Guest guest Posted September 7, 2000 Report Share Posted September 7, 2000 > > ALPHA LIPOIC ACID > > > > > > DESCRIPTION > > > > Alpha lipoic acid, (also known as lipoic acid and thioctic acid) is a > > sulphur-containing vitamin-like antioxidant. Alpha lipoic acid is produced > > naturally in the body and found in the food sources of liver, brewer's > > yeast, and potatoes. Alpha lipoic acid has dual role in human health; it > is > > a powerful antioxidant and a key component for producing cellular energy. > As > > an antioxidant, alpha lipoic acid is unique in that it is both water- and > > fat-soluble; thus it can be used throughout the body. It also extends and > > enhances the effect of other antioxidants, which are used to defend the > body > > against free radical damage. In its metabolic role, alpha lipoic acid is a > > fundamental coenzyme in two vital reactions that lead to the production of > > cellular energy (ATP). Alpha lipoic acid was first isolated in 1957 and > > originally, seemed to be a member of the vitamin B-complex. Alpha lipoic > > acid would have been the first fat-soluble B vitamin isolated. Most human > > coenzymes are produced from some of the B-complex vitamins or are > themselves > > vitamins (Passwater 1995). Alpha lipoic acid is not considered a vitamin, > > but is termed a " conditionally essential " nutrient. This is because > > presumably the body can produce sufficient levels or it is acquired in > > sufficient quantities from food (Murray 1996). The human body can make > > enough alpha lipoic acid to prevent a recognizable deficiency disease, > > though not enough to perform all its functions. The optimal level of alpha > > lipoic acid varies with each person depending on biochemical differences, > > lifestyle, exercise and how much oxidative stress they experience. Certain > > diseases, environmental conditions and age can cause a deficiency in > lipoic > > acid, and thus the body often doesn't make enough to meet all its > metabolic > > and antioxidant needs. > > > > METHOD OF ACTION > > > > Alpha lipoic acid is involved in the metabolic process of converting > > carbohydrates into energy. When sugar is metabolized in the production of > > energy, it is converted into pyruvic acid. The pyruvate is broken down by > an > > enzyme complex that contains lipoic acid, niacin and thiamine. Since the > > human body tends to have only the minimum amount of alpha lipoic acid to > > prevent recognizable disease, supplementation may help improve energy > > metabolism. This is particularly applicable in people with lower than > normal > > levels, for example, individuals with diabetes, liver cirrhosis, heart > > disease and HIV. > > > > As an antioxidant, since alpha lipoic acid is both water- and fat-soluble, > > it is effective against a broader range of free radicals than vitamin C > > (water soluble) and vitamin E (fat-soluble). Because of it unique size and > > chemical structure, lipoic acid has access to virtually the entire body, > > whereas most antioxidants only protect isolated areas of the body. Inside > > the cell, alpha lipoic acid is quickly broken down to dihydrolipoic acid, > > and even more potent free-radical scavenger. Supplementation with lipoic > > acid wards off scurvy (vitamin C deficiency). > > > > THERAPEUTIC APPROACHES > > > > The principal uses of alpha lipoic acid are in the treatment of diabetes > and > > HIV/AIDS. It has also been used in cases of liver cirrhosis, heart > disease, > > cataracts, heavy-metal toxicity and detoxification support. Alpha lipoic > > acid is available in supplemental form of tablets and capsules. For use as > a > > general antioxidant, the recommended dose is 20 to 50 mg daily. In the > > treatment of diabetes, the recommended dose is 300 to 600 mg daily. In the > > treatment of AIDS, the recommended dose is 150 mg three times daily > (Murray, > > 1996). Although lipoic acid deficiency states have not been demonstrated > in > > human beings, animal studies show that a deficiency of lipoic acid results > > in reduced muscle mass, brain atrophy, failure to thrive and increased > > lactic acid accumulation. > > > > DIABETES > > > > Alpha lipoic acid has been used in Europe for over three decades to treat > > diabetic neuropathy, to help regulate blood sugar, and prevent diabetic > > retinopathy and cardiopathy. Alpha lipoic acid is an approved drug in > > Germany for the treatment of diabetic neuropathy. Alpha lipoic acid > > normalizes blood sugar levels in diabetics and also reduces the secondary > > effects of diabetes, including