-IBIS-1.7.0-
rx
antioxidant
Alpha Lipoic Acid
Nutrition
Definition
Alpha Lipoic Acid:
» synonym: Thioctic Acid
» common names: Alpha-lipoic acid, lipoic acid, thioctic acid, acetate replacing factor, biletan, lipoicin, thioctacid, thioctan.
» chemical names: 1 ,2-dithiolane-3-pentanoic acid; 1,2-dithiolane-3-valeric acid; 6,8-thioctic acid; alpha-lipoic acid; 5-(1,2-dithiolan-3-yl) valeric acid.
» overview:
Alpha Lipoic acid is a potent antioxidant in both fat- and water-soluble mediums. Its antioxidant activity extends to both the oxidized and reduced form. ALA is a vitamin-like, "universal antioxidant". Dihydrolipoic Acid (DHLA) is capable of regenerating ascorbic acid from dehydroascorbic acid, directly regenerating vitamin C and indirectly regenerating vitamin E. Researchers have found lipoic acid to increase intracellular glutathione levels as well as Coenzyme Q10. It functions to produce energy, and its ability to scavenge free radicals has been clearly demonstrated. Clinically, lipoic acid seems to have the potential to prevent diabetes by influencing glucose metabolism and preventing complications associated with chronic hyperglycemia, such as neuropathy and cataracts. Lipoic acid may also be useful in the treatment of glaucoma, ischemia-reperfusion injury, amanita mushroom poisoning, and cellular oxidative damage. Its use in AIDS, cancer, and liver ailments offers promising results such as reduction of pathologies associated with these diseases.
» food sources:
The body synthesizes small amounts of alpha-lipoic acid, thus it is not a true vitamin and is not essential in the diet of humans or animals.
There is limited information regarding food sources of this nutrient. However, any foods that contain mitochondria, especially red meats, are believed to provide the highest levels of alpha-lipoic acid. Other sources may include spinach, broccoli, potatoes, yeast, kidney, heart, liver, and skeletal muscle.
A variety of supplements are also available.
(Ensminger A, et al. 1994:1318-1319; Murray M. 1996; 343-346; Ley B. 1996.)
» history: In the 1930s, it was found that a certain 'potato growth factor' was necessary for growth of certain bacteria. (Dupre S, Spoto G, Materese RM, et al. 1980; 202: 361-365.) In 1951, a fat-soluble coenzyme factor was discovered from work done with lactic acid bacteria. Reed et al, isolated this naturally occurring d-form, identified as 'alpha-lipoic acid', and found it to be an important growth factor for many bacteria and protozoa. It was originally classified as a vitamin; however, it subsequently was found to be synthesized by animals and humans. (Carreau JP. 1979; 62: 152-158.)
» chemistry:
Alpha-lipoic acid is a molecule with 2 sulfur high-energy bonds. It functions as a coenzyme with pyrophosphatase in carbohydrate metabolism to convert pyruvic acid to acetyl-coenzyme A (Kreb's cycle) to produce energy.
(Ensminger A, et al. 1994:1318-1319.)
Lipoic acid functions in the same manner as many B-complex vitamins. The enzymatic pathway for de novo synthesis has not been clearly identified; however, cysteine appears to be the source of sulfur, and octanoate serves as the intermediate precursor for the 8-carbon fatty acid. (Dupre S, et al. 1980; 202: 361-365.)
It is readily converted to its reduced form, dihydrolipoic acid (DHLA), in many tissues of the body.
» pharmacology:
Pharmacokinetics and bioavailability of different enantiomers of alpha lipoic acid (ALA) have been performed in 12 subjects. (Hermann H, et al. 1996; 4(3): 167-174)
Pharmacology of ALA has been studied in the areas of oxidation, diabetes, AIDS, cancer, and liver ailments; with findings in the following areas: Suppression of T-4 metabolism, exerting a lipid-lowering effect in rats, (Segermann J, et al. Arzneimittel-Forschung 1991;41(12): 1294-1298.) treatment in Wilson's disease, (Budavari S, et al, eds. The Merck Index, 11th ad. 1989) and treatment in cardiovascular disease. (Hermann H, et al. European J Pharm Sci 1996; 4(3): 167-174)
» requirements:
RDA: No RDA has been established.
The human body has the ability to synthesize alpha-lipoic acid; thus it is not considered an essential nutrient. Consequently, humans are usually not deficient in alpha-lipoic acid.
» therapeutics:
AIDS/HIV: Patients with HIV have a compromised antioxidant defense system, which may benefit from alpha-lipoic acid's role as an effective antioxidant. A small pilot study was conducted administering 150 mg ALA 3 times daily to HIV patients. It increased glutathione in all 10 patients and increased vitamin C in most patients as well. In addition, it improved the T-helper lymphocyte to T-helper suppressor cell ratio in 6 of the 10 patients. ALA significantly inhibits replication of HIV by reducing the activity of reverse transcriptase, the enzyme which facilitates the reproduction of the virus from the DNA of lymphocytes. In another report, ALA was found to also inhibit activation of "nuclear factor kappa-B," a substance involved in AIDS progression.
(Fuchs, J, et al. Arzneim Forsch 43, 1359-1362, 1993; Suzuki Y, et al. Biochemical and Biophysical Research Communications 1992;189:1709-1715.)
Whether it is beneficial to supplement HIV-positive patients with alpha-lipoic acid is inconclusive at this time.
(Baur A et al. Klin Wochenschr 1991; 69:722-24.)
Antioxidant Activity: Alpha-lipoic acid is unique in its ability to act as an antioxidant in fat- and water-soluble tissues in both its oxidized and reduced forms. It is readily absorbed from an oral dose and transported across cell membranes; thus, protection occurs both inside and outside of cells. Because of these advantages and its low toxicity, alpha-lipoic acid is receiving increased attention as a potentially effective therapeutic agent in clinical conditions associated with free radical damage. Lester Packer, PhD, of the University of California at Berkeley, has suggested alpha-lipoic acid is an ideal antioxidant candidate because of its role in the following: specificity of free radical quenching, metal chelating activity, interaction with other antioxidants, and effects on gene expression.
(Packer L, et al. Free Rad Biol Med 1995; 19: 227-250.)
The antioxidant function of alpha-lipoic acid was discovered in 1959 by Rosenburg and Culik, who reported that it prevented both scurvy symptoms in vitamin C-deficient guinea pigs and vitamin E deficiency in rats fed a diet lacking a-tocopherol. (Rosenburg HR, et al. Arch Biochem Biophys 1959; 80: 86-93.)
Podda et al reported alpha-lipoic acid prevents symptoms of vitamin E deficiency in mice fed a vitamin E-deficient diet; however, it had no effect on sustaining vitamin E tissue concentrations.
(Podda M, Tritschler HJ, Ulrich H, Packer L. Biochem Biophys Res Commun 1994 Oct 14; 204(1): 98-104.)
ALA is effective against a broader range of free radicals than vitamin C (water-soluble) and vitamin E (fat-soluble) alone because it is both water and fat-soluble.
Alpha-lipoic acid has a low redox potential, and through its reduced form, DHLA, very readily donates electrons to other compounds. Ascorbic acid, and indirectly vitamin E, are thought to be regenerated by DHLA. (Scholich H, et al. Biochem Biophys Acta 1989; 1001: 256-261.) Experimental evidence indicates optimal reduction of dehydroascorbic to ascorbic acid is achieved in the presence of pyruvate, alpha-lipoic acid, and ATP. (Xu DP, et al. J Bioenerg Biomembr 1996; 28: 77-85.) Busse et al found alpha-lipoic acid can cause an increase in intracellular glutathione, an important antioxidant. (Busse E, et al. Arzneim Forsch 1992 June; 42 (6): 829-31.) DHLA can regenerate Coenzyme Q10, and NADPH or NADH via glutathione. (Kagan V, et al. Biochem Biophys Res Comm 1990; 169: 851-857.)
Experts are in general agreement that alpha-lipoic acid is capable of scavenging hydroxyl radicals, hypochlorous acid, and singlet oxygen, but not hydrogen peroxide, peroxyl, and superoxide.
(Packer L, et al. Free Rad Biol Med 1995; 19: 227-250; Passwater, RA. 1995: 1-47; Scott BC, et al. Free Rad Res 1994; 20: 119-133. Suzuki YJ, et al. Free Rad Res Comms 1991; 15: 255-263.) DHLA is both an antioxidant and prooxidant in studies where hydroxyl radicals were generated. It protects against single strand DNA breaks induced by singlet oxygen, although it does not do so directly and several steps might be involved in the process. (Suzuki YJ, et al. Free Rad Res Comms 1991; 15: 255-263.)
Sandhya et al indicate alpha-lipoic acid acts in a dose-dependent manner as a nephroprotective agent against experimentally induced gentamicin toxicity. (Sandhya P, et al. J Appl Toxicol 1997 Nov-Dec; 17(6): 405-408.)
