.
This research has shown that LA has applications in preventing different pathologies associated with diabetes. In fact, LA has shown to be of potential benefit in both Type I (insulin-dependent) and Type 2 (noninsulin -dependent) diabetes. Complications induced by diabetes, such as neuropathy and cataract formation, have been linked to the excessive generation of oxygen free radicals. In the case of Type I diabetes, LA has been shown to significantly reduce the development of diabetes in an animal model often used to study Type I diabetes. One of the major physiological defects that occurs in Type II diabetes is insulin resistance. Therefore, improvement of insulin action on glucose transport is essential to successful therapeutic intervention. LA has been shown to impove glucose utilization in numerous tissues, including muscle. This increase in muscle glucose utilization is particularly important, as muscle is the major organ of glucose removal after meals.
One of the common complications of diabetes is diabetic neuropathy. This is probably caused by a decrease in endoneural blood flow and oxygen tension that results in endoneural hypoxia, increased oxidative stress, and an impairment of nerve conduction. Antioxidants like glutathione have been shown to prevent diabetic neuropathy in animal models, and numerous clinical trials using diabetic humans have been carried out utilizing LA supplements. In fact, the use of LA supplementation for diabetic neuropathy is approved in Germany.
In the case of cataracts, another common pathology resulting from diabetes, LA has been demonstrated to reduce the incidence of cataracts in several animal models. The authors hypothesized that LA, ...prevents oxidative stress in diabetic conditions by sparing vitamin C, whose transport is affected by the disease. Since vitamin C and glucose share the same carrier in noninsulin dependent tissues, the elevated blood glucose in diabetes competitively inhibits the cell entry of vitamin C, thus resulting in a localized intracellular vitamin C deficiency. Because LA utilizes other transport systems to enter cells, and recycles vitamin C, it can help to prevent a localized intracellular vitamin C deficiency. In the words of the reviews authors, Lipoic Acid has been shown to have a number of beneficial effects, both in prevention and treatment of diabetes. Lipoic acid may act in a number of ways that are especially protective in diabetes. Because insulin resistance generally increases with age in nondiabetics as well, LA has the potential of protecting more than just diabetics from the negative effects of insulin resistance and the pathologies it is linked to.
LA and HIV
Oxidative stress is now believed to play a major role in several aspects of Human Immunodeficiency Virus (HIV) infection. These roles include the activation of virus replication, immunosupression, and tumor initiation and promotion. Additionally, HIV patients have been shown to be deficient in numerous antioxidants. A recent study is presented that obtained significant improvements in HIV-positive patients supplemented with 150 mg of LA three times daily for two weeks. At the end of the study almost all patients exhibited increases in plasma vitamin C and glutathione, as well as decreased markers of lipid peroxidation. Additionally, most patients demonstrated improvements in immune cell counts. LA has also been shown to prevent HIV replication in cultured cells. The authors believe these results suggest that further research is warranted on the effects of lipoic acid in HIV infection.
LA and Radiation
Radiation exposure is known to generate large amounts of free radicals, and numerous antioxidant compounds have been studied for their effects on irradiation injury.
Interestingly, the effects of LA on irradiation of humans has been studied in the region affected by the Chernobyl accident. Current residents are exposed to continuous low-level radiation, and researchers examined various blood and urinary parameters in children living in areas affected by the Chernobyl accident. These researchers found that LA treatment lowered markers for blood peroxidation to values seen in nonradiation-exposed children, while a combination of LA and vitamin E further lowered levels of peroxidation to better than normal levels. Interestingly, vitamin E alone had no effect. Liver and kidney functions were also normalized by LA treatment. The authors state that, ...it appears that lipoic acid, alone or together with vitamin E, is an effective treatment for radiation exposure, lessening indices of oxidative damage and normalizing organ function.
LA Supplementation
No serious side effects of LA administration has been found in animal or human studies. Even in long term studies utilizing very large doses of LA, no functional or laboratory
adverse effects have been found. Additionally, no evidence exists to suggest that LA is carcinogenic or teratogenic. In fact, the only serious side effect documented in animal studies has been found in severely thiamine (vitamin B1) deficient animals given high doses of LA by injection. These complications were prevented by administering LA with thiamine. Thus, patients with possible thiamine deficiency, like alcoholics, should receive LA along with supplemental thiamine. Because LA has been marketed for diabetic
neuropathy in Germany, there is clinical experience in large numbers of people. The side effects seen with LA supplementation are rare and have usually been limited to allergic skin reactions or hypoglycemia (low blood sugar) in diabetic patients as a result of improved glucose utilization. Neither of these are dangerous, though diabetics may have to lower their oral medication or insulin dosage to prevent the development of hypoglycemia as a result of improved glucose metabolism. This should be done under a physicians supervision. The dosages of LA that have been used in studies has ranged from 30 to 1000 milligrams per day. For most people interested in taking advantage of LAs remarkable properties, 100 to 300 milligrams per day seems to be a reasonable dose.
As the authors state in the conclusion of their review, Lipoic acid and its reduced form, DHLA, have been referred to as a universal antioxidant that functions in both membrane and aqueous phases. Both lipoic acid and DHLA have substantial antioxidant properties. These include their ability to directly quench a variety of reactive oxygen species, inhibit reactive oxygen-generators, and spare other antioxidants. Taken in its entirety, the growing tide of positive research into the varied beneficial properties and effects of LA should ensure its emergence from obscurity in the near future. Without question, the potential benefits of LA are greater than many antioxidants and supplements that have become household words.
Reference:
L. Packer, E.H.Witt, H.J. Tritschler, Free Rad Biol and Med 1995; 19: 227-250.