Alpha (R) Lipoic Acid

R-lipoic acid is the biologically active form of the key 'mitochondrial antioxidant,' alpha lipoic acid. R-lipoic acid is directly involved in cellular metabolism and is a vital component of the intracellular antioxidant cycle, able to scavenge a variety of free radicals and reactive oxygen species (ROS) while recycling vitamins C, E and glutathione. R-lipoic readily crosses the blood brain barrier and has been shown effective for elevating intracellular glutathione levels. R-LA helps regulate neuronal calcium homeostasis, regulates pro-inflammatory cytokines, and alters the expression of 'toxic genes.' R-lipoic acid has been used to treat diabetes and has been recommended as a "neuroprotective agent." Because R-lipoic is the naturally occurring form found in mitochondrial complexes it offers substantially greater antioxidant and neuroprotective benefits at substantially lower doses than the synthetic forms of lipoic acid currently available.

Alpha-lipoic acid (ALA) is a unique, vitamin-like antioxidant that can combat radiation sickness, repair damaged livers, treat diabetes and diabetes-related conditions (polyneuropathy) and protect against oxidative processes that promote premature aging and degenerative diseases.

Although lipoic acid is produced naturally in the body, researchers were virtually unaware of its existence until the 1930s. When pure samples were isolated in the 1950s, ALA was first believed to be a new vitamin. Later, researchers discovered that ALA is, in fact, an essential coenzyme with a vital role in mitochondrial electron transport reactions involved in converting glucose into ATP to produce energy. By 1988 researchers had also learned that ALA is a powerful biological antioxidant, although one with some very unique health properties. What most impressed researchers was the discovery that ALA functions as both a fat and water-soluble antioxidant that can easily cross cell membranes. Thus, ALA can confer free radical protection to both interior and exterior cellular structures.

What is R-Lipoic Acid?
Alpha_(R)_Lipoic Acid
(R)-5-(1,2-dithiolan-3-yl) pentanoic acid
Lipoic acid (LA) is an organosulfur compound derived from octanoic acid. LA contains two vicinal sulfur atoms (at C6 and C8) attached via a disulfide bond and is thus considered to be oxidized.
How is it Made?
The precursor to lipoic acid, octanoic acid, is made via fatty acid biosynthesis in the form of octanoyl acyl carrier protein. In eukaryotes a second fatty acid biosynthetic pathway in the mitochondria is used for this purpose. The octanoate is transferred from a thioester of acyl carrier protein to an amide of the lipoyl domain by an octanoyltransferase. The sulfur centers are inserted into the 6th and 8th carbons of octanoate via radical s-adenosyl methionine mechanism, by lipoyl synthase. The sulfurs are from the lipoyl synthase polypeptide. As a result, lipoic acid is synthesized on the lipoyl domain and no free lipoic acid is produced. Lipoic acid can be removed whenever proteins are degraded and by the action of a specific enzyme, called lipoamidase. Free lipoate can be attached to the lipoyl domain by the enzyme lipoate protein ligase. The ligase activity of this enzyme requires ATP. Lipoate protein ligases proceed via an enzyme bound lipoyl adenylate intermediate.
Where is it Found?
A healthy body makes enough alpha-lipoic acid. It is also found in red meat, organ meats (such as liver), and yeast (particularly Brewer's yeast).
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Product related PDF file:
Benefits of Alpha Lipoic Acid.
Functions of Alpha-Lipoic-Acid.
The Uses and Benefits of Alpha Lipoic Acid.

Benefits / Uses

Regenerating Vitamins E and C
Human aging is marked by a decline in the concentration, synthesis and recycling of central antioxidants, such as vitamin E, vitamin C, co-enzyme Q-10 and glutathione. This loss of antioxidant function seriously impairs the body's ability to control free radicals. Left unchecked, free radicals - dangerous, unpaired electrons - proliferate throughout the body, damaging cell membranes and organs, impairing immune function, disrupting DNA strands and contributing to the progression of cancer and other degenerative diseases. In recent years researchers have shown how alpha-lipoic acid recycles vitamins E and C to stave off free radical damage.