The body routinely converts ALA to dihydrolipoic acid, an even more powerful antioxidant. Both forms "quench" the dangerous peroxynitrite radicals, which are responsible in part for heart, lung, and neurological disease and inflammation as well. (Whiteman M, at al. Febs Letters 1996; 379:74-76.)
In oxidative stress models such as ischemia, reperfusion injury, and radiation injury, ALA has been shown to be beneficial.
(Schonheit K, et al. Biochemica et Biophysica Acta 1995; 1271:335-342; Cao X, et al. Free Radical Research 1995; 23:365-370.)
Cancer: There is limited information available concerning alpha-lipoic acid's role in cancer. Its mechanism of action and anticarcinogenic and cytoprotective effects have been addressed.
(Dovinova I. Ceska Slov Farm 1996 Sep; 45(5): 237-241.)
ALA administration, in conjunction with cyclophosphamide, lowered the toxic effects of this anticancer drug when tested in animals.
(Berger M, et al. Arzneimittel-Forschung 1983; 33(9): 1286-1288.)
Cataracts: High levels of activity of the enzyme aldose reductase have been associated with diabetic cataracts. Aldose reductase is inhibited by alpha-lipoic acid in rat lenses. (Ou P, et al. Free Radic Res 1996; 25: 337-346.) Dietary supplementation of alpha-lipoic acid has been shown to prevent cataract formation caused by buthionine sulfoximine-induced (BSO) inhibition of glutathione synthesis in newborn rats.
(Maitra I, et al. Free Radic Biol Med 1995; 18: 823-829.) The protective effects of alpha-lipoic acid against BSO-induced cataracts appear to be stereospecific. Both a racemic mixture and R-alpha-lipoic acid were able to decrease cataract formation, while S-alpha-lipoic acid had no effect. Maitra et al suggest alpha-lipoic acid's protective effect for BSO-induced cataract formation is probably due to its protective effects on lens antioxidants. (Maitra I, et al. Biochem Biophys Res Commun 1996; 221:422-429.)
Diabetes: Alpha-lipoic acid has been shown to be beneficial in type I and type II diabetes, by preventing various pathologies associated with this disease, such as reperfusion injury, macular degeneration, cataracts, and neuropathy. (Murray, M. 1996; 343-346; Ley, B, 1996; Schonheit, K, at al. Biochemica et Biophysica Acta 1995; 1271:335-342; Nagamatsu M, at al. Diabetes Care 1995; 18:1160-1167.) It has been used to reduce pain associated with nerve damage. (Packer L, et al. Free Rad Biol Med 1995; 19:227-250) ALA reduced diabetic neuropathy in rats, in a dose-dependent manner. In part, the mechanism was suggested to be caused by reduction of the effects of oxidative stress. (Nagamatsu M, at al. Diabetes Care 1995; 18:1160-1167.) ALA improves blood flow to peripheral nerves and stimulates regeneration of nerve fibers. A German study evaluating 800 mg/day of ALA in diabetics with damaged autonomic nervous systems was compared against a placebo. After 4 months, sympathetic systems showed improvement and autonomic nerve disorder decreased in the ALA group. (Ziegler D, et al. Diabetes Care 1997; 20:369-373.) Diabetic polyneuropathy has been treated clinically in Germany with alpha-lipoic acid for over 20 years. Findings indicate alpha-lipoic acid can correct neuropeptide deficits in diabetic rats. (Garrett NE, et al. Neurosci Lett 1997; 222: 191-194.) A model of streptozotocin-induced diabetic neuropathy was evaluated using alpha-lipoic acid and measuring improved nerve blood flow (NBF) after one month in age controlled rats. The alpha-lipoic acid-supplemented rats exhibited normal NBF. (Nagamatsu M, et al. Diabetes Care 1995 Aug; 18(8): 1160-1167.) A three-week multicenter double-blind, placebo-controlled trial of alpha-lipoic acid administered intravenously at 1200, 600, or 100 mg was conducted in patients with diabetic neuropathy. Symptom scoring including pain, burning, paresthesia, and numbness was conducted at baseline and at each visit. Intravenous treatment with 600 mg/day for three weeks was superior to placebo in reducing symptoms of neuropathy and caused no significant adverse reactions.
(Ziegler D, et al. Diabetoogia 1995; 38: 1425-1433.) In a non-blinded study of diabetic patients with both type I and II diabetes, 600 mg/day of alpha-lipoic acid was given for two weeks, followed by 300 mg/day for 10 weeks. Albuminuria decreased 50% as compared to placebo controls. A clinical improvement in neurological symptoms was found in the alpha-lipoic acid group but not in the control group.
(Kehler W, et al, 1993: 33-53.)
ALA is approved in Germany to treat diabetic neuropathy. The most commonly used therapeutic dosage to improve diabetic neuropathies is 600mg per day. ALA also improves the diabetic condition by improving blood sugar metabolism, by facilitating better conversion of sugar into energy. (Murray, M. 1996; 343-346) In 13 non-insulin-dependent diabetes mellitus patients, ALA increased insulin-stimulated glucose disposal. Metabolic clearance rate for glucose rose by 50% compared with the control group. (Jacob S, et al. Arzneimittel-Forschung 1995; 45(8): 872-874.) In heart tissue of diabetic rats, high doses of alpha-lipoic acid first normalized glucose uptake and utilization, and consequently normalized oxygen uptake, myocardial ATP levels, and cardiac output, while a low dose of alpha-lipoic acid normalized lactate and pyruvate production. (Strodter D, et al. Diabetes Res Clin Pract 1995; 29: 19-26.) In cell cultures, alpha-lipoic acid stimulated basal glucose transport and had a positive effect on insulin-stimulated glucose uptake. (Estrada DE, et al. Diabetes 1996 Dec; 45 (12): 1798-1804.) Alpha-lipoic acid administration prevented diabetes in 70% of diabetes induced animals. This effect was thought to be secondary to DHLA suppression of nitric oxide release from macrophages involved in islet cell inflammation.
(Faust A, et al. Int J Immunopharmac 1994; 16: 61-66.) In a type II diabetic model using insulin-resistant obese Zucker rats, alpha-lipoic acid increased the uptake of glucose in the absence of insulin. (Henricksen EJ, Jacob S, Tritschler HJ, et al. Diabetes 1994; Supplement 1:122A.)
Glycation of protein caused by elevated blood and tissue glucose is believed to contribute to many of the complications seen in 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. (Packer L, et al. Free Rad Biol Med 1995; 19:227-250.) Packer and Kawabata found that noncovalent binding of alpha-lipoic acid to albumin protected proteins against glycation. (Kawabata T, et al. Biochem Biophys Res Comms 1994; 203: 99-104.)
Type II diabetic humans given an acute dose of alpha-lipoic acid (1000 mg intravenously) experienced 50% improvement in insulin-stimulated glucose disposal. (Jacob S, Henriksen EJ, Schiemann AL, Simon I, Clancy DE, Tritschler HJ, Jung W, Augustin HJ, Dietze GJ. Arzneimittelforschung 1995 Aug; 45(8): 872-874.) In an uncontrolled pilot study 20 patients with type II diabetes received daily alpha-lipoic acid (500 mg/500 ml NaCl, 0.9%) parenterally for ten days. An increase of insulin-stimulated glucose disposal of approximately 30% was reported; however, no changes in fasting plasma levels for glucose or insulin were found during the short period of treatment and observation. (Jacob S, et al. Exp Clin Endocrinol Diabetes
1996; 104: 284-288.)
Because many of the systemic complications of diabetes mellitus, such as polyneuropathy and cataract formation, appear to be secondary to free radical damage, alpha-lipoic acid and DHLA have been proposed as possible therapeutic agents in these conditions. When ALA was compared with antioxidant vitamin E, results failed to justify the higher cost of ALA over less-expensive and equally effective nutritional antioxidants. (Murray, M. 1996; 343-346.)
Glaucoma: 150 mg per day improves visual function in people with both stage I and stage II glaucoma.
(Filina AA, et al. Vestn Oftalmol 1995; 111:6-1118.)
Ischemia-Reperfusion Injury: Ischemia-reperfusion injury occurs when free radicals are produced in a burst during reinstitution of blood flow to the tissue. This is significant in cardiac tissue following thrombus-dissolving treatment and in brain tissue following stroke. Scheer et al demonstrated DHLA prevents ischemia-reperfusion injury in rat mitochondria. (Scheer B, Zimmer G. Arch Biochem Biophys 1993; 302: 385-390.) Assadnazaria et al found DHLA accelerated the recovery of the aortic flow during reperfusion and increased ATP synthesis in the rat heart. (Assadnazari H, et al. Arzneimittel-Forschung 1993; 43: 425-432.) In middle cerebral artery occlusion in mice, treatment with DHLA, but not alpha-lipoic acid, reduced the size of the infarct. (Prehn JH, et al. J Cereb Blood Flow Metab 1992; 12: 78-87.) Based upon their findings, Wolz et al suggest alpha-lipoic acid must be reduced to DHLA, which is then responsible for the neuroprotection. (Wolz P, Krieglstein J. Neuropharmacology 1996; 35: 369-375.) The combination of vitamin E supplementation with DHLA perfusion synergistically improves cardiac functional recovery during post-ischemic reperfusion or post-hypoxic reoxygenation of the rat heart. The glutathione status of the cardiac tissue shows significant elevation of reduced glutathione in vitamin E supplemented rat hearts, while elevation of oxidized glutathione was observed in DHLA perfused hearts. (Haramaki N, et al. Biochem Mol Biol Int 1995; 37: 591-597.)
