Introducing... R-Lipoic Acid |
Does your lipoic acid supplement contain only the form found in nature? Or does it also include a synthetic by-product that may interfere with the natural form's beneficial effects? |
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R-Lipoic Acid and R-Dihydrolipoic Acid
The only naturally occurring forms of alpha lipoic acid:
Alpha-Lipoic Acid Occurs In 3 Different Forms
When molecules are produced by industrial synthesis they exist in a "racemic form", which is a 50/50 composition of the two enantiomers. Enantiomers are mirror image molecules which are chemically unique.
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Alpha-lipoic acid consists of a 50/50 mixture of the R-(natural) and S- (unnatural) enantiomers and is called a 'racemic' mixture. It is the most widely available commercial form of lipoic acid.
There is evidence that the two enantiomers of alpha-lipoic acid have different biological activities.
R-Lipoic Acid (the R (+) enantiomer) is the form of lipoic acid that occurs naturally in plants, animals and the body and is responsible for the specific beneficial effects of alpha lipoic acid. R-lipoic acid (RLA) is the only form that functions as a cofactor for mitochondrial enzymes. Of primary significance, R-lipoic acid has shown to be ten times more effective than racemic alpha lipoic acid for reducing inflammation.
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enantiomers in the patent literature. | |
S-Lipoic acid (The S (-) enantiomer) is not found in nature. S-Lipoic acid (SLA) is a by-product from chemical synthesis of racemic alpha-lipoic acid and may inhibit the most essential properties of the R form, including interactions with proteins, enzymes and genes.
Alpha-lipoic acid consists of 50/50 racemic mixture of the R and S enantiomers. Much of the research over the past 30 years has been done with racemic alpha lipoic acid because the R form was not commercially available. This was due to its instability and tendency to form polymerization products once isolated from the S form, and due to the challenges of delivering the R form to the body in bio-available dosage forms compared to racemic alpha-lipoic acid.
There is a clear indication of what the specific uses are claimed for the different
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Functions in Health and Disease |
-Lipoic Acid (RLA) and its reduced form, R-Dihydrolipoic Acid (R-DHLA) may prove to be the most important nutraceutical compounds on the market today
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The redox couple has powerful antioxidant functions, serves as a critical co-factor in ATP production, regulates lipid and carbohydrate metabolism, signal transduction, gene transcription and cellular proliferation.
RLA/R-DHLA is neuroprotective, chelates heavy metals, can reverse enzyme and DNA oxidative damage and crosses the blood brain barrier. R-Lipoic Acid has been shown to be more effective by a factor of 8-10 over the commercially available alpha lipoic acid for reducing inflammation, and with R-DHLA, regulates the pro-inflammatory COX-2 and LOX pathways. This indicates the unnatural SLA is interfering with the body's utilization of the R form. |
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R-Lipoic Acid (RLA) and R-Dihydrolipoic acid have superior activity in vivo
Some recent studies have suggested that the S-enantiomer has an inhibiting effect on the R-enantiomer, substantially reducing its biological activity and actually adding to oxidative stress rather than reducing it. Furthermore, the S-enantiomer has been found to reduce the expression of GLUT-4s in cells, responsible for glucose uptake, and hence reduce insulin sensitivity.
The superior activity of R-Lipoic Acid is due to stereospecific binding, whereas SLA competitively inhibits interactions at the redox-active sites of signaling proteins, transcription factorsa, histonesb and flavoenzymesc.