retinopathy, cataract formation, nerve and > > heart damage, as well as increasing energy levels. It is used in the > > treatment of both insulin-dependent and non-insulin dependent diabetes. > > Alpha lipoic acid helps control blood sugar by facilitating the conversion > > of sugar into energy. Alpha lipoic acid reduces glycation (also known as > > glycosylation), which is the process in which proteins react with excess > > glucose. This sugar reaction to protein is just as detrimental as oxygen > > damage (free radical damage). Alpha lipoic acid helps to keep blood sugar > > levels under control and reduced levels of glucose mean less glycation. > This > > is important in reducing diabetic side effects and slowing aging. In > > summary, alpha lipoic acid's effect on diabetes is through its potent > > antioxidant capabilities, as well improving blood sugar metabolism, > reducing > > glycosylation of proteins, improving blood flow to the peripheral nerves, > > and actually stimulating regeneration of nerve fibers (see Current > Abstracts > > under Diabetes listing). > > > > AIDS > > > > Individuals infected with the HIV virus tend to have a compromised > > antioxidant defense system. During HIV infection, key cells of the immune > > system called CD lymphocytes lose their ability to make and to transport > > glutathione. Antioxidants such as glutathione prevent HIV viral > replication > > while reactive oxidants tend to stimulate the virus. Glutathione is a > major > > cellular antioxidant, and thus, the CD lymphocytes are exposed to excess > > oxidative stress and this contributes to immune system failure. Alpha > lipoic > > acid is a powerful antioxidant and facilitator of glutathione production. > A > > strong antioxidant defense system can help prevent this oxidative damage > and > > help keep the immune system strong. > > > > A study was conducted by Dr. Fuchs and colleagues, to determine the > > short-term effect of supplemental lipoic acid. Alpha lipoic acid was given > > as a supplement (150 mg three times daily for a two week period) to > > HIV-infected patients. Lipoic acid supplementation increased total > > glutathione in seven of seven patients, plasma ascorbate in nine of ten > > patients, total plasma sulfur groups in eight of nine patients, and T > helper > > lymphocytes and T helper/suppressor cell ratio in six of ten patients. The > > conclusion of this study is that lipoic acid supplementation led to > > significant beneficial changes in the blood of HIV-infected patients > (Fuchs, > > et al., 1993) > > > > Alpha lipoic acid has been beneficial to cancer patients suffering with > > peripheral neuropathy, a damaging side effect of chemotherapy. Lipoic acid > > also protects against cancer as a result of its potent antioxidant > effects. > > Lipoic acid protects a complex called Nuclear Factor kappa-B and prevents > it > > from activating oncogenes. Oncogenes are genes that contribute to cancer > > cell proliferation. When these genes are altered by either NF kappa-B or a > > carcinoen, they cause the cell to become malignant. Lipoic acid can enter > > the cytosol of cells and protect NF kappa-B from activation by free > radical, > > radiation, or even sunlight. > > > > Alpha lipoic acid may be helpful in other conditions including Liver > > cirrhosis, hepatitis, heart disease, cataracts, heavy metal toxicity, and > > support during detoxification. Its role in detoxification is as a chelator > > (remover) of heavy metals and toxic minerals from the body. > > > > Alpha lipoic acid protects the nervous system and may be involved in > > regenerating the nerves. It is being studied in the treatment of Parkinson > 's > > disease and Alzheimer's disease. > > > > Alpha lipoic acid has been shown to improve antibody response in > > immunosuppressed animals (Quillin 1998). > > > > TOXICITY FACTORS > > > > Alpha lipoic acid supplementation is very safe. In over 30 years of > > extensive use and testing in European clinical trials in the treatment of > > diabetic neuropathy, there have been no reported side effects (Quillin, > > 1998, Murray, 1996). As a precaution, until further information is > > available, alpha lipoic acid is not recommended for pregnant women. Animal > > studies show very low toxicity (Murray, 1996). > > > > CURRENT ABSTRACTS > > > > DIABETES > > > > Ziegler D; Gries FA. Alpha-lipoic acid in the treatment of diabetic > > peripheral and cardiac autonomic neuropathy. Diabetes Research Institute > at > > the Heinrich Heine University, Dusseldorf, Germany.: Diabetes 1997 Sep;46 > > Suppl 2:S62 > > > > Antioxidant