The effect of alpha-lipoic acid was examined on the morbidity and mortality of rats subjected to reperfusion following cerebral ischemia induced by bilateral carotid artery occlusion and hypotension. Alpha-lipoic acid reduced the mortality rate from 78% to 26% during 24 hours of reperfusion. (Panigrahi M, Sadguna Y, Shivakumar BR, et al. Brain Res 1996; 717: 184-188.) Gerbils were protected against cerebral ischemia-reperfusion injury with alpha-lipoic acid in a study conducted by Cao et al. (Cao X, Phillis JW. Free Radic Res 1995 Oct; 23 (4): 365-370.)
Liver ailments: Alpha-lipoic acid has been used as an antidote to Amanita mushroom poisoning. Infusions of alpha-lipoic acid were used to treat Amanita mushroom poisoning from 1974 to 1978 in 75 patients, in which sixty-seven patients recovered, compared to an expected rate of between 10-50%. (Bartter FC, et al. 1980: 197-202.) Nagy et al and Sabeel et al both report comprehensive protocols, including the administration of alpha-lipoic acid, supporting the use of it in the treatment of individuals with Amanita poisoning. (Nagy I, et al. Clin Investig 1994; 72: 794-798. Sabeel Al, et al. Mycopathologia 1995; 131: 107-114.) A review on mushroom intoxication's employing ALA and other antidotes is available. (Lampe K. Clinical Toxicology 1974; 7(1): 115-121.)
Metal Chelation: Alpha-lipoic acid appears capable of chelating transition metals in biological systems. It forms stable complexes with copper, manganese and zinc ions. (Sigel H, et al. Arch Biochem Biophys 1978; 187: 208-214.) Its ability to chelate iron remains equivocal. (Devasaayam TP, et al. Chem-Biol Interations 1993; 86: 79-92. Bast A, Haenen GR. Biochem Biophys Acta 1988; 983: 558-561.)
Arsenite: Mice were protected from arsenite poisoning with alpha-lipoic acid administration when the ratio of alpha-lipoic acid to arsenite was at least 8:1. Protection occurred even when the administration was after severe symptoms of poisoning presented. (Grunert, RR. Arch Biochem Biophys 1960; 86: 190-194.)
Copper: Evidence suggests alpha-lipoic acid might chelate copper. Ou et al report the R-enantiomer and racemic mixture of alpha-lipoic acid seemed more effective than the S-enantiomer in their assays of metal chelation. (Ou P, Tritschler HJ, Wolff SP. Biochem Pharmacol 1995; 50: 123-126.)
Cadmium: In isolated hepatocytes, alpha-lipoic acid has been found to reduce cadmium-induced toxicity, although DHLA was much more effective. (Muller L, Menzel H. Biochem Biophys Acta 1990; 1052: 386-391.) Sumathi et al also reported alpha-lipoic acid offers significant hepatoprotection against cadmium toxicity, even under glutathione-depleted experimental conditions. (Sumathi R, et al. Jpn J Med Sci Biol 1996; 49: 39-48.) In a rat model, a dose of 30 mg of alpha-lipoic acid completely prevented cadmium-induced lipid peroxidation in the brain, heart, and testicles. (Sumathi R, et al. Med Sci Res 1994; 22: 23-25.)
Mercury: In vitro experiments have indicated alpha-lipoic acid, while not the most effective chelating agent, will remove mercury from renal slices. (Keith Rl, et al. Toxicology 1997; 116: 67-75.)
Alpha-lipoic acid administration to rats increased biliary excretion of injected mercury 12-37 fold but decreased the excretion of cadmium, zinc, copper, and methylmercury. (Gregus Z, et al. Toxicol Appl Pharmacol 1992; 114: 88-96.)
» maintenance dose: 20-50 mg per day.
» therapeutic dose:
The amount of alpha-lipoic acid used in research has ranged from 150-600 mg per day, with 600 mg per day being used to treat diabetic neuropathies and 150 mg per day for glaucoma. In circumstances other than these pathologies, nutritionally-oriented practitioners prescribe much lower levels, usually in the range of 20-50 mg per day, to achieve the general antioxidant effect of alpha-lipoic acid. However, no clear and convincing research has been published to support the general benefits of supplementation.
» side effects/toxicity:
No adverse events from ALA supplementation have been reported.
Alpha-lipoic acid is considered to be extremely safe in the amounts utilized clinically.
As no studies have confirmed the safety or documented any dangers of using alpha-lipoic acid during pregnancy, supplementation with alpha-lipoic acid should be avoided by pregnant women until it is shown to be safe.
The LD50 is approximately 400-500 mg/kg after oral dosing in dogs.
(Packer L, et al. 1995; 19: 227-250.)
Thiamine Deficiency: Alpha-lipoic acid should not be given in high doses to patients suspected of having a thiamine deficiency unless the thiamine deficiency is also corrected. Individuals who may be deficient in vitamin B1 (such as alcoholics) should supplement vitamin B1 along with alpha lipoic acid. High doses of alpha-lipoic acid (20 mg/kg) administered intraperitoneally to rats is reported to cause fatal complications. The prior administration of thiamine prevents these adverse effects.
(Gal, EM. 1965; 207: 535.)
Glycine conjugation of benzoic acid: Gregus et al have expressed concern regarding alpha-lipoic acid's impact on glycine conjugation of benzoic acid. They report alpha-lipoic acid inhibited glycine conjugation of benzoic acid in a dose-dependent manner in experimental animals.
(Gregus Z, et al. 1996; 24: 682-688.)
Diabetes: Alpha-lipoic acid supplementation in diabetes may require a reduction of insulin dosage or other oral diabetic medications. Blood sugar levels must be closely monitored. In addition, ALA use may spare vitamins C and E, as well as other antioxidants.
(Murray, M. 1996; 343-346.)
» side effects:
Side effects from alpha-lipoic acid are quite rare.
Skin rashes have been reported.
Improved glucose utilization due toALA can result in hypoglycemia in diabetic patients. Daily administration of alpha-lipoic acid in animals has interfered with the actions of the vitamin biotin; whether this has significance for humans remains unknown.
(Zempleni J, et al. J Nutr 1997; 127:1776-1781.)
» contraindications: Use of alpha lipoic acid, and other antioxidants, is contraindicated during radiation therapy and some forms of chemotherapy. See Chemotherapy.
Interactions:
nutrient affecting other nutrient: Biotin
Research has found that long-term use of alpha lipoic acid has interfered with the action of the vitamin biotin in animals. No confirmatory research has found similar problems with humans.
(Zempleni J, et al. J Nutr 1997;127:1776-1781.)
nutrient affecting drug toxicity: Aminoglycosides
mechanism: Free radical generation due to aminoglycosides plays an important role in drug-induced damage to the liver, kidneys and inner ear. Alpha lipoic acid is a powerful antioxidant and free radical scavenger.
(Tran Ba Huy P, Deffrennes D. Acta Otolaryngol [Stockh] 1988;105:511-515.)
research: Sandhya et al found that lipoic acid administration brought about a decrease in the degree of lipid peroxidation due to gentamicin in rats. Conlon et al conducted studies using guinea pigs to the investigate the ability of the alpha-lipoic acid (100 mg/kg/day) to attenuate the cochlear damage induced by 450 mg/kg/day, i.m. of the aminoglycoside amikacin. Their results showed that animals receiving alpha lipoic acid in combination with amikacin demonstrated a significantly less severe changes in cochlear function compared with animals receiving amikacin alone.
(Sandhya P, et al. J Appl Toxicol 1997 Nov-Dec;17(6):405-408; Conlon BJ, et al. Hear Res. 1999 Feb;128(1-2):40-44.)
nutritional support: Since the preliminary research on this topic has involved animals and not human patients no conclusive recommendations can be offered. However, a diverse set of clinical studies have demonstrated alpha lipoic acid's role as a potent anti-oxidant and its ability to enhance protective systems in the liver and kidney in a variety of situations. Therefore, while supplementation with alpha lipoic acid might be advisable for individuals using aminoglycosides, the available research literature provides no specific indications as to the appropriate dosage for this particular situation. However, any individual using alpha-lipoic acid in relation to gentamicin should do so only under supervision of a the prescribing physician and a nutritionally-trained healthcare professional.
nutrient affecting drug toxicity: Gentamicin
mechanism: Gentamicin tends to cause kidney damage and research with test rats indicates that alpha lipoic acid decreases the lipid peroxidation which plays an important role in these adverse effects.