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Regulatory proteins that initiate the transcription of certain genes upon binding with DNA. |
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Small proteins that are rich in basic amino acids and that bind to DNA, forming chromatin. |
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Proteins that use a specific redox cycle to catalyze a variety of biological redox transformations. | |
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The Benefits Of R-Lipoic Acid |
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R-Lipoic Acid significantly reduces inflammation, an underlying cause of the degenerative diseases of aging and is more potent by a factor of 10 over commercial ALA.1 |
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R-Lipoic acid was found to reach higher plasma levels than S-lipoic acid when given orally as the racemic mixture in a human study.2 |
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R-Lipoic Acid protects body fats against oxidative damage and reverses stress damage in the heart.3 |
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R-Lipoic Acid was more effective than the S form in a battery of metal chelation tests. One hypothesis of the cause of diabetic complications involves overloading by transition metals which could explain the stereospecific effect of the R-form.4 |
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R-Lipoic Acid is the form of lipoic acid found in nature and therefore the form preferred by critical mitochondrial enzymes.5, 6 A significant factor in aging is the decay of the mitochondria - and as we age, the efficiency of the mitochondria diminishes, as well as their quantity per cell. |
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R-Lipoic acid is the only form of lipoic acid that was shown to expand total life span in immuno-suppressed mice.7 |
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R-Lipoic acid was much more effective than S-lipoic acid in enhancing insulin-stimulated glucose transport and metabolism in insulin-resistant rat skeletal muscle.8 |
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R-Lipoic acid was more effective than racemic alpha-lipoic acid and S -alpha-lipoic acid in preventing cataracts in rats.9 |
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R-Lipoic Acid increases cellular and mitochondrial antioxidant activity and prevents mitochondrial decay. This effectively attenuates the reported increase in oxidative stress with aging.10 |
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R-Lipoic Acid improves memory, reverses cognitive dysfunction, and protects the brain from neurodegeneration associated with aging.10-12, 25 |
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R-Lipoic Acid supplementation improves metabolic activity and lowers oxidative stress and damage evident in aging.12, 13 |
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R-Lipoic Acid significantly increase insulin sensitivity, enhances glucose transport, increases metabolic rate and reduces the gain in body fat from aging.13, 14 |
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R-Lipoic Acid has insulin-mimetic effects in glucose uptake in insulin resistant cells and may have therapeutic implications in restoring glucose availability in tissues such as the skeletal muscle.15, 16 |
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R-Lipoic Acid significantly increases or maintain levels of other antioxidants including Coenzyme Q10, vitamin C, vitamin E and glutathione.16-18 |
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R-Lipoic Acid prevents depletion of the glutathione pool within the cytoplasm and mitochondria. Pre-treatment of PC12 cells with R-Lipoic Acid leads to the preservation of mitochondrial complex I activity lost due to glutathione depletion.18 |
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R-Lipoic Acid increases the activity of the crucial mitochondrial PDH enzyme, important for nutrient metabolism (inhibited by age-related diseases such as diabetes) whereas SLA inhibits it.19 |
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R-Lipoic Acid , the natural enantiomer, is more effective than the S-(-) enantiomer at enhancing insulin-stimulated glucose transport and non-oxidative and oxidative glucose metabolism.20 |
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R-Lipoic Acid was reduced six to eight times more rapidly than S-lipoate in the rat heart.21 |
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R-lipoic acid prevented hyperglycemia, reduced insulin levels, and increased free radical scavenging potential.22 |
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R-Lipoic Acid, through its positive effects on cellular energy metabolism, attenuates metabolic dysfunction associated with advanced glycation endproducts (AGEs). AGEs accumulate on long-lived proteins, including beta-amyloid plaques in Alzheimer's disease and contributes to neuronal dysfunction and cell death.23, 24 |
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R-Lipoic Acid, a membrane permeable antioxidant, prevents the up-regulation of the AGE -induced gene expression responsible for regulating nitric oxide (NO) production. NO oxidizes and nitrates proteins which are markers of a chronic neuroinflammatory condition. This mechanism is relevant for Alzheimer's disease and for many chronic inflammatory conditions.25 |
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R-Lipoic Acid is the preferred substrate for the mitochondrial enzyme, dihydrolipoamide dehydrogenase, reacting 24 times faster than the S-enantiomer.26 | |
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Pro-oxidant Effects
It is now clear that many of the positive benefits and dangerous side effects of R-lipoic acid are the result of pro-oxidant effects. Since R-lipoic acid can interchange between a reduced form and an oxidized form, it displays reducing (antioxidant) and pro-oxidant properties related to dosage, 1/2 life and metabolism.