One of the central components in the antioxidant cycle is vitamin E, a potent biological antioxidant that works to stabilize highly reactive free radicals in lipid (fatty) tissues and membranes (lipoproteins). In the process of quenching fatty free radicals, such as lipid peroxyl and lipid alkoxyl radicals, vitamin E becomes a free radical itself, though one that is far less reactive or damaging than the original.
The vitamin E radical is then regenerated by vitamin C (ascorbic acid). This process recycles vitamin E from a radical back into an antioxidant again, but results in the formation of a new free radical in the form of unstable vitamin C - a semiascorbyl radical. Vitamin C is next recycled by glutathione, a thiol (sulfur-containing compound). Up to this point vitamins E, C and glutathione work in concert to control free radicals and prevent cellular damage. But this is also an important stage where the antioxidant regeneration cycle runs into a limiting factor determined by the availability of glutathione.

ALA Boosts Glutathione Levels
Dr. Lester Packer, senior scientist at Lawrence Berkeley Laboratory and head of the Packer Lab at the University of California, has spent over 35 years studying how antioxidants like vitamins C, E and glutathione interact in the body. Dr. Packer first discovered several years ago how vitamin E is 'recycled' by vitamin C.

Despite their detailed understanding of the antioxidant regeneration cycle, when Dr. Packer and other researchers tested methods for boosting antioxidant levels they ran into a problem when attempting to increase cellular glutathione levels. Whereas increasing one's intake of dietary or supplemental sources can readily elevate levels of vitamins E and C, cellular glutathione is only produced in the body. Glutathione, when taken orally, is broken down in the stomach before reaching the bloodstream. What does end up being absorbed can raise serum levels, but the effect inside of cells is minimal.

This problem was solved when Packer and his team turned to ALA. 'Alpha-lipoic acid proved to be the missing link,' Packer said. They discovered that in addition to being a powerful antioxidant in its own right, ALA is able to raise intracellular glutathione levels. ALA is easily absorbed when taken orally, and once inside cells it is quickly converted to its most potent form, dihydrolipoic acid, an even more potent free-radical neutralizer. Because both alpha-lipoic acid and dihydrolipoic acid are antioxidants, their combined actions give them greater antioxidant potency than any other natural antioxidant now known.

Most Potent Antioxidant
According to Dr. Packer, ALA is more potent than vitamins C and E, and CoQ10, and may, in fact, be the most important antioxidant ever discovered. "The therapeutic potential of alpha-lipoic acid is just beginning to be explored,' observed Packer, 'but this compound holds great promise."
ALA also is important in cell metabolism and is required for production of energy inside cells. Without ALA, cells could not metabolize sugars for energy and would just shut down. This makes alpha-lipoic acid a metabolic antioxidant, able to draw on the cell's own metabolism to magnify its protective effects and that of other antioxidants.

Experiments carried out by Dr. Packer and colleagues suggest that ALA may also have much broader use in treating other diseases and may have general health benefits when taken as a daily supplement like other antioxidants. 'Alpha-lipoic acid could have far-reaching consequences in the search for prevention and therapy of chronic degenerative diseases such as diabetes and cardiovascular disease,' stated Dr. Packer. 'And because it's the only antioxidant that can easily get into the brain, it could be useful in preventing damage from a stroke.'

Erectile dysfunction
Whether alpha lipoic acid helps those with sexual dysfunction is not fully understood but this nutrient does not seem to have a rapid action for this purpose. Effective products are available to enhance sexuality such as Passion Rx which enhances healthy sexual pleasure, erectile function, orgasms and climaxes.

Eye health, retina studies
R alpha lipoic acid protects retinal pigment epithelial cells from oxidative damage.
Invest Ophthalmol Vis Sci. 2005 Nov. Voloboueva LA, Liu J, Suh JH, Ames BN, Miller SS. Biophysics Graduate Group, University of California, Berkeley, USA.

