By: Hemmi N. Bhagavan, Ph.D., F.A.C.N.

Alpha-Lipoic acid is a naturally-occurring compound. It is produced in our body and is also derived from the foods we eat. Lipoic acid, also known as thioctic acid, is a relatively small molecule that plays a crucial role in our metabolic processes. It occurs in two forms, i.e. isomers called R and S, R being the natural form. Lipoic acid was initially discovered in potato extracts as a growth factor for bacteria. It was later isolated by Dr. Lester Reed and his colleagues at the University of Texas in Austin (Reed et al, 1951). Lipoic acid is now recognized as an important component of metabolic systems in all organisms from bacteria to humans. Its chemical name is 1,2-dithiolane-3-pentanoic acid. Lipoic acid is both lipid (fat)-soluble and water-soluble. This confers upon it certain unique physicochemical characteristics and provides a distinct advantage over other antioxidants.

Dietary sources:

Red meat is a relatively good source of Alpha-Lipoic acid. Since the function of lipoic acid in the body is mostly confined to the energy-producing mitochondria in the cells, tissues and organs with high energy demands are good sources. Heart, muscle and liver are good examples. Among the other sources are spinach, brewer’s yeast and wheat germ.

Under normal conditions, lipoic acid produced in our body along with what is derived from our diet is thought to meet our needs. However, under conditions of oxidative stress, the available lipoic acid may not be adequate enough to provide optimal protection. Those who are not meat-eaters are particularly more vulnerable.

Requirements:

There is no established requirement like the RDA (Recommended Dietary Allowance) for lipoic acid because it is synthesized in the body. For the same reason it is not considered a dietary essential although it is metabolically essential. Under conditions of oxidative stress, what is produced in the body may not be sufficient to prevent free radical damage in the body; lipoic acid supplementation would certainly be of benefit. In this regard, it may be considered a "conditionally-essential" nutrient, like coenzyme Q10 and carnitine.

Function:

Alpha-Lipoic acid has two important functions in our body. First, it serves as a coenzyme (i.e. facilitating the action of enzymes) in several metabolic pathways. Second, it is an important antioxidant (Packer et al, 1995).

Alpha-Lipoic acid is a coenzyme for a group of enzymes (i.e. biological catalysts) responsible for the eventual conversion of fats, carbohydrates and proteins in to biological energy (i.e. adenosine triphosphate or ATP). This process takes place in a special cellular compartment called the mitochondria. Mitochondria are literally the fuel cells within each and every cell. Energy, produced by the terminal oxidation (burning) of the metabolic intermediates, is stored in the form of ATP and is readily available to meet the energy needs of the cell.

Alpha-Lipoic acid possesses potent antioxidant activity in both the lipid and aqueous phases in our body. It is a unique antioxidant in that its antioxidant activity extends to both its oxidized form and the reduced form. Naturally, the reduced form dihydrolipoic acid (DHLA) is more powerful than lipoic acid. The antioxidant activity of lipoic acid relates to scavenging reactive oxygen species and chelating metals, whereas DHLA can, in addition, regenerate endogenous antioxidants such vitamin C, vitamin E and glutathione, and also repair oxidative damage. Most of the therapeutic effects of lipoic acid are attributable to its antioxidant properties (Packer et al, 1995). The ranking of an antioxidant is dependent upon its redox potential, i.e. its ability to be oxidized and reduced. The redox potential of lipoic acid is higher than that of vitamin C or glutathione, thus making it a very potent antioxidant. We could also call lipoic acid a "broad spectrum" antioxidant because of its activity in both the aqueous and lipid phases.

Therapeutic applications:

Diabetes: This tops the list of therapeutic uses. There is good evidence to suggest that increased production of reactive oxygen species and oxidant stress is associated with type 1 and type 2 diabetes mellitus and also insulin resistance. Data also indicate that the increased production of free radicals play an important role in the etiology of diabetic complications such as polyneuropathy. Many of the biochemical pathways associated with hyperglycemia (high blood glucose) such as increased protein glycation (binding of glucose to proteins) are known to result in the increased production of free radicals. Laboratory studies show that oxidative stress can impair insulin-stimulated glucose transport and activation of insulin receptor. Lipoic acid has been shown to protect against the damaging effects of oxidative stress (Packer et al, 1995). The significance of the role of oxidative stress in the etiology of diabetes mellitus and its complications is now recognized by organizations such as the American Diabetes Association.