(Sandhya P, Varalakshmi P. J Appl Toxicol 1997 Nov-Dec;17(6):405-408.)
nutritional support: Since the preliminary research on this topic has involved rats and not human patients no conclusive recommendations can be offered. However, a diverse set of clinical studies have demonstrated alpha lipoic acid's role as a potent anti-oxidant and its ability to enhance protective systems in the liver and kidney in a variety of situations. Therefore, while supplementation with alpha lipoic acid might be advisable for individuals using gentamicin, the available research literature provides no specific indications as to the appropriate dosage for this particular situation. However, any individual using alpha lipoic acid in relation to gentamicin should do so only under supervision of a the prescribing physician and a nutritionally-trained healthcare professional.
nutrient affecting drug toxicity: Haloperidol
research: Balijepalli et al examined the effects of a variety of classical and atypical neuroleptic drugs and found that haloperidol was the most potent inhibitor of mitochondrial NADH ubiquinone oxido-reductase (complex I) activity. They found that in vitro treatment of mouse brain slices with haloperidol resulted in a loss of glutathione (GSH), while pretreatment of slices with GSH and alpha lipoic acid abolished haloperidol-induced loss of complex I activity.
(Balijepalli S, et al. Neuropharmacology 1999 Apr;38(4):567-577.)
nutritional support: Preliminary evidence indicates that supplementation with alpha-lipoic acid (and/or glutathione) could potentially reduce depletion of naturally occurring glutathione and other adverse side effects due to use of haloperidol. No definitive advise or dosage recommendations can be offered given the lack of clinical trials. However, physicians experienced in nutritional therapies often suggest 20-50 mg of alpha lipoic acid per day for general antioxidant protection while prescribing dosages of 800 mg per day and 150 mg per day, respectively, in the treatment of diabetic neuropathies and glaucoma. Individuals concerned about preventing the damaging effects of haloperidol should consult their prescribing physician and/or nutritionally trained healthcare professional about possible benefits of supplementing with alpha-lipoic acid (and/or glutathione). Alpha lipoic acid has no known toxic effects at commonly used dosages and has never been shown to inhibit the therapeutic efficacy of haloperidol.
Footnotes
[Alpha-lipoic acid in diabetic neuropathy. Action mechanism and therapy. Clinical picture and pathogenesis of diabetic neuropathy]. Internist (Berl) 1994 Jun;35(6 Alpha-liponsa):1-4. [Article in German]
Assadnazari H, Zimmer G, Freisleben HJ, et al. Cardioprotective efficiency of dihydrolipoic acid in working rat hearts during hypoxia and reoxygenation. P nuclear magnetic resonance investigations. Arzneimittel-Forschung 1993;43:425-432.
Baker H, Deangelis B, Baker ER, Hutner SH. A practical assay of lipoate in biologic fluids and liver in health and disease. Free Radic Biol Med 1998 Sep;25(4-5):473-479.
Abstract: A procedure for assaying lipoic acid concentration in biologic fluids and tissues was devised using a eukaryotic protozoan Tetrahymena thermophila. T.thermophila has a specific and sensitive (30 pg/ml) requirement for lipoic acid. Unlike humans and other microorganisms, T.thermophila can not synthesize lipoic acid; hence, its requirement for exogenous lipoic acid is specific. The lipoic acid supplied to T. thermophila by the processing of biologic fluids and tissues during the assay procedure, permits the derivation of a practical assay for lipoate concentration as described here. Lipoate concentration in biologic fluids and tissue obtained from healthy humans, compared to those obtained from patients with renal and liver disease, indicate deviations from normal during disease. Absorption chartings of 200 mg of DL-alpha-lipoic acid in humans indicate a peak concentration of lipoate in plasma 2 h after ingestion and then a steady descent of lipoate to a baseline level after 24 h. With this practical assay, it is now possible to chart lipoate's antioxidant activity and therapeutic action during health and disease.
Balijepalli S, Boyd MR, Ravindranath V. Inhibition of mitochondrial complex I by haloperidol: the role of thiol oxidation. Neuropharmacology 1999 Apr;38(4):567-577.
Abstract: We have examined the effects of a variety of classical and atypical neuroleptic drugs on mitochondrial NADH ubiquinone oxido-reductase (complex I) activity. Sagittal slices of mouse brain incubated in vitro with haloperidol (10 nM) showed time- and concentration-dependent inhibition of complex I. Similar concentrations of the pyridinium metabolite of haloperidol (HPP+) failed to inhibit complex I activity in this model; indeed, comparable inhibition was obtained only at a 10000-fold higher concentration of HPP+ (100 microM). Treatment of brain slices with haloperidol resulted in a loss of glutathione (GSH), while pretreatment of slices with GSH and alpha-lipoic acid abolished haloperidol-induced loss of complex I activity. Incubation of mitochondria from haloperidol treated brain slices with the thiol reductant, dithiothreitol, completely regenerated complex I activity demonstrating thiol oxidation as a feasible mechanism of inhibition. In a comparison of different neuroleptic drugs, haloperidol was the most potent inhibitor of complex I, followed by chlorpromazine, fluphenazine and risperidone while the atypical neuroleptic, clozapine (100 microM) did not inhibit complex I activity in mouse brain slices. The present studies support the view that classical neuroleptics such as haloperidol inhibit mitochondrial complex I through oxidative modification of the enzyme complex.
Bartter FC, Berkson B, Gallelli J, et al. Thiotic acid in the treatment of poisoning with alpha-amanitin. In: Faulstich H, Kommerell B, Wieland T, eds. Amanita Toxins and Poisoning. Badan-Baden. Verlg Gerhard Witzstrock; 1980:197-202.
Bassendine MF, Jones DE, Yeaman SJ. Biochemistry and autoimmune response to the 2-oxoacid dehydrogenase complexes in primary biliary cirrhosis. Semin Liver Dis 1997 Feb;17(1):49-60. (Review)
Abstract: Pyruvate dehydrogenase complex (PDC), 2-oxo-glutarate dehydrogenase complex (OGDC), and the branched-chain 2-oxoacid dehydrogenase complex (BCOADC) constitute the 2-oxoacid dehydrogenase family of multienzyme complexes. These complexes, which are larger than ribosomes and which consist of multiple copies of E1, E2, and E3 subunits together with regulatory kinases and phosphatases and, in the case of PDC, an E3-binding protein (protein X), each play an important role in oxidative metabolism in mitochondria. Primary biliary cirrhosis (PBC) is associated with a high incidence of autoantibodies directed at mitochondrial autoantigens (the antimito-chondrial antibodies), identified as the E2 components of PDC, OGDC, and BCOADC, together with protein X and the E1 alpha and E1 beta subunits of PDC. The dominant B-cell autoepitope in PBC has been identified as the inner lipoic acid binding domain of PDC-E2, with the lipoic acid co-factor, which plays a critical role in E2 enzymatic activity, playing a role in autoantibody binding to antigen. Autoreactive CD4+ T cells specific for human PDC-E2 are also present in both the peripheral blood and liver mononuclear cell infiltrates of PBC patients. The mechanism of break-down of B-cell and T-cell self-tolerance to these ubiquitous mitochondrial antigens in such an organ-specific manner remains unclear. The apparent importance of autoreactive responses to these self-antigens does, however, raise the possibility that antigen-specific immunotherapy may offer a novel route to therapy in PBC.
Bast A, Haenen GR. Interplay between lipoic acid and glutathione in the protection against microsomal lipid peroxidation. Biochem Biophys Acta 1988;963:558-561.
Baur A, Harrer T, Peukert M, Jahn G, Kalden JR, Fleckenstein B. Alpha-lipoic acid is an effective inhibitor of human immuno-deficiency virus (HIV-1) replication. Klin Wochenschr 1991 Oct 2;69(15):722-724.
Abstract: Alpha-lipoic acid, a naturally occurring disulfide-compound that acts as a cellular coenzyme, inhibits replication of HIV-1 in cultured lymphoid T-cells. Alpha-lipoic acid was added 16 hours after infection of the T-cell lines Jurkat, SupT1 and Molt-4 with HTLV IIIB and HIV-1 Wal (a wild type HIV-1 isolate). We observed a dose dependent inhibition of HIV-1-replication in CPE (Cytopathic effect) formation, reverse transcriptase activity and plaque formation on CD4-transformed HeLa-cells. An over 90% reduction of reverse transcriptase activity could be achieved with 70 micrograms alpha-lipoic acid/ml, a complete reduction of plaque-forming units at concentrations of greater than or equal to 35 micrograms alpha-lipoic acid/ml. An augmentation of the antiviral activity was seen by combination of zidovudine and low dose of alpha-lipoic acid (7 micrograms/ml). Trypan blue staining revealed no toxic effects of alpha-lipoic acids on peripheral blood mono-nuclear cells and T-cell lines even in concentrations of greater than or equal to 70 micrograms/ml. Therefore, we propose the inclusion of alpha-lipoic acid into chemotherapy trials in combination with zidovudine.