Pretreatment of fetal retinal pigment epithelial cells with R alpha lipoic acid significantly reduced the levels of reactive oxygen species. The present study suggests that the protective effect involves multiple pathways and that R ALA could be effective against age-associated increase in oxidative stress and mitochondrial dysfunction in retinal pigment cells. It also seems to benefit patients suffering from glaucoma.

Liver health and glutathione preservation
R-alpha-lipoic acid reverses the age-associated increase in susceptibility of hepatocytes to tert-butylhydroperoxide both in vitro and in vivo. Antioxid Redox Signal. 2000 Fall.

Hepatocytes were isolated from young and old rats and incubated with various concentrations of tert-butylhydroperoxide (t-BuOOH). The t-BuOOH concentration that killed 50% of cells in 2 hr declined nearly two-fold in cells from young rats to those from old rats. This increased sensitivity of hepatocytes from old rats may be due, in part, to changes in glutathione levels. Cells from old animals were incubated with either R- or S-lipoic acid for 30 min prior to the addition of t-BuOOH. The physiologically relevant R-form, a coenzyme in mitochondria, as opposed to the (S)-form significantly protected hepatocytes against t-BuOOH toxicity. Dietary supplementation of R-lipoic acid for 2 weeks also completely reversed the age-related decline in hepatocellular glutathione levels and the increased vulnerability to t-BuOOH as well. An identical supplemental diet fed to young rats did not enhance the resistance to t-BuOOH, indicating that antioxidant protection was already optimal in young rats.

Loss of smell (Olfactory)
Alpha lipoic acid may help regenerate loss of smell after a cold.Alpha Lipoic acid in the treatment of smell dysfunction following viral infection of the upper respiratory tract. Hummel T. Laryngoscope 2002 Nov. Department of Otorhinolaryngology, University of Dresden Medical School, Germany.

Loss of taste (dysgeusia)
Researchers at the University of Medicine and Surgery, in Napoli, Italy, selected two homogenous groups, each of 22 patients with idiopathic dysgeusia, an altered perception of taste, matched for age and sex, for an open trial of alpha lipoic acid compared with placebo. The 22 patients in the study group were treated for 2 months. The 22 patients in the control group were treated for 2 months with carboxymethylcellulose. The latter group was then treated with alpha lipoic acid for 2 months. The results showed significant symptomatic improvements compared with placebo, in both groups of patients with dysgeusia treated with alpha lipoic acid, suggesting that idiopathic dysgeusia may be a neuropathy comparable to the burning mouth syndrome.

Feeding alpha lipoic acid and acetyl-l-carnitine to old rats improves performance on memory tasks by lowering oxidative damage and improving mitochondrial function.

Multiple sclerosis
Alpha Lipoic acid in multiple sclerosis: a pilot study.
Mult Scler. 2005 Apr. Yadav V, Marracci G, Lovera J, Woodward W, Bogardus K, Marquardt W, Shinto L, Morris C, Bourdette D. Department of Veterans Affairs Medical Center, Portland, OR
Thirty-seven multiple sclerosis subjects were randomly assigned to one of four groups for 14 days: placebo, ALA 600 mg twice a day, 1200 mg once a day and 1200 mg twice a day. We found that subjects taking 1200 mg had substantially higher peak serum levels than those taking 600 mg and that peak levels varied considerably among subjects. We conclude that oral alpha lipoic acid is generally well tolerated and appears capable of reducing serum matrix metalloproteinase-9 and soluble intercellular adhesion molecule-1 levels. It may prove useful in treating multiple sclerosis by inhibiting MMP-9 activity and interfering with T-cell migration into the CNS.

Skin health, benefit of cream
Randomized, placebo-controlled, double blind study on the clinical efficacy of a cream containing 5% alpha lipoic acid related to photoageing of facial skin.
Br J Dermatol. 2003 Oct.