In patients with type 2 diabetes, lipoic acid supplementation has been shown to improve insulin-sensitivity and oral glucose tolerance (Jacob et al, 1999). Lipoic acid has been used extensively in Germany for the treatment of diabetes particularly with respect to diabetic peripheral neuropathy (Nickander et al, 1996). If blood sugar is not controlled properly, it could lead to increased protein glycation and associated complications such as neurologic damage. Lipoic acid can block this process and potentially prevent peripheral neuropathy in diabetics, or if the patients already have the condition, lipoic acid has been shown to afford significant relief from the painful condition. There is also some evidence to show that lipoic acid may help diabetics with cardiac autonomic neuropathy (Ziegler et al, 1997).

Atherosclerosis: It is now generally accepted that oxidized LDL (low density lipoproteins) is a risk factor for atherosclerosis. Lipoic acid has been shown to protect LDL exposed to oxidative stress (Kagan et al, 1991). Diabetics are known to be at higher risk for atherosclerosis. One reason is the glycation of LDL due to high blood glucose. Increased glycation is associated with increased production of free radicals. Thus glycated LDL increases the risk for atherosclerosis in diabetics. Based upon laboratory data on the ability of lipoic acid to block protein glycation (Schleicher et al, 1997), it appears that lipoic acid may help reduce the risk for atherosclerosis by more than one mechanism.

Neurodegenerative disorders: Laboratory studies show that lipoic acid can protect brain cells (neurons) that are exposed to free radical damage due to increased oxidant stress. Animal data support this observation. According to Dr. Lester Packer at the University of California in Berkeley, lipoic acid may have a role in amyotrophic lateral sclerosis (Lou Gehrig’s disease), multiple sclerosis, head injuries, and spinal cord damage. It is possible that lipoic acid may also have a role in other neurologic diseases such as Parkinson’s and Huntington’s (Packer et al, 1997).

Hearing loss: There is experimental evidence for the potential usefulness of lipoic acid in conditions leading to hearing loss. Data show that the ototoxicity induced by the drug cisplatin is related to free radical damage and can be prevented by lipoic acid (Rybak and Somani, 1999). Cochlear damage following either systemic or topical application of aminoglycoside antibiotics (neomycin) is a recognized phenomenon that also involves free radical damage, and lipoic acid, both topically and orally, has been shown to afford protection against hearing loss (Conlon and Smith, 2000). There is also data to show that lipoic acid can improve hearing in an aging animal model and also reduce some of the effects of aging by upregulating mitochondrial function (Seidman et al, 2000).

Ischemia/reperfusion injury: This is what happens when a tissue is deprived of blood flow for a period of time and then the resumption of blood flow (reperfusion) causes a burst of free radical formation leading to tissue damage. Examples are damage to the brain during a stroke or to the heart after clot dissolution. There is good experimental evidence that demonstrates the beneficial effect of lipoic acid in preventing reperfusion injury (Cao and Phillis, 1995).

Liver diseases: Alpha-Lipoic acid has been used as a therapeutic agent in a number of conditions relating to liver disease. These include alcohol-induced damage, mushroom poisoning and metal intoxication, and significant clinical improvement with lipoic acid treatment has been reported (Packer et al, 1995).

Cataracts: Diabetics are particularly at higher risk for developing cataracts. High blood sugar leads to an accumulation of sorbitol in the lens, which is implicated in the development of cataracts. The enzyme responsible for this conversion is called aldose reductase, and lipoic acid has been shown to block its activity (Ou et al, 1996). Another mechanism for a beneficial role of lipoic acid in cataracts is its ability to generate glutathione, a key antioxidant and a molecule necessary for various metabolic activities within the lens.

Glaucoma: The efficacy of lipoic acid supplementation was tested in a study involving human subjects with open-angle glaucoma. Significant improvements were observed with respect to both the biochemical measures and visual function as compared with the control group receiving only local hypotensive therapy (Filina et al, 1995).

HIV and other infections: Laboratory findings show that lipoic acid is an effective inhibitor of human immuno-deficiency virus (HIV-1) replication (Baur et al, 1991). HIV patients are also known to have low tissue levels of the potent antioxidant glutathione. Glutathione plays an important role in our immune system. In one study, it was found that treatment of immune system cells called the T cells with lipoic acid dramatically increased their glutathione levels. Lipoic acid should therefore be considered a potential therapeutic agent in a number of diseases involving glutathione, including HIV infection.