Berger, M, et al. Arzneimittel-Forschung 1983;33(9):1286-1288.
Biewenga GP, Haenen GR, Bast A. The pharmacology of the antioxidant lipoic acid. Gen Pharmacol 1997 Sep;29(3):315-31 (Review)
Abstract: 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.
Biewenga G, Haenen GR, Bast A. The role of lipoic acid in the treatment of diabetic polyneuropathy. Drug Metab Rev 1997 Nov;29(4):1025-1054. (Review)
Budavari S, et al, eds. The Merck Index, 11th ad. Rahway: Merck and Co. 1989.
Busse E, Zimmer G, Schopohl B, Kornhuber B. Influence of alpha-lipoic acid on intracellular glutathione in vitro and in vivo. Arzneimittelforschung 1992 Jun;42(6):829-831
Abstract: The influence of alpha-lipoic acid (CAS 62-46-4) on the amount of intracellular glutathione (GSH) was investigated in vitro and in vivo. Using murine neuroblastoma as well as melanoma cell lines in vitro, a dose-dependent increase of GSH content was observed. Dependent on the source of tumor cells the increase was 30-70% compared to untreated controls. Normal lung tissue of mice also revealed about 50% increase in glutathione upon treatment with lipoic acid. This corresponds with protection from irradiation damage in these in vitro studies. Survival rate of irradiated murine neuroblastoma was increased at doses of 100 micrograms lipoic acid/d from 2% to about 10%. In agreement with the in vitro studies, in vivo experiments with whole body irradiation (5 and 8 Gy) in mice revealed that the number of surviving animals was doubled at a dose of 16 mg lipoic acid/kg. Improvement of cell viability and irradiation protection by the physiological compound lipoic acid runs parallel with an increase of intracellular GSH/GSSG ratio.
Bustamante J, Lodge JK, Marcocci L, Tritschler HJ, Packer L, Rihn BH. Alpha-lipoic acid in liver metabolism and disease. Free Radic Biol Med 1998 Apr;24(6):1023-1039. (Review)
Abstract: 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 to 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 an 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.
Cao X, Phillis JW. The free radical scavenger, alpha-lipoic acid, protects against cerebral ischemia-reperfusion injury in gerbils. Free Rad Res 1995;23:365-370.
Abstract: alpha-Lipoic acid (thioctic acid) was tested for its neuroprotective activity in a Mongolian gerbil model of forebrain ischemia/reperfusion. Adult gerbils were treated for 7 days with two intraperitoneal injections per day of alpha-lipoic acid (20 mg/kg), vehicle or saline and on the 7th day the animals were subjected to 5 min of forebrain ischemia. Ischemic injury was assessed by monitoring the increases in locomotor activity and from the extent of damage to the CA1 hippocampal pyramidal cell layer after 5 days of recovery. By both criteria, alpha-lipoic acid was neuroprotective against ischemia/reperfusion evoked cerebral injury.
Carreau JP. Biosynthesis of lipoic acid via unsaturated fatty acids. Meth Enzmol 1979;62:152-158.
Conlon BJ, Aran JM, Erre JP, Smith DW. Attenuation of aminoglycoside-induced cochlear damage with the metabolic antioxidant alpha-lipoic acid. Hear Res. 1999 Feb;128(1-2):40-44.
Abstract: Free radical generation is increasingly implicated in a variety of pathological processes, including drug toxicity. Recently, a number of studies have demonstrated the ability of gentamicin to facilitate the generation of radical species both in vivo and in vitro, which suggests that this process plays an important role in aminoglycoside-induced ototoxicity. Free radical scavengers are compounds capable of inactivating free radicals, thereby attenuating their tissue damaging capacity. In this study we have determined the ability of the powerful free radical scavenger alpha-lipoic acid (100 mg/kg/day) to attenuate the cochlear damage induced by a highly ototoxic regimen of the aminoglycoside amikacin (450 mg/kg/day, i.m.). Experiments were carried out on pigmented guinea pigs initially weighing 200-250 g. Changes in cochlear function were characterized as shifts in compound action potential (CAP) thresholds, estimated every 5 days, by use of chronic indwelling electrodes implanted at the round window, vertex, and contralateral mastoid. Results showed that animals receiving alpha-lipoic acid in combination with amikacin demonstrated a significantly less severe elevation in CAP thresholds compared with animals receiving amikacin alone (P < 0.001; t-test). These results provide further evidence of the recently reported intrinsic role of free radical generation in aminoglycoside ototoxicity, and highlight a potential clinical therapeutic use of alpha-lipoic acid in the management of patients undergoing aminoglycoside treatment.
Devasagayam TP, Subramanian M, Pradhan DS, Sies H. Prevention of singlet oxygen induced DNA damage by lipoate. Chem-Biol Interations 1993;86:79-92.
Dovinova I [alpha-Lipoic acid--a natural disulfide cofactor and antioxidant with anticarcinogenic effects]. Ceska Slov Farm 1996 Sep;45(5):237-241 (Review) [Article in Slovak]
Abstract: The present survey summarizes the data about the structure, function and methods of investigation of the natural substance alpha-lipoic acid. This compound is an important growth factor of many microorganisms and at the same time a disulfide cofactor of dehydrogenases in oxidative phosphorylation. It is a physiological constituent of biological membranes, an efficient antioxidant and a scavenger of free radicals. Lipoic acid possesses anticarcinogenic and preventive effects which protect the calls from damage.
Dupre S, Spoto G, Materese RM, et al. Biosynthesis of alpha-lipoic acid in the rat: Incorporation of S- and C-labeled precursors. Arch Biochem Biophys 1980;202:361-365.
Ensminger, A, et al. Foods and Nutrition Encyclopedia, 2nd edition. Boca Raton, FL: CRC Press Inc. 1994:1318-1319.
Eremeeva ME, Silverman DJ. Effects of the antioxidant alpha-lipoic acid on human umbilical vein endothelial cells infected with Rickettsia rickettsii. Infect Immun 1998 May;66(5):2290-9
Abstract: Rickettsia rickettsii infection of endothelial cells is manifested in very distinctive changes in cell morphology, consisting of extensive dilatation of the membranes of the endoplasmic reticulum and outer nuclear envelope and blebbing of the plasma membrane, as seen by transmission electron microscopy (D. J. Silverman, Infect. Immun. 44:545-553, 1984). These changes in cellular architecture are thought to be due to oxidant-mediated cell injury, since their occurrence correlates with dramatic alterations in cellular metabolism, particularly with regard to antioxidant systems. In this study, it was shown that R. rickettsii infection of human umbilical vein endothelial cells resulted in a significant depletion of intracellular reduced glutathione (thiol) content at 72 and 96 h and decreased glutathione peroxidase activity at 72 h postinfection. Infected cells displayed a dramatic increase in the concentration of intracellular peroxides by 72 h. Supplementation of the cell culture medium with 100, 200, or 500 microM alpha-lipoic acid, a metabolic antioxidant, after inoculation with R. rickettsii restored the intracellular levels of thiols and glutathione peroxidase and reduced the intracellular peroxide levels in infected cells. These effects were dose dependent. Treated infected monolayers maintained better viability at 96 h after inoculation with R. rickettsii than did untreated infected cells. Moreover, supplementation of the cell culture medium with 100 microM alpha-lipoic acid for 72 h after infection prevented the occurrence of morphological changes in the infected cells. The presence of 100 or 200 microM alpha-lipoic acid did not influence rickettsial growth in endothelial cells, nor did it affect the ability of R. rickettsii to form lytic plaques in Vero cells. Treatment with 500 microM alpha-lipoic acid decreased by 50% both the number and size of lytic plaques in Vero cells, and it also decreased the recovery of viable rickettsiae from endothelial cells. However, under all treatment conditions, a significant number of rickettsiae could be detected microscopically. Furthermore, the rickettsiae apparently retained their capacity for intracellular movement, since they possessed long polymerized actin tails after 72 and 96 h of treatment regardless of the concentration of alpha-lipoic acid used. Since alpha-lipoic acid does not seem to exhibit direct antirickettsial activity except with long-term exposure at very high concentrations, the mechanism of its protective activity for endothelial cells infected with rickettsiae may involve complex changes in cellular metabolism that only indirectly affect rickettsiae.
Estrada DE, Ewart HS, Tsakiridis T, Volchuk A, Ramlal T, Tritschler H, Klip A . Stimulation of glucose uptake by the natural coenzyme alpha-lipoic acid/thioctic acid: participation of elements of the insulin signaling pathway. Diabetes 1996;45:1798-1804.