treatment has been shown to prevent nerve dysfunction in > > experimental diabetes, providing a rationale for a potential therapeutic > > value in diabetic patients. The effects of the antioxidant alpha-lipoic > acid > > (thioctic acid) were studied in two multicenter, randomized, double-blind > > placebo-controlled trials. In the Alpha-Lipoic Acid in Diabetic Neuropathy > > Study, 328 patients with NIDDM and symptomatic peripheral neuropathy were > > randomly assigned to treatment with intravenous infusion of alpha-lipoic > > acid using three doses (ALA 1,200 mg; 600 mg; 100 mg) or placebo (PLAC) > over > > 3 weeks. The total symptom score (TSS) (pain, burning, paresthesia, and > > numbness) in the feet decreased significantly from baseline to day 19 in > ALA > > 1,200 and ALA 600 vs. PLAC. Each of the four individual symptom scores was > > significantly lower in ALA 600 than in PLAC after 19 days (all P < 0.05). > > The total scale of the Hamburg Pain Adjective List (HPAL) was > significantly > > reduced in ALA 1,200 and ALA 600 compared with PLAC after 19 days (both P > < > > 0.05). In the Deutsche Kardiale Autonome Neuropathie Studie, patients with > > NIDDM and cardiac autonomic neuropathy diagnosed by reduced heart rate > > variability were randomly assigned to treatment with a daily oral dose of > > 800 mg alpha-lipoic acid (ALA) (n = 39) or placebo (n = 34) for 4 months. > > Two out of four parameters of heart rate variability at rest were > > significantly improved in ALA compared with placebo. A trend toward a > > favorable effect of ALA was noted for the remaining two indexes. In both > > studies, no significant adverse events were observed. In conclusion, > > intravenous treatment with alpha-lipoic acid (600 mg/day) over 3 weeks is > > safe and effective in reducing symptoms of diabetic peripheral neuropathy, > > and oral treatment with 800 mg/day for 4 months may improve cardiac > > autonomic dysfunction in NIDDM. > > > > Roy S; Sen CK; Tritschler HJ; Packer L Modulation of cellular reducing > > equivalent homeostasis by alpha-lipoic acid. Mechanisms and implications > for > > diabetes and ischemic injury. Department of Molecular and Cell Biology, > > University of California, Berkeley 94720-3200, U.S.A. > > sashwati@... Biochem Pharmacol 1997 Feb 7;53(3):393-9 > > > > The therapeutic potential of alpha-lipoic acid (thioctic acid) was > evaluated > > with respect to its influence on cellular reducing equivalent homeostasis. > > The requirement of NADH and NADPH as cofactors in the cellular reduction > of > > alpha-lipoic acid to dihydrolipoate has been reported in various cells and > > tissues. However, there is no direct evidence describing the influence of > > such reduction of alpha-lipoate on the levels of cellular reducing > > equivalents and homeostasis of the NAD(P)H/NAD(P) ratio. Treatment of the > > human Wurzburg T-cell line with 0.5 mM alpha-lipoate for 24 hr resulted in > a > > 30% decrease in cellular NADH levels. alpha-Lipoate treatment also > decreased > > cellular NADPH, but this effect was relatively less and slower compared > with > > that of NADH. A concentration-dependent increase in glucose uptake was > > observed in Wurzburg cells treated with alpha-lipoate. Parallel decreases > > (30%) in cellular NADH/NAD+ and in lactate/pyruvate ratios were observed > in > > alpha-lipoate-treated cells. Such a decrease in the NADH/NAD+ ratio > > following treatment with alpha-lipoate may have direct implications in > > diabetes, ischemia-reperfusion injury, and other pathologies where > reductive > > (high NADH/NAD+ ratio) and oxidant (excess reactive oxygen species) > > imbalances are considered as major factors contributing to metabolic > > disorders. Under conditions of reductive stress, alpha- lipoate decreases > > high NADH levels in the cell by utilizing it as a co- factor for its own > > reduction process, whereas in oxidative stress both alpha-lipoate and its > > reduced form, dihydrolipoate, may protect by direct scavenging of free > > radicals and recycling other antioxidants from their oxidized forms. > > > > S; Henriksen EJ; Schiemann AL; Simon I; Clancy DE; Tritschler HJ; > Jung > > WI; Augustin HJ; Dietze GJ Enhancement of glucose disposal in patients > with > > type 2 diabetes by alpha-lipoic acid. Department of Internal Medicine, > City > > Hospital, Baden-Baden, Germany. Arzneimittelforschung 1995 Aug;45(8):872-4 > > > > Insulin resistance of skeletal muscle glucose uptake is a prominent > feature > > of Type II diabetes (NIDDM); therefore pharmacological interventions > should > > aim to improve insulin sensitivity. Alpha-lipoic acid (CAS 62-46-4, > thioctic > > acid, ALA), a natural occurring compound frequently used for treatment of > > diabetic polyneuropathy, enhances glucose utilization in various > > experimental models. To see whether this compound also augments insulin > > mediated glucose disposal in NIDDM, 13 patients received either ALA (1000 > > mg/Thioctacid/500 ml NaCl, n = 7) or vehicle only (500 ml NaCl, n = 6) > > during a glucose-clamp study. Both groups were comparable in age, > body-mass > > index and duration of diabetes and had a similar degree of insulin > > resistance at baseline. Acute parenteral administration of ALA resulted in > a > > significant increase of insulin-stimulated glucose disposal; metabolic > > clearance rate (MCR) for glucose rose by about 50% (3.76 ml/kg/min = pre > vs. > > 5.82 ml/kg/min = post, p < 0.05), whereas the control group did not show > any > > significant change (3.57 ml/kg/min = pre vs. 3.91 ml/kg/min = post). This > is > > the first clinical study to show that alpha-lipoic acid increases insulin > > stimulated glucose disposal in NIDDM. The mode of action of ALA and its > > potential use as an antihyperglycemic agent require further investigation. > > > > HIV & AIDS > > > > Suzuki YJ; Aggarwal BB; Packer L Alpha-lipoic acid is a potent inhibitor > of > > NF-kappa B activation in human T cells. Department of Molecular & Cell > > Biology, University of California, Berkeley. > > > > Biochem Biophys Res Commun 1992 Dec 30;189(3):1709-15 > > > > Acquired immunodeficiency syndrome (AIDS) results from infection with a > > human immunodeficiency virus (HIV). The long terminal repeat (LTR) region > of > > HIV proviral DNA contains binding sites for nuclear factor kappa B > (NF-kappa > > , and this transcriptional activator appears to regulate HIV activation. > > Recent findings suggest an involvement of reactive oxygen species (ROS) in > > signal transduction pathways leading to NF-kappa B activation. The present > > study was based on reports that antioxidants which eliminate ROS should > > block the activation of NF- kappa B and subsequently HIV transcription, > and > > thus antioxidants can be used as therapeutic agents for AIDS. Incubation > of > > Jurkat T cells (1 x 10(6) cells/ml) with a natural thiol antioxidant, > > alpha-lipoic acid, prior to the stimulation of cells was found to inhibit > > NF-kappa B activation induced by tumor necrosis factor-alpha (25 ng/ml) or > > by phorbol 12-myristate 13-acetate (50 ng/ml). The inhibitory action of > > alpha-lipoic acid was found to be very potent as only 4 mM was needed for > a > > complete inhibition, whereas 20 mM was required for N- acetylcysteine. > These > > results indicate that alpha-lipoic acid may be effective in AIDS > > therapeutics. > > > > Merin JP; Matsuyama M; Kira T; Baba M; Okamoto T Alpha-lipoic acid blocks > > HIV-1 LTR-dependent expression of hygromycin resistance in THP-1 stable > > transformants. Department of Molecular Genetics, Nagoya City University > > Medical School, Japan.FEBS Lett 1996 Sep 23;394(1):9-13 > > > > Gene expression of human immunodeficiency virus (HIV) depends on a host > > cellular transcription factors including nuclear factor-kappaB (NF- > kappaB). > > The involvement of reactive oxygen intermediates (ROI) has been implicated > > as intracellular messengers in the inducible activation of NF-kappaB. In > > this study, we compared the efficacy of two antioxidants, alpha-lipoic > acid > > (LA) and N-acetylcysteine (NAC), which are widely recognized NF-kappaB > > inhibitors. Here, we demonstrate that LA has a more potent activity in > > inhibiting NF-KappaB-mediated gene expression in THP-1 cells that have > been > > stably transfected with a plasmid bearing a hygromycin B resistance gene > > under the control of HIV- 1 long terminal repeat (LTR) promoter. The > > spontaneous activation of NF- kappaB in this cell culture system leads to > > expression of the hygromycin phosphotransferase gene hence rendering the > > cells resistance to hygromycin B. In this study, the effect of the test > > compounds against transcriptional activity of HIV-1 LTR was evaluated > based > > on the degree of cellular toxicity due to the inhibitory activity on the > > expression of hygromycin B resistance gene in the presence of hygromycin > B. > > We also found that 0.2 mM LA could cause 40% reduction in the HIV-1 > > expression from the TNF-alpha-stimulated OM 10.1, a cell line latently > > infected with HIV-1. On the other hand, 10 mM NAC was required to elicit > the > > same effect. Furthermore, the initiation of HIV-1 induction by TNF-alpha > was > > completely abolished by 1 mM LA. These findings confirm the involvement of > > ROI in NF-kappaB-mediated HIV gene expression as well as the efficacy of > LA > > as a therapeutic regimen for HIV infection and acquired immunodeficiency > > syndrome (AIDS). Moreover, this study validates the applicability of our > > present assay system which we primarily designed for the screening of > > candidate drugs against HIV-1 gene expression. > > > > Han D; Tritschler HJ; Packer L. Alpha-lipoic acid increases intracellular > > glutathione in a human T- lymphocyte Jurkat cell line. Department of > > Molecular and Cell Biology, University of California at Berkeley > 94720-3200. > > Biochem Biophys Res Commun 1995 Feb 6;207(1):258-64. > > > > The addition of exogenous alpha-lipoic acid to cellular medium causes a > > rapid increase of intracellular unbound thiols in Jurkat cells, a human > > T-lymphocyte cell line. The rise of cellular thiols is a result of the > > cellular uptake and reduction of lipoic acid to dihydrolipoic acid and a > > rise in intracellular glutathione. Although the level of dihydrolipoic > acid > > is 100-fold lower than glutathione, the cellular concentration of > > dihydrolipoic acid might be responsible for the modulation of total > cellular > > thiol levels. Rises in glutathione correlate with the levels of > > intracellular dihydrolipoic acid (p < .01). This increase in glutathione > is > > not the result of expression of new proteins like gamma-glutamylcysteine > > synthetase, since the rise in glutathione was not inhibited by > > cycloheximide, a protein synthesis inhibitor. Lipoic acid administration > is > > therefore a potential therapeutic agent in an array of diseases with > > glutathione anomalies including HIV infection. > > > > Sen CK; Roy S; Han D; Packer L. Regulation of cellular thiols in human > > lymphocytes by alpha-lipoic acid: a flow cytometric analysis. Department > of > > Molecular and Cell Biology, University of California, Berkeley 94720-3200, > > USA. Free Radic Biol Med 1997;22(7):1241-57 > > > > Modulation of cellular thiols is an effective therapeutic strategy, > > particularly in the treatment of AIDS. Lipoic acid, a metabolic > antioxidant, > > functions as a redox modulator and has proven clinically beneficial > effects. > > It is also used as a dietary supplement. We utilized the specific > > capabilities of N-ethylmaleimide to block total cellular thiols, > > phenylarsine oxide to block vicinal dithiols, and buthionine sulfoximine > to > > deplete cellular GSH to flow cytometrically investigate how these thiol > > pools are influenced by exogenous lipoate treatment. Low concentrations of > > lipoate and its analogue lipoamide increased Jurkat cell GSH in a > > dose-dependent manner between 10 (25 microM for lipoamide) to 100 microM. > > This was also observed in mitogenically stimulated peripheral blood > > lymphocytes (PBL). Studies with Jurkat cells and its Wurzburg subclone > > showed that lipoate dependent increase in cellular GSH was similar in CD4+ > > and - cells. Chronic (16 week) exposure of cells to lipoate resulted in > > further increase of total cellular thiols, vicinal dithiols, and GSH. High > > concentration (2 and 5 mM) of lipoate exhibited cell shrinkage, thiol > > depletion, and DNA fragmentation effects. Based on similar effects of > > octanoic acid, the cytotoxic effects of lipoate at high concentration > could > > be attributed to its fatty acid structure. In certain diseases such as > AIDS > > and cancer, elevated plasma glutamate lowers cellular GSH by inhibiting > > cystine uptake. Low concentrations of lipoate and lipoamide were able to > > bypass the adverse effect of elevated extracellular glutamate. A > > heterogeneity in the thiol status of PBL was observed. Lipoate, lipoamide, > > or N-acetylcysteine corrected the deficient thiol status of cell > > subpopulations. Hence, the favorable effects of low concentrations of > > lipoate treatment appears clinically relevant. > > > > ANTIOXIDANT > > > > Packer L. alpha-Lipoic acid: a metabolic antioxidant which regulates > > NF-kappa B signal > > > > transduction and protects against oxidative injury. Department of > Molecular > > and Cell Biology, University of California, Berkeley, Drug Metab Rev 1998 > > May;30(2):245-75. > > > > Although the metabolic role of alpha-lipoic acid has been known for over > 40 > > years, it is only recently that its effects when supplied exogenously have > > become known. Exogenous alpha-lipoic