Aging: Glycation of proteins is one of the factors that has been implicated in the process of aging. As we age, the amount of glycated proteins in our body increases. As mentioned earlier, diabetics are at much higher risk for glycation. There is evidence to show that lipoic acid is able to block or reduce the process of glycation in tissues (Schleicher et al, 1997). Another proposed risk factor in aging is the long-term effects of protein glycation, which involve oxidative changes leading to the formation of advanced gycosylated end-products (AGE). There is experimental evidence to show that lipoic acid can protect proteins exposed to oxidative stress (Kagan et al, 1991, Packer et al, 1995). Thus lipoic acid appears to have the potential to slow the process of aging.

Other potential benefits: Among the other conditions where lipoic acid has been found beneficial are radiation injury, smoking, heavy metal poisoning and Chagas disease (Packer et al, 1995).

Dosage forms:

Alpha-Lipoic acid is available in the form of capsules and tablets. A new hydrosoluble form has been introduced recently (LipoGel®, Tishcon Corporation, Westbury, NY 11590) in a soft gelatin capsule formulation that has superior bioavailability. Combinations of LipoGel® with other antioxidants such as coenzyme Q10 (Q-Gel®) and vitamin E, and other micronutrients are also available and they have many useful applications.

Regulatory status:

Alpha-Lipoic acid is available in the USA as a dietary supplement. A monograph on lipoic acid is under preparation by the US Pharmacopeia.

In closing, it is truly amazing how a relatively small and simple molecule like lipoic acid could have such a profound effect on so many diverse systems and functions in our body. It thus becomes readily apparent that maintaining adequate lipoic acid status is crucial for our long-term health and well being.

References

Baur A, Harrer T, Peukert M, Alpha-lipoic acid as an effective inhibitor of human immuno-deficiency virus (HIV-1) replication. Klin Wochenschr 1991;69:722-4.

Cao X, Phillis JW. The free radical scavenger, alpha-lipoic acid protects against reperfusion injury following cerebral ischemia in rats. Free Rad Res 1995;23:365-70.

Conlon BJ, Smith DW. Topical aminoglycoside toxicity: attempting to protect the cochlea. Acta Otolaryngol 2000;120:596-9.

Filina AA, Davydova NG, Endrikhovskii SN, Lipoic acid as a means of metabolic therapy of open-angle glaucoma. Vestn oftalmol 1995;111:6-8.

Jacob S, Ruus P, Hermann R, Tritschler HJ, Maerker E, Renn W, Augustin HJ, Dietze GJ, Rett K. Oral administration of RAC-alpha-lipoic acid modulates insulin sensitivity in patients with type-2 diabetes mellitus: a placebo-controlled pilot trial. Free Radic Biol Med. 1999;27:309-14.

Kagan V, Freisleben H-J, Tsuchiya M, Forte T, Packer L. Generation of probucol radicals and their reduction by ascorbate and dihydrolipoic acid in human low density lipoproteins. Free Rad Res Comm 1991;15:265-76.

Nickander KK, McPhee BR, Low PA, Tritschler HJ. Alpha-lipoic acid: antioxidant potency against lipid peroxidation of neural tissues in vitro and implications for diabetic neuropathy. Free Rad Biol Med 1996;21:631-9.

Ou P, Nourooz-Zadeh, J, Tritschler HJ, Wolff S. Activation of aldose reductase in rat lens and metal-ion chelation by aldose reductase inhibitors and lipoic acid. Free Rad Res 1996;25:337-46.

Packer L, Tritschler HJ, Wessel K. Neuropretection by the metabolic antioxidant alpha-lipoic acid. Free Rad Biol Med 1997;22:359-78

Packer L, Witt EH, Tritschler HJ. Alpha-lipoic acid as a biological antioxidant. Free Rad Biol Med 1995;19:227-50.

Reed LJ, DeBusk BG, Gunsalus IC, Hornberger CS. Crystalline alpha-lipoic acid: A catalytic agent associated with pyruvate dehydrogenase. Science 1951;27:93-94.

Rybak LP, Somani S. Ototoxicity. Amelioration by protective agents. Ann N Y Acad Sci 1999;884:143-51.

Schleicher E, Wagner E, Nerlich A. Increased accumulation of the glycooxidation product N(epsilon)-carboxymethyl lysine in human tissues in diabetes and aging. J Clin Invest 1997;99:457-68.

Seidman MD, Khan MJ, Bai U, Shirwany M, Quirk WS. Biologic activity of mitochondrial metabolites on aging and age-related hearing loss. Am J Otol 2000;21:161-7.

Ziegler D, Schatz H, Conrad F, Gries FA. Effects of treatment with the antioxidant alpha-lipoic acid on cardiac autonomic neuropathy in NIDDM patients: a 4-month randomized controlled multicenter trial (DEKAN study). Diabetes Care 1997;20:369-73.