Abstract: Thioctic acid (alpha-lipoic acid), a natural cofactor in dehydrogenase complexes, is used in Germany in the treatment of symptoms of diabetic neuropathy. Thioctic acid improves insulin-responsive glucose utilization in rat muscle preparations and during insulin clamp studies performed in diabetic individuals. The aim of this study was to determine the direct effect of thioctic acid on glucose uptake and glucose transporters. In L6 muscle cells and 3T3-L1 adipocytes in culture, glucose uptake was rapidly increased by (R)-thioctic acid. The increment was higher than that elicited by the (S)-isomer or the racemic mixture and was comparable with that caused by insulin. In parallel to insulin action, the stimulation of glucose uptake by thioctic acid was abolished by wortmannin, an inhibitor of phosphatidylinositol 3-kinase, in both cell lines. Thioctic acid provoked an upward shift of the glucose-uptake insulin dose-response curve. The molar content of GLUT1 and GLUT4 transporters was measured in both cell lines. 3T3-L1 adipocytes were shown to have >10 times more glucose transporters but similar ratios of GLUT4:GLUT1 than L6 myotubes. The effect of (R)-thioctic acid on glucose transporters was studied in the L6 myotubes. Its stimulatory effect on glucose uptake was associated with an intracellular redistribution of GLUT1 and GLUT4 glucose transporters, similar to that caused by insulin, with minimal effects on GLUT3 transporters. In conclusion, thioctic acid stimulates basal glucose transport and has a positive effect on insulin-stimulated glucose uptake. The stimulatory effect is dependent on phosphatidylinositol 3-kinase activity and may be explained by a redistribution of glucose transporters. This is evidence that a physiologically relevant compound can stimulate glucose transport via the insulin signaling pathway.
Faust A, Burkart V, Ulrich H et al. Effect of lipoic acid on cyclophosphamide-induced diabetes and insulitis in nonobese diabetic mice. Int J Immunopharmac 1994;16:61-66.
Filina AA, Davydova NG, Endrikhovskii SN, et al. Lipoic acid as a means of metabolic therapy of open-angle glaucoma. Vestn Oftalmol 1995;111:6-8.
Fuchs, J, et al. Studies on lipoate effects on blood redox state in human immunodeficiency virus infected patients. Arzneim Forsch 43, 1359-1362, 1993.
Gal EM. Reversal of selective toxicity of (-)-alpha-lipoic acid by thiamine in thiamine-deficient rats. Nature 1965;207:535.
Garrett NE, Malcangio M, Dewhurst M, Tomlinson DR. alpha-lipoic acid corrects neuropeptide deficits in diabetic rats via induction of trophic support. Neurosci Lett 1997;222:191-194.
Gregus Z, Fekete T, Halaszi E, Klaassen CD. Lipoic acid impairs glycine conjugation of benzoic acid and renal excretion of benzoylglycine. Drug Metab Dispos 1996;24:682-688.
Gregus Z, Stein AF, Varga F. Effect of lipoic acid on biliary excretion of glutathione and metals. Toxicol Appl Pharmacol 1992;114:88-96.
Grunert RR. The effect of DL alpha-lipoic acid on heavy-metal intoxication in mice and dogs. Arch Biochem Biophys 1960;86:190-194.
Han D, Handelman G, Marcocci L, Sen CK, Roy S, Kobuchi H, Tritschler HJ, Flohe L, Packer L. Lipoic acid increases de novo synthesis of cellular glutathione by improving cystine utilization. Biofactors 1997;6(3):321-338.
Abstract: Lipoic acid (thiotic acid) is being used as a dietary supplement, and as a therapeutic agent, and is reported to have beneficial effects in disorders associated with oxidative stress, but its mechanism of action remains unclear. We present evidence that lipoic acid induces a substantial increase in cellular reduced glutathione in cultured human Jurkat T cells human erythrocytes, C6 glial cells, NB41A3 neuroblastoma cells, and peripheral blood lymphocytes. The effect depends on metabolic reduction of lipoic acid to dihydrolipoic acid. Dihydrolipoic acid is released into the culture medium where it reduces cystine. Cysteine thus formed is readily taken up by the neutral amino acid transport system and utilized for glutathione synthesis. By this mechanism lipoic acid enables cystine to bypass the xc- transport system, which is weakly expressed in lymphocytes and inhibited by glutamate. Thereby lipoic acid enables the key enzyme of glutathione synthesis, gamma-glutamylcysteine synthetase, which is regulated by uptake-limited cysteine supply, to work at optimum conditions. Flow cytometric analysis of freshly prepared human peripheral blood lymphocytes, using monobromobimane labeling of cellular thiols, reveals that lipoic acid acts mainly to normalize a subpopulation of cells severely compromised in thiol status rather than to increase thiol content beyond physiological levels. Hence lipoic acid may have clinical relevance in restoration of severely glutathione deficient cells.
Haramaki N, Assadnazari H, Zimmer G, et al. The influence of vitamin E and dihydrolipoic acid on cardiac energy and glutathione status under hypoxia-reoxygenation. Biochem Mol Biol Int 1995;37:591-597.
Henricksen EJ, Jacob S, Tritschler HJ, et al. Chronic thioctic treatment increases insulin-stimulated glucose transport activity in skeletal muscle of obese Zucker rats. Diabetes 1994;Supplement 1:122A
Hermann, H, at al. European J Pharm Sci 1996;4(3):167-174.
Hounsom L, Horrobin DF, Tritschler H, Corder R, Tomlinson DR. A lipoic acid-gamma linolenic acid conjugate is effective against multiple indices of experimental diabetic neuropathy. Diabetologia 1998 Jul;41(7):839-843.
Abstract: Untreated streptozotocin-diabetic (7 weeks duration) rats showed reductions (all p < 0.01; percentages in brackets) in motor and sensory nerve conduction velocity (MNCV; 14%, SNCV; 17%) and in sciatic nerve contents of nerve growth factor (NGF; 57%), substance P (SP; 53%) and neuropeptide Y (NPY; 39%). Treatment with a gamma linolenic acid-alpha-lipoic acid conjugate (GLA-LA; 35 mg x day(-1) x rat(-1)) attenuated (p < 0.05) these reductions to MNCV (8%), SNCV (5%), NGF (19%), SP (23%), NPY (20%), such that the values in GLA-LA-treated diabetic rats did not differ significantly from those of control non-diabetic animals. Treatment with alpha-lipoic acid alone at 100 mg/kg i.p. was without effect on these variables except for NGF (33% reduction, p < 0.05) and treatment with the antioxidant, butylated hydroxytoluene (1.5% dietary supplement) did not affect any deficits. These data show that GLA-LA is effective in improving both electrophysiological and neurochemical correlates of experimental diabetic neuropathy.
Jacob 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. Arzneimittelforschung 1995 Aug;45(8):872-874.
Abstract: 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.
Jacob S, Henriksen EJ, Tritschler HJ, et al. Improvement of insulin-stimulated glucose-disposal in type 2 diabetes after repeated
parenteral administration of thioctic acid. Exp Clin Endocrinol Diabetes 1996;104:284-288.
Kagan V, Serbinova E, Packer L. Antioxidant effects of ubiquinones in microsomes and mitochondria are mediated by tocopherol recycling. Biochem Biophys Res Comm 1990;169:851-857.
Kawabata T, Packer L. Alpha-lipoate can protect against glycation of serum albumin, but not low density lipoprotein. Biochem Biophys Res Comms 1994;203:99-104.
Kehler W, Kuklinski B, Ruhlmann C, Plotz C. Diabetes mellitus-a free radical associated disease: Effects of adjuvant supplementation of antioxidants. In: Gries FA, Wessel K, eds. The role of antioxidants in diabetes mellitus: Oxygen radicals and anti-oxidants in diabetes. Frankfurt am Maine: pmi. Verl-Gruppe; 1993:33-53.
Keith RL, Setiarahardjo I, Fernando Q, et al. Utilization of renal slices to evaluate the efficacy of chelating agents for removing mercury from the kidney. Toxicology 1997;116:67-75.
Khanna S, Atalay M, Lodge JK, Laaksonen DE, Roy S, Hanninen O, Packer L, Sen CK. Skeletal muscle and liver lipoyllysine content in response to exercise, training and dietary alpha-lipoic acid supplementation. Biochem Mol Biol Int 1998 Oct;46(2):297-306.
Abstract: In human cells, alpha-lipoic acid (LA) is present in a bound lipoyllysine form in mitochondrial proteins that play a central role in oxidative metabolism. The possible effects of oral LA supplementation, a single bout of strenuous exercise and endurance exercise training on the lipoyllysine content in skeletal muscle and liver tissues of rat were examined. Incorporation of lipoyl moiety to tissue protein was not increased by enhanced abundance of LA in the diet. Endurance exercise training markedly increased lipoyllysine content in the liver at rest. A bout of exhaustive exercise also increased hepatic lipoyllysine content. A significant interaction of exhaustive exercise and training to increase tissue lipoyllysine content was evident. In vastus lateralis skeletal muscle, training did not influence tissue lipoyllysine content. A single bout of exhaustive exercise, however, clearly increased the level of lipoyllysine in the muscle. Comparison of tissue lipoyllysine data with that of free or loosely-bound LA results showed a clear lack of association between the two apparently related parameters. Tightly protein-bound lipoyllysine pool in tissues appeared to be independent of the loosely-bound or free LA status in the tissue.