It is suggested that pro-oxidants produced by R-lipoic acid are involved in activation of insulin receptors and in elevated glucose uptake in muscle and fat cells. On the other hand, R-lipoic acid appears to protect the insulin-signaling cascade from oxidative stress-induced insulin resistance through its reducing capacities
R-lipoic acid and R-Dihydrolipoic acid can effectively induce apoptosis in human colon cancer cells by a prooxidant mechanism that is initiated by an increased uptake of oxidizable substrates into mitochondria.28
The ability of R-lipoic acid and/or R-Dihydrolipoic acid to function as either anti- or pro-oxidants, at least in part, is determined by the type of oxidative stress and the physiological circumstances.27-30
Stability, Absorption and Dissolution
R-Lipoic Acid, despite all its potential health benefits, when separated from the S form, is physically unstable. R-Lipoic Acid deteriorates relatively rapidly at slightly above room temperature into a sticky insoluble polymer.31 Moisture and the heat of friction during encapsulation and the compression of tablets are sufficient to initiate this process. Even a partially polymerized product can pose significant problems in the manufacturing and stability of a dosage form. The polymer reduces the disintegration and dissolution of tablets or capsules, reduces GI absorption and lowers the bioavailability to less than 10%. Numerous factors affect absorption. Racemic-ALA has poor solubility and absorption from the GI tract, as 20- 30% reaches the plasma vs. an intra venous dose. R-Lipoic Acid is even less soluble and polymerizes on contact with the low pH environment of the stomach.32
GeroNova Research has 4 years of experience in producing and processing R-Lipoic Acid into stabilized, finished dietary ingredients for the nutritional supplement market. GeroNova stabilizes R-Lipoic Acid, creates highly bio-available dosage forms, introduced R-Dihydrolipoic Acid to the market and is constantly researching better ways to build these valuable molecules and make them affordable to health care practitioners and the public.
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References |
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Pharmaceutical composition containing R-.alpha.-lipoic acid or S-.alpha.-lipoic acid as active ingredient. Ulrich H, Weischer CH, et al. US Patent 5,728,735, 1998. |
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Enantioselective pharmacokinetics and bioavailability of different racemic a-lipoic acid formulations in healthy volunteers. Hermann R, Niebch G, Borbe HO, et al. Eur J Pharm Sci. 1996;4:167-174. |
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Oxidative stress in the aging rat heart is reversed by dietary supplementation with (R)-(alpha)-lipoic acid. Suh JH, Shigeno ET, et al. FASEB J 2001 Mar; 15(3): 700-6. |
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Thioctic (lipoic) acid: a therapeutic metal-chelating antioxidant? Ou P, Tritschler HJ, Wolff SP. Biochem Pharmacol 1995; 50:123-126. |
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Cytosolic and mitochondrial systems for NADH- and NADPH-dependent reduction of alpha-lipoic acid. Haramaki N, Han D, Handelman GJ, et al., Free Radic Biol Med.1997;22(3):535-42. |
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Incorporation of the enantiomers of lipoic acid into the pyruvate dehydrogenase complex from Escherichia coli in vivo. Oehring R, Bisswanger H. Biol Chem Hoppe Seyler. 1992 Jun;373(6):333-5. |
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Influence of selegiline and lipoic acid on the life expectancy of immunosuppressed mice. Freisleben HJ, Neeb A, et al. Arzneimittelforschung 1997 Jun; 47(6): 776-80. |
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Differential effects of lipoic acid stereoisomers on glucose metabolism in insulin-resistant skeletal muscle. Streeper RS, Henriksen EJ, et al .Am J Physiol. 1997;273(1 Pt 1):E185-191. |
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Stereospecific effects of R-lipoic acid on buthionine sulfoximine-induced cataract formation in newborn rats. Maitra I, Serbinova E, Tritschler HJ, Packer L. Biochem Biophys Res Commun. 1996;221(2):422-429. |
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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. Liu, Head E, et al. Proc Natl Acad Sci U S A 2002 Feb 19; 99(4): 2356-61. |
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Mitochondrial decay in the aging rat heart: evidence for improvement by dietary supplementation with acetyl-L-carnitine and/or lipoic acid. Hagen TM, Moreau R, et al. Ann N Y Acad Sci. 2002 Apr;959:491-507. |