Alpha lipoic acid or the reduced form dihydrolipoate (DHLA) is a potent scavenger with anti-inflammatory properties. Previous uncontrolled studies with topical treatment with 5% alpha-lipoic acid-containing creams indicate a beneficial effect on photoageing skin. Our results indicate twelve weeks of treatment with a cream containing 5% alpha lipoic acid improves clinical characteristics related to photoageing of facial skin.

R Alpha Lipoic Acid as a Chelating Agent
Studies with rats and mice have shown that R Alpha Lipoic Acid provided protection against the toxic effects of arsenic, cadmium and mercury. It may also bind to other metals including iron, copper and zinc. The chelating action of R Alpha Lipoic Acid is considered to be relatively weak compared to other chelating agents. Some of the harmful effects of heavy metal poisoning are associated with oxidative damage. In addition, lipoic acid's antioxidant properties reduce the harmful effects of heavy metals.

Reduction of Aging from Glycation by R Alpha Lipoic Acid
Glycation is the formation of chemical bonds between protein molecules and glucose. This process impairs the physiological function of those proteins and contributes to the effects of aging and many disease processes, especially those associated with diabetes. These sugar-damaged proteins are referred to as advanced glycosylation end products (AGEs). AGEs increase with the length of hyperglycemia and are thought to be responsible for the kidney damage and advanced atherosclerosis seen in diabetes. Researchers have found that noncovalent binding of alpha-lipoic acid to albumin protected proteins against glycation. Thus R Alpha Lipoic Acid acts as an anti-aging nutrient by both its anti-oxidant properties and its anti glycation properties.

(R)-Lipoic Acid More Effective
Natural ALA, referred to as R-lipoic acid or (R)-ALA, is found in exceedingly miniscule amounts in animal and plant tissues, tightly bound to mitochondrial complexes. Because of the extreme difficulty (and high cost) of isolating natural (R)-ALA, researchers in the US and Europe originally conducted studies with synthetic lipoic acid. Unlike natural (R)-ALA, synthetic lipoic acid contains a 50/50 mixture of two forms (enantiomers) called (R)-ALA and (S)-ALA. Both (R)- and (S)- forms of ALA are isomers - essentially mirror-image molecular formulas, with the atomic arrangements reversed.
Working with synthetic ALA, researchers were able to gain valuable insights into its role as a coenzyme in mitochondrial energy production, and an antioxidant and antioxidant-recycling nutrient. They then began to map out the impressive range of protective health benefits conferred by supplemental ALA. In time researchers had access to pure samples of the natural, biological version, (R)-ALA. They quickly learned that while the body can utilize both forms of ALA, there is a strong preference for the natural, more biologically active (R) form. For example, researchers in Germany reported that, unlike the natural form, (S)-ALA does not improve ATP synthesis in isolated cells. Furthermore, the R-form increased membrane fluidity and transport, while the S-form tended to decrease fluidity.

As a nutritional supplement, doses of 50 to 100 mg. per day are generally recommended. As a Therapeutic agent, higher doses may be used. In Germay, dosages of 600 mg. per day are prescribed for preventing the damaging effects of hyperglycemia in diabetes. Larger doses, 1200 mg. given intravenously, have been used to treat aminita mushroom poisoning. These dosages refer to alpha lipoic acid and alpha lipoic acid contains equal amounts of the R and S version of the molecule. When the R version only is used, only half of the dose is required.

Possible Side-Effects / Precautions / Possible Interactions
There are no indications that low doses, have side effects. Higher doses could cause nausea or stomach upset, along with over-stimulation, fatigue, and insomnia. High doses could also potentially lower blood sugar. This is often beneficial to patients who have diabetes, but it requires close monitoring of blood sugar levels.

Possible Interactions
If you are currently being treated with any of the following medications, you should not use alpha-lipoic acid without first talking to your health care provider.
Insulin and drugs that lower blood sugar -- Apha-lipoic acid can combine with these drugs to further reduce blood sugar levels, resulting in hypoglycemia (low blood sugar). Tell your doctor before taking alpha-lipoic acid and monitor your blood sugar levels closely; your doctor may need to adjust your medication doses.