Kobberling J, Hompesch M. alpha-Lipoic acid in NIDDM patients with cardiac autonomic neuropathy. Diabetes Care 1997 Dec;20(12):1918-20 (Letter)
Lampe, K. Clinical Toxicology 1974;7(1):115-121.
Ley, B. The Potato Antioxidant, Alpha Lipoic Acid. BL Publications. 1996.
Low PA, Nickander KK, Tritschler HJ. The roles of oxidative stress and antioxidant treatment in experimental diabetic neuropathy. Diabetes 1997 Sep;46 Suppl 2:S38-42.
Abstract: Oxidative stress is present in the diabetic state. Our work has focused on its presence in peripheral nerves. Antioxidant enzymes are reduced in peripheral nerves and are further reduced in diabetic nerves. That lipid peroxidation will cause neuropathy is supported by evidence of the development of neuropathy de novo when normal nerves are rendered alpha-tocopherol deficient and by the augmentation of the conduction deficit in diabetic nerves subjected to this insult. Oxidative stress appears to be primarily due to the processes of nerve ischemia and hyperglycemia auto-oxidation. The indexes of oxidative stress include an increase in nerve, dorsal root, and sympathetic ganglia lipid hydroperoxides and conjugated dienes. The most reliable and sensitive index, however, is a reduction in reduced glutathione. Experimental diabetic neuropathy results in myelinopathy of dorsal roots and a vacuolar neuropathy of dorsal root ganglion. The vacuoles are mitochondrial; we posit that lipid peroxidation causes mitochondrial DNA mutations that increase reduced oxygen species, causing further damage to mitochondrial respiratory chain and function and resulting in a sensory neuropathy. Alpha-lipoic acid is a potent antioxidant that prevents lipid peroxidation in vitro and in vivo. We evaluated the efficacy of the drug in doses of 20, 50, and 100 mg/kg administered intraperitoneally in preventing the biochemical, electrophysiological, and nerve blood flow deficits in the peripheral nerves of experimental diabetic neuropathy. Alpha-lipoic acid dose- and time-dependently prevented the deficits in nerve conduction and nerve blood flow and biochemical abnormalities (reductions in reduced glutathione and lipid peroxidation). The nerve blood flow deficit was 50% (P < 0.001). Supplementation dose-dependently prevented the deficit; at the highest concentration, nerve blood flow was not different from that of control nerves. Digital nerve conduction underwent a dose-dependent improvement at 1 month (P < 0.05). By 3 months, all treated groups had lost their deficit. The antioxidant drug is potentially efficacious for human diabetic sensory neuropathy.
Maitra I, Serbinova E, Tritschler HJ, Packer L. Alpha-lipoic acid prevents buthionine sulfoximine-induced cataract formation in newborn rats. Free Radic Biol Med 1995;18:823-829.
Maitra I, Serbinova E, Tritschler HJ, Packer L. Stereospecific effects of R-lipoic acid on buthionine sulfoximine-induced cataract formation in newborn rats. Biochem Biophys Res Commun 1996;221:422-429.
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. FEBS Lett 1996 Sep 23;394(1):9-13
Abstract: 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.
Muller L, Menzel H. Studies on the efficacy of lipoate and dihydrolipoate in the alteration of cadmium toxicity in isolated hepatocytes. Biochem Biophys Acta 1990;1052:386-391.
Murray, M. Encyclopedia of Nutritional Supplements. Rocklin, CA: Prima Publishing. 1996;343-346.
Nagamatsu M, Nickander KK, Schmelzer JD, Raya A, Wittrock DA, Tritschler H, Low PA. Lipoic acid improves nerve blood flow, reduces oxidative stress, and improves distal nerve conduction in experimental diabetic neuropathy. Diabetes Care 1995 Aug;18(8):1160-1167.
Abstract: OBJECTIVE--To determine whether lipoic acid (LA) will reduce oxidative stress in diabetic peripheral nerves and improve neuropathy. RESEARCH DESIGN AND METHODS--We used the model of streptozotocin-induced diabetic neuropathy (SDN) and evaluated the efficacy of LA supplementation in improving nerve blood flow (NBF), electrophysiology, and indexes of oxidative stress in peripheral nerves affected by SDN, at 1 month after onset of diabetes and in age-matched control rats. LA, in doses of 20, 50, and 100 mg/kg, was administered intraperitoneally five times per week after onset of diabetes. RESULTS--NBF in SDN was reduced by 50%; LA did not affect the NBF of normal nerves but improved that of SDN in a dose-dependent manner. After 1 month of treatment, LA-supplemented rats (100 mg/kg) exhibited normal NBF. The most sensitive and reliable indicator of oxidative stress was reduction in reduced glutathione, which was significantly reduced in streptozotocin-induced diabetic and alpha-tocopherol-deficient nerves; it was improved in a dose-dependent manner in LA-supplemented rats. The conduction velocity of the digital nerve was reduced in SDN and was significantly improved by LA. CONCLUSIONS--These studies suggest that LA improves SDN, in significant part by reducing the effects of oxidative stress. The drug may have potential in the treatment of human diabetic neuropathy.
Nagy I, Pogatsa-Murray G, Zalanyi S Jr, et al. Amanita poisoning during the second trimester of pregnancy. A case report and a review of the literature. Clin Investig 1994;72:794-798.
Nichols, T. Alpha-Lipoic Acid: Biological Effects and Clinical Implications. Alt Med Rev 1997;2(3):177-183. (Review)
Abstract: Alpha-Lipoic acid is unique in its ability to act as an antioxidant in fat- and water-soluble tissues in both its oxidized and reduced forms. It is readily absorbed from an oral dose. Because of its myriad biological activities, including an ability to chelate metals and to scavenge a wide array of free radicals, a-lipoic acid is considered by several experts to be an ideal antioxidant. Clinical applications for this nutrient include the following conditions: diabetic polyneuropathy, cataracts, glaucoma, ischemia-reperfusion injury, and Amanita mushroom poisoning. Because of its unique characteristics a-lipoic acid is likely to have therapeutic application in a wide range of additional clinical conditions.
Ou P, Nourooz-Zadeh J, Tritschler HJ, Wolff SP. Activation of aldose reductase in rat lens and metal-ion chelation by aldose reductase inhibitors and lipoic acid. Free Radic Res 1996;25:337-346.
Ou P, Tritschler HJ, Wolff SP. Thioctic (lipoic) acid: a therapeutic metal-chelating antioxidant? Biochem Pharmacol 1995;50:123-126.
Packer L. alpha-Lipoic acid: a metabolic antioxidant which regulates NF-kappa B signal transduction and protects against oxidative injury. Drug Metab Rev 1998 May;30(2):245-275. (Review)
Abstract: 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 (Fig. 12). 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, Roy S, Sen CK. Alpha-lipoic acid: a metabolic antioxidant and potential redox modulator of transcription. Adv Pharmacol 1997;38:79-101 (Review)
Packer L, Tritschler HJ, Wessel K. Neuroprotection by the metabolic antioxidant alpha-lipoic acid. Free Radic Biol Med 1997;22(1-2):359-378. (Review)
Abstract: 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.
Packer L, Witt EH, Tritschler HJ. Alpha-lipoic acid as a biological antioxidant. Free Rad Biol Med 1995;19:227-250.
Panigrahi M, Sadguna Y, Shivakumar BR, et al. alpha-lipoic acid protects against reperfusion injury following cerebral ischemia in rats. Brain Res 1996;717:184-188.
Passwater RA. Lipoic Acid: The Metabolic Antioxidant. New Canaan, CT: Keats Publishing, Inc; 1995:1-47.
Podda M, Tritschler HJ, Ulrich H, Packer L. Alpha-lipoic acid supplementation prevents symptoms of vitamin E deficiency. Biochem Biophys Res Commun 1994 Oct 14;204(1):98-104.
Abstract: alpha-Lipoic acid, an essential cofactor in mitochondrial dehydrogenases, has recently been shown to be a potent antioxidant in vitro, as well as being capable of regenerating vitamin E in vitro. In this study, using a new animal model for rapid vitamin E deficiency in adult animals and a new technique for tissue extraction of oxidized and reduced alpha-lipoic acid, we examined the antioxidant action of alpha-lipoic acid in vivo. Vitamin E-deficient adult hairless mice displayed obvious symptoms of deficiency within five weeks, but if the diet was supplemented with alpha-lipoic acid the animals were completely protected. At five weeks on a vitamin E-deficient diet animals exhibited similar decreases in tissue vitamin E levels, whether supplemented or unsupplemented with alpha-lipoic acid: vitamin E levels in liver, kidney, heart, and skin decreased 70 to 85%; levels in brain decreased only 25%. These data show that there was no effect of alpha-lipoic acid supplementation on vitamin E tissue concentrations, arguing against a role for alpha-lipoic acid in regenerating vitamin E in vivo.