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Oxidative stress in the aging rat heart is reversed by dietary supplementation with (R)-(alpha)-lipoic acid. Suh JH, Shigeno ET, et al. FASEB J 2001 Mar; 15(3): 700-6. |
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(R)-alpha-Lipoic acid-supplemented Old Rats Have Improved Mitochondrial Function, Decreased Oxidative Damage, and Increased Metabolic Rate. Hagen TM, Ingersoll RT, et al. FASEB J 1999 13:411-418. |
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Oral administration of RAC-alpha-lipoic acid modulates insulin sensitivity in patients with type-2 diabetes mellitus: a placebo-controlled pilot trial. Jacob S, Ruus P, et al. Free Rad Biol Med 1999 Aug;27(3-4):309-14. |
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R-alpha-Lipoic Acid Action on Cell Redox Status, the Insulin Receptor, and Glucose Uptake in 3T3-L1 Adipocytes. Moines H, Trios O, et al. Arch Biochem Biophys 2002 Jan 15; 397(2): 384-91. |
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Cytokine-induced glucose uptake in skeletal muscle: redox regulation and the role of alpha-lipoic acid. Khanna S, Packer L, et al. Am J Physiol. 1999 May;276(5 Pt 2):R1327-33. |
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Age-associated decline in ascorbic acid concentration, recycling, and biosynthesis in rat hepatocytes--reversal with (R)-alpha-lipoic acid supplementation. Lykkesfeldt J, Ames BN et al. FASEB J 1998 Sep; 12(12): 1183-9. |
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Pre-treatment with R-lipoic acid alleviates the effects of GSH depletion in PC12 cells: implications for Parkinson's disease therapy. Bharat S, Cochran BC, et al. Neurotoxicology. 2002 Oct;23(4-5):479-86. |
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Stereospecific effects of lipoic acids on mammalian pyruvate dehydrogenase complex. Hong YS, Jacobia SJ, et al. Free Radic Biol Med. 1999 Mar;26(5-6):685-94. |
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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, Volchuk A, Ramlal T, Tritschler H, Klip A. Diabetes. 1996 Dec;45(12):1798-804. |
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Cytosolic and mitochondrial systems for NADH- and NADPH-dependent reduction of alpha-lipoic acid. Haramaki N, Han D, et al. Free Radic Biol Med 1997; 22(3): 535-42 |
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ALS/Lt: a new type 2 diabetes mouse model associated with low free radical scavenging potential. Mathews CE, Bagley R, Leiter EH. Diabetes. 2004 Apr;53(4):1177-8. |
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Advanced glycation endproducts induce changes in glucose consumption, lactate production, and ATP levels in SH-SY5Y neuroblastoma cells by a redox-sensitive mechanism. de Arriba SG, Loske C, et al. J Cereb Blood Flow Metab. 2003 Nov;23(11):1307-13. |
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Anti-inflammatory antioxidants attenuate the expression of inducible nitric oxide synthase mediated by advanced glycation endproducts in murine microglia. Wong A, Dukic-Stefanovic S, et al. Eur J Neurosci . 2001 Dec;14(12):1961-7. |
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Neuroprotection by the metabolic Antioxidant alpha Lipoic Acid. Packer, L, Tritschler, H; Wessel K, 1997 Free Rad Biol Med 22, Nos 1/2, 359-378. |
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Interaction of alpha-lipoic acid enantiomers and homologues with the enzyme components of the mammalian pyruvate dehydrogenase complex. Loffelhardt S, Bonaventura C, et al. Biochem Pharmacol. 1995 Aug 25;50(5):637-46. |
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Cho KJ, Moini H, et al. Alpha-lipoic acid decreases thiol reactivity of the insulin receptor and protein tyrosine phosphatase 1B in 3T3-L1 adipocytes. Biochem Pharmacol. 2003 Sep 1;66(5):849-58. |
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Wenzel U, Nickel A, et al. alpha-Lipoic acid induces apoptosis in human colon cancer cells by increasing mitochondrial respiration with a concomitant O2-*-generation. Apoptosis. 2005 Mar;10(2):359-68. |
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Utilization of the Insulin-Signaling Network in the Metabolic Actions of alpha-Lipoic Acid-Reduction or Oxidation? Antioxid Redox Signal. Konrad D. 2005 Jul-Aug;7(7-8):1032-9. |
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Prooxidant activities of alpha-lipoic acid on oxidative protein damage in the aging rat heart muscle. Cakatay U, Kayali R et al. Arch Gerontol Geriatr. 2005 May-Jun;40(3):231-40. |
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Disulfide Polymers of DL-alpha-lipoic Acid, Thomas and Reed (JACS 78, 6148 (1956). |
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Asta Medica, US Patent 6,348,490. | |
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