acid is reduced intracellularly by at > > least two and possibly three enzymes, and through the actions of its > reduced > > form, it influences a number of cell process. These include direct radical > > scavenging, recycling of other antioxidants, accelerating GSH synthesis, > and > > modulating transcription factor activity, especially that of NF-kappa B. > > These mechanisms may account for the sometimes dramatic effects of > > alpha-lipoic acid in oxidative stress conditions (e.g., brain ischemia- > > reperfusion), and point the way toward its therapeutic use. > > > > Packer L; Witt EH; Tritschler HJ alpha-Lipoic acid as a biological > > antioxidant. Department of Molecular & Cell Biology, University of > > California, Berkeley 94720, USA. Free Radic Biol Med 1995 Aug;19(2):227-50 > > > > Alpha-Lipoic acid, which plays an essential role in mitochondrial > > dehydrogenase reactions, has recently gained considerable attention as an > > antioxidant. Lipoate, or its reduced form, dihydrolipoate, reacts with > > reactive oxygen species such as superoxide radicals, hydroxyl radicals, > > hypochlorous acid, peroxyl radicals, and singlet oxygen. It also protects > > membranes by interacting with vitamin C and glutathione, which may in turn > > recycle vitamin E. In addition to its antioxidant activities, > dihydrolipoate > > may exert prooxidant actions through reduction of iron. alpha-Lipoic acid > > administration has been shown to be beneficial in a number of oxidative > > stress models such as ischemia- reperfusion injury, diabetes (both > > alpha-lipoic acid and dihydrolipoic acid exhibit hydrophobic binding to > > proteins such as albumin, which can prevent glycation reactions), cataract > > formation, HIV activation, neurodegeneration, and radiation injury. > > Furthermore, lipoate can function as a redox regulator of proteins such as > > myoglobin, prolactin, thioredoxin and NF-kappa B transcription factor. We > > review the properties of lipoate in terms of (1) reactions with reactive > > oxygen species; (2) interactions with other antioxidants; (3) beneficial > > effects in oxidative stress models or clinical conditions. > > > > Biewenga GP; Haenen GR; Bast A; The pharmacology of the antioxidant lipoic > > acid Leiden/Amsterdam Center for Drug Research, Vrije Universiteit, > > Department of Pharmacochemistry, The Netherlands. Gen Pharmacol 1997 > > Sep;29(3):315-31 > > > > 1. Lipoic acid is an example of an existing drug whose therapeutic effect > > has been related to its antioxidant activity. 2. Antioxidant activity is a > > relative concept: it depends on the kind of oxidative stress and the kind > of > > oxidizable substrate (e.g., DNA, lipid, protein). 3. In vitro, the final > > antioxidant activity of lipoic acid is determined by its concentration and > > by its antioxidant properties. Four antioxidant properties of lipoic acid > > have been studied: its metal chelating capacity, its ability to scavenge > > reactive oxygen species (ROS), its ability to regenerate endogenous > > antioxidants and its ability to repair oxidative damage. 4. Dihydrolipoic > > acid (DHLA), formed by reduction of lipoic acid, has more antioxidant > > properties than does lipoic acid. Both DHLA and lipoic acid have > > metal-chelating capacity and scavenge ROS, whereas only DHLA is able to > > regenerate endogenous antioxidants and to repair oxidative damage. 5. As a > > metal chelator, lipoic acid was shown to provide antioxidant activity by > > chelating Fe2+ and Cu2+; DHLA can do so by chelating Cd2+. 6. As > scavengers > > of ROS, lipoic acid and DHLA display antioxidant activity in most > > experiments, whereas, in particular cases, pro-oxidant activity has been > > observed. However, lipoic acid can act as an antioxidant against the > > pro-oxidant activity produced by DHLA. 7. DHLA has the capacity to > > regenerate the endogenous antioxidants vitamin E, vitamin C and > glutathione. > > 8. DHLA can provide peptide methionine sulfoxide reductase with reducing > > equivalents. This enhances the repair of oxidatively damaged proteins such > > as alpha-1 antiprotease. 9. Through the lipoamide dehydrogenase-dependent > > reduction of lipoic acid, the cell can draw on its NADH pool for > antioxidant > > activity additionally to its NADPH pool, which is usually consumed during > > oxidative stress. 