Thyroid-regulating medications, Levothyroxine -- Apha-lipoic acid may lower levels of thyroid hormone. Blood hormone levels and thyroid function tests should be monitored closely in people taking thyroid hormones who are also taking alpha-lipoic acid.

Research Studies / References
Packer L, Tritschler HJ, Wessel K. Neuroprotection by the metabolic antioxidant alpha-lipoic acid. Free Radic Biol Med 1997;22(1-2):359-78.

L. Packer, E.H.Witt, H.J. Tritschler, Free Rad Biol and Med 1995; 19: 227-250.

Lykkesfeldt J, Hagen TM, Vinarsky V, Ames BN. Age-associated decline in ascorbic acid concentration, recycling, and biosynthesis in rat hepatocytes - reversal with (R)-alpha-lipoic acid supplementation. FASEB J 1998 Sep;12(12):1183-9.

Liu J, Atamna H, Kuratsune H, Ames BN. Delaying brain mitochondrial decay and aging with mitochondrial antioxidants and metabolites. Ann N Y Acad Sci 2002 Apr;959:133-66.

Liu J, Head E, Gharib AM, Yuan W, Ingersoll RT, Hagen TM, Cotman CW, Ames BN. Memory loss in old rats is associated with brain mitochondrial decay and RNA/DNA oxidation: partial reversal by feeding acetyl-L-carnitine and/or R-alpha -lipoic acid. Proc Natl Acad Sci USA 2002 Feb 19;99(4):2356-61.

Hagen TM, Liu J, Lykkesfeldt J, Wehr CM, Ingersoll RT, Vinarsky V, Bartholomew JC, Ames BN. Feeding acetyl-L-carnitine and lipoic acid to old rats significantly improves metabolic function while decreasing oxidative stress. Proc Natl Acad Sci USA 2002 Feb 19;99(4):1870-5.

Hofmann M, Mainka P, Tritschler H, Fuchs J, Zimmer G. Decrease of red cell membrane fluidity and -SH groups due to hyperglycemic conditions is counteracted by alpha-lipoic acid. Arch Biochem Biophys 1995 Dec 1;324(1):85-92.

Haramaki N, Assadnazari H, Zimmer G, Schepkin V, Packer L. The influence of vitamin E and dihydrolipoic acid on cardiac energy and glutathione status under hypoxia-reoxygenation. Biochem Mol Biol Int 1995 Oct;37(3):591-7.

Zimmer G, Beikler TK, Schneider M, Ibel J, Tritschler H, Ulrich H. Dose/response curves of lipoic acid R-and S-forms in the working rat heart during reoxygenation: superiority of the R-enantiomer in enhancement of aortic flow. J Mol Cell Cardiol 1995 Sep;27(9):1895-903.

Haramaki N, Packer L, Assadnazari H, Zimmer G. Cardiac recovery during post-ischemic reperfusion is improved by combination of vitamin E with dihydrolipoic acid. Biochem Biophys Res Commun 1993 Nov 15;196(3):1101-7.

Moini, H., Tirosh, O., R-Alpha Lipoic Acid Action on Cell Redox Status, the Insulin Receptor, and Glucose Uptake in 3T3-L1 Adipocytes; Archives of Biochem & BioPhys 397, No2 384-391 (2002).

Liu, J. Killilea, D.W., Age-associated mitochondrial oxidative decay: Improvement of carnitine acetyltransferase substrate binding affinity and activity in brain by feeding old rats acetyl-L-carnitine and/or R-alpha-lipoic acid. Proc Nat Acad Sci 99, 1876-1881 (2002).

Hager, K., Marahrens, A., Alpha lipoic acid as a new treatment option for Alzheimer type dementia, Arch Geron Geriatr 32 (3): 275-282 (2001).

Hermann, R.; Niebch, G.; Enantioselective pharmacokinetics and bioavailability of different racemic alpha lipoic acid formulations in healthy volunteers. Eur J Pharm Sci 4: 167-174 (1996).