10. Within drug-related antioxidant pharmacology, lipoic > > acid is a model compound that enhances understanding of the mode of action > > of antioxidants in drug therapy. > > > > GLYCATION > > > > Bierhaus A; Chevion S; Chevion M; Hofmann M; Quehenberger P; Illmer T; > > Luther T; Berentshtein E; Tritschler H; Muller M; Wahl P; Ziegler R; > Nawroth > > PP Advanced glycation end product-induced activation of NF-kappaB is > > suppressed by alpha-lipoic acid in cultured endothelial cells. Department > of > > Internal Medicine, University of Heidelberg, Germany. Diabetes 1997 > > Sep;46(9):1481-90. > > > > Depletion of cellular antioxidant defense mechanisms and the generation of > > oxygen free radicals by advanced glycation end products (AGEs) have been > > proposed to play a major role in the pathogenesis of diabetic vascular > > complications. Here we demonstrate that incubation of cultured bovine > aortic > > endothelial cells (BAECs) with AGE albumin (500 nmol/l) resulted in the > > impairment of reduced glutathione (GSH) and ascorbic acid levels. As a > > consequence, increased cellular oxidative stress led to the activation of > > the transcription factor NF-kappaB and thus promoted the upregulation of > > various NF-kappaB-controlled genes, including endothelial tissue factor. > > Supplementation of the cellular antioxidative defense with the natural > > occurring antioxidant alpha- lipoic acid before AGE albumin induction > > completely prevented the AGE albumin-dependent depletion of reduced > > glutathione and ascorbic acid. Electrophoretic mobility shift assays > (EMSAs) > > revealed that AGE albumin- mediated NF-kappaB activation was also reduced > in > > a time- and dose- dependent manner as long as alpha-lipoic acid was added > at > > least 30 min before AGE albumin stimulation. Inhibition was not due to > > physical interactions with protein DNA binding, since alpha-lipoic acid, > > directly included into the binding reaction, did not prevent binding > > activity of recombinant NF-kappaB. Western blots further demonstrated that > > alpha-lipoic acid inhibited the release and translocation of NF- kappaB > from > > the cytoplasm into the nucleus. As a consequence, alpha- lipoic acid > reduced > > AGE albumin-induced NF-kappaB mediated transcription and expression of > > endothelial genes relevant in diabetes, such as tissue factor and > > endothelin-1. Thus, supplementation of cellular antioxidative defense > > mechanisms by extracellularly administered alpha-lipoic acid reduces AGE > > albumin-induced endothelial dysfunction in vitro. > > > > LIVER DISEASE > > > > Bustamante J; Lodge JK; Marcocci L; Tritschler HJ; Packer L; Rihn BH. > > Alpha-lipoic acid in liver metabolism and disease. Department of Molecular > > and Cell Biology, University of California, Berkeley. Free Radic Biol Med > > 1998 Apr;24(6):1023-39 > > > > R-alpha-Lipoic acid is found naturally occurring as a prosthetic group in > > alpha-keto acid dehydrogenase complexes of the mitochondria, and as such > > plays a fundamental role in metabolism. Although this has been known for > > decades, only recently has free > > > > supplemented alpha-lipoic acid been found to affect cellular metabolic > > processes in vitro, as it has the ability to alter the redox status of > cells > > and interact with thiols and other antioxidants. Therefore, it appears > that > > this compound has important therapeutic potential in conditions where > > oxidative stress is involved. Early case studies with alpha-lipoic acid > were > > performed with little knowledge of the action of alpha-lipoic acid at a > > cellular level, but with the rationale that because the naturally > occurring > > protein bound form of alpha-lipoic acid has a pivotal role in metabolism, > > that supplementation may have some beneficial effect. Such studies sought > > evaluate the effect of supplemented alpha-lipoic acid, using low doses, on > > lipid or carbohydrate metabolism, but little or no effect was observed. A > > common response in these trials was an increase in glucose uptake, but > > increased plasma levels of pyruvate and lactate were also observed, > > suggesting that a inhibitory effect on the pyruvate dehydrogenase complex > > was occurring. During the same period, alpha-lipoic acid was also used as > a > > therapeutic agent in a number of conditions relating to liver disease, > > including alcohol-induced damage, mushroom poisoning, metal > intoxification, > > and CCl4 poisoning. Alpha-Lipoic acid supplementation was successful in > the > > treatment for these conditions in many cases. Experimental studies and > > clinical trials in the last 5 years using high doses of alpha-lipoic acid > > (600 mg in humans) have provided new and consistent evidence for the > > therapeutic role of antioxidant alpha-lipoic acid in the treatment of > > insulin resistance and diabetic polyneuropathy. This new insight should > > encourage clinicians to use alpha-lipoic acid in diseases affecting liver > in > > which oxidative stress is involved. > > > > NEURODEGENERATIVE DISEASES > > > > Packer L; Tritschler HJ; Wessel K Neuroprotection by the metabolic > > antioxidant alpha-lipoic acid. > > > > Department of Molecular and Cell Biology, University of California, > Berkeley > > 94720-3200, USA. Free Radic Biol Med 1997;22(1-2):359-78 > > > > Reactive oxygen species are thought to be involved in a number of types of > > acute and chronic pathologic conditions in the brain and neural tissue. > The > > metabolic antioxidant alpha-lipoate (thioctic acid, 1, 2- > > dithiolane-3-pentanoic acid; 1, 2-dithiolane-3 valeric acid; and 6, 8- > > dithiooctanoic acid) is a low molecular weight substance that is absorbed > > from the diet and crosses the blood-brain barrier. alpha- Lipoate is taken > > up and reduced in cells and tissues to dihydrolipoate, which is also > > exported to the extracellular medium; hence, protection is afforded to > both > > intracellular and extracellular environments. Both alpha-lipoate and > > especially dihydrolipoate have been shown to be potent antioxidants, to > > regenerate through redox cycling other antioxidants like vitamin C and > > vitamin E, and to raise intracellular glutathione levels. Thus, it would > > seem an ideal substance in the treatment of oxidative brain and neural > > disorders involving free radical processes. Examination of current > research > > reveals protective effects of these compounds in cerebral > > ischemia-reperfusion, excitotoxic amino acid brain injury, mitochondrial > > dysfunction, diabetes and diabetic neuropathy, inborn errors of > metabolism, > > and other causes of acute or chronic damage to brain or neural tissue. > Very > > few neuropharmacological intervention strategies are currently available > for > > the treatment of stroke and numerous other brain disorders involving free > > radical injury. We propose that the various metabolic antioxidant > properties > > of alpha-lipoate relate to its possible therapeutic roles in a variety of > > brain and neuronal tissue pathologies: thiols are central to antioxidant > > defense in brain and other tissues. The most important thiol antioxidant, > > glutathione, cannot be directly administered, whereas alpha-lipoic acid > can. > > In vitro, animal, and preliminary human studies indicate that alpha- > lipoate > > may be effective in numerous neurodegenerative disorders. > > > > REFERENCES > > > > REFERENCES > > > > Berkson, B. 1998, The Alpha Lipoic Acid Breakthrough. Rockilin, CA: Prima > > Publishing. > > > > Fuchs, J. et al., Studies on lipoate effects on blood redox state in human > > immunodeficiency virus (HIV 1) replication. Arzeim Forsch 43, > > 1359-1362,1993. > > > > Golan, R.1995. Optimal Wellness. New York: Ballentine books. > > > > , S. et al., Enhancement of Glucose Disposal in Patients with Type 2 > > diabetes by Alpha Lipoic Acid. Arzeim Forsch 45,872-874,1995. > > > > Klip, A. et al.,Glucose Transporters of Muscle Cells in Culture. Molecular > > Biology of Diabetes. N.J.: Humana Press, 1994. > > > > Murray, M. 1996. Encyclopedia of Nutritional Supplements. Rocklin, Ca: > Prima > > Publishing. > > > > Murray, M. & Pizzorno, J. 1998, Encyclopedia of Natural Medicine. Rocklin, > > CA: Prima Publishing. > > > > Packer, L. Antioxidant Properties of Lipoic Acid and its Therapeutic > Effects > > in Prevention of Diabetes Complications and Cataracts. ls NY Acad Sci > > 738, 257-264, 1994. > > > > Packer, L. & Tritschler, H. Alpha Lipoic as a Biological Antioxidant. Free > > Rad Biol Med 19, 227-250, 1995. > > > > Passwater, R. 1995. Lipoic Acid: The Metabolic Antioxidant.New Canaan, > > Conneticut: Keats Publishing. > > > > Quillin, P. & N. 1998. Beating Cancer with Nutrition. Tulsa, OK.: Nutrtion > > Times Press. > > > > Quillin, P. & Reynolds, A. 1988. The La Costa Book of Nutrition. New york: > > Pharos Books. > > > > Quillin, P. 1989. Healing Nutrients. New York: Random House. > > > > , B. et al., Lipoic and Dihydrolipoic Acids as Antioxidants: A > Critical > > Review. Free Rad Res 20, 119-133, 1994. > > > > Somer, E.1995. The Essential Guide to Vitamins and Minerals.New York: > > Harper. > > > > Wagh, S. et al., Mode of Action of Lipoic Acid in Diabetes. Journal of > > Bioscience. 11:59-75 (1987). > > > > Quote Link to comment Share on other sites More sharing options...
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