Prehn JH, Karkoutly C, Nuglisch J, et al. Dihydrolipoate reduces neuronal injury after cerebral ischemia. J Cereb Blood Flow Metab 1992;12:78-87.
Rabinovic AD, Hastings TG. Role of endogenous glutathione in the oxidation of dopamine. J Neurochem. 1998 Nov;71(5):2071-2078.
Abstract: Intrastriatal injection of dopamine causes the selective degeneration of tyrosine hydroxylase-containing terminals and an increase in content of cysteinyl-catechols, an index of dopamine oxidation. Both of these effects can be attenuated by coadministration of antioxidants such as glutathione. Therefore, we investigated the effects of decreased endogenous glutathione on the neurotoxic potential of dopamine. We observed that pretreatment with either L-buthionine sulfoximine, a specific inhibitor of glutathione synthesis, or diethyl maleate, which forms adducts with glutathione, caused significant decreases in endogenous glutathione levels at the time of dopamine injection. Pretreatment with L-buthionine sulfoximine potentiated the formation of protein cysteinyl-dopamine after intrastriatal injection of 1.0 micromol of dopamine. We also observed that intrastriatal injection of 1.0 micromol of dopamine decreased striatal glutathione content in all pretreatment conditions. However, injection of a low dose (0.05 micromol of dopamine) caused a decrease in striatal glutathione levels only in the L-buthionine sulfoximine-pretreated rats. Diethyl maleate pretreatment was not effective in potentiating either cysteinyl-catechol formation or glutathione loss after dopamine injection. We conclude that dopamine contributes to cellular oxidative stress and that this can be exacerbated, or at least unmasked, if glutathione synthesis is compromised.
Reed LJ, DeBusk BG, Gunsalus IC, et al. Crystalline alpha-lipoic acid: a catalytic agent associated with pyruvate dehydrogenase. Science 1951;114:93-94.
Rosenburg HR, Culik R. Effects of alpha-lipoic acid on vitamin C and vitamin E deficiencies. Arch Biochem Biophys 1959;80:86-93.
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. Biochem Pharmacol 1997 Feb 7;53(3):393-399.
Abstract: 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.
Sabeel AI, Kurkus J, Lindholm T. Intensive hemodialysis and hemoperfusion treatment of Amanita mushroom poisoning. Mycopathologia 1995;131:107-114.
Sandhya P, Mohandass S, Varalakshmi P. Role of DL alpha-lipoic acid in gentamicin induced nephrotoxicity. Mol Cell Biochem 1995;145:11-17.
Abstract: The intraperitoneal administration of gentamicin (100 mg kg[-1] day[-1]) to rats is associated with an increased production of malondialdehyde (MDA), which is an end product of lipid peroxidation in the kidney. The level of glutathione (GSH) and the activity of three antioxidant systems--superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx)--were also decreased in the kidney. The liver, however, did not show any such alterations. Gentamicin (100 mg kg[-1] day[-1]) plus lipoic acid administration (25 mg kg[-1] day[-1]) by gastric intubation brought about a decrease in the degree of lipid peroxidation. An increase in the GSH level and in the activity of SOD, CAT and GPx was also observed. From these observations it can be concluded that administration of DL-alpha-lipoic acid prevents lipid peroxidation, which may, at least partly, play an important role in the injury cascade of gentamicin-induced nephrotoxicity.
Sastrasinh M, Weinberg JM, Humes HD. The effect of gentamicin on calcium uptake by renal mitochondria. Life Sci. 1982 Jun 28;30(26):2309-2315.
Abstract: The effect of the nephrotoxic aminoglycoside antibiotic, gentamicin, on calcium uptake by renal cortical mitochondria was assessed in vitro. Gentamicin was found to be a competitive inhibitor of mitochondrial Ca++ uptake. This effect displayed a dose response with a Ki of 233 microM and occurred at gentamicin concentrations below those that inhibit mitochondrial electron transport. These results further demonstrate the potential for gentamicin to alter membrane function and thereby contribute to toxic cell injury via its interactions with divalent cations.
Scheer B, Zimmer G. Dihydrolipoic acid prevents hypoxic/reoxygenation and peroxidative damage in rat mitochondria. Arch Biochem Biophys 1993;302:385-390.
Scholich H, Murphy ME, Sies H. Antioxidant activity of dihydrolipoate against microsomal lipid peroxidation and its dependence on a-tocopherol. Biochem Biophys Acta 1989;1001:256-261.
Schonheit K, Gille L, Nohl H. Effect of alpha-lipoic acid and dihydrolipoic acid on ischemia/reperfusion injury of the heart and heart mitochondria. Biochem Biophys Acta 1995 Jun 9;1271(2-3):335-342.
Abstract: The aim of the present study was to evaluate a possible interference of alpha-lipoic acid (LA) or its reduced form (dithiol dihydrolipoic acid = DHLA) in the cardiac ischemia/reperfusion injury both at the level of the intact organ and at the subcellular level of mitochondria. In order to follow the effect of LA on the ischemia/reperfusion injury of the heart the isolated perfused organ was subjected to total global ischemia and reperfusion in the presence and absence of different concentrations of LA. Treatment with 0.5 microM LA improved the recovery of hemodynamic parameters; electrophysiological parameters were not influenced. However, application of 10 microM LA to rat hearts further impaired the recovery of hemodynamic functions and prolonged the duration of severe rhythm disturbances in comparison to reperfusion of control hearts. Treatment of isolated mitochondria with any concentration of DHLA could not prevent the impairment of respiratory-linked energy conservation caused by the exposure of mitochondria to 'reperfusion' conditions. However, DHLA was effective in decreasing the formation and the existence of mitochondrial superoxide radicals (O2.-). Apart from its direct O(2.-)-scavenging activities DHLA was also found to control mitochondrial O2.- formation indirectly by regulating redox-cycling ubiquinone. It is suggested that impairment of this mitochondrial O2.- generator mitigates postischemic oxidative stress which in turn reduces damage to hemodynamic heart function.
Scott BC, Arouma OI, Evans PJ, et al. Lipoic and dihydrolipoic acid as antioxidants: a critical evaluation. Free Rad Res 1994;20:119-133.
Segermann J, Hotze A, Ulrich H, Rao GS. Effect of alpha-lipoic acid on the peripheral conversion of thyroxine to triiodothyronine and on serum lipid-, protein- and glucose levels. Arzneimittelforschung 1991 Dec;41(12):1294-1298.
Abstract: The influence of alpha-lipoic acid (LA, thioctic acid, CAS 62-46-4) on thyroid hormone metabolism and serum lipid-, protein- and glucose levels was investigated. In the first setup of experiments administration of LA together with thyroxine (T4) for 9 days suppressed the T4 induced increase of T3 generation by 56%. This suppression was similar to that affected by 6-propylthiouracil (54%). LA or T4 alone did not affect the cholesterol level, but together they led to a reduction. LA decreased the triglyceride level by 45%; the decrease induced by T4 or LA plus T4 was not significant. Total protein and albumin levels decreased by LA plus T4 treatment when compared to the LA control. The slight increase in glucose level by LA or T4 alone was not observed when they were administered together. In the second setup of experiments the administration of T4 for 22 days increased the serum T3 level 3-fold. When LA was combined with T4 and the treatment continued, the T3 production decreased by 22%. T4 reduced cholesterol level by 30%, and LA plus T4 further reduced it by 47%. The triglycerides were not affected. A moderate decrease in total protein was observed after treatment with T4 plus LA; T4 and LA plus T4 decreased the albumin level. The decrease in serum glucose by T4 recovers by LA treatment. These results demonstrate that LA interferes with the production of T3 from T4 when it is co-administered with T4. The elevated level of T3, after T4 administration, is reduced by treatment with LA.
Sen CK. Redox signaling and the emerging therapeutic potential of thiol antioxidants. Biochem Pharmacol 1998 Jun 1;55(11):1747-1158. (Review)
Abstract: Oxidation-reduction (redox) based regulation of signal transduction and gene expression is emerging as a fundamental regulatory mechanism in cell biology. Electron flow through side chain functional CH2-SH groups of conserved cysteinyl residues in proteins account for their redox-sensing properties. Because in most intracellular proteins thiol groups are strongly "buffered" against oxidation by the highly reduced environment inside the cell, only accessible protein thiol groups
with high thiol-disulfide oxidation potentials are likely to be redox sensitive. The list of redox-sensitive signal transduction pathways is steadily growing, and current information suggests that manipulation of the cell redox state may prove to be an important strategy for the management of AIDS and some forms of cancer. The endogenous thioredoxin and glutathione
systems are of central importance in redox signaling. Among the thiol agents tested for their efficacy to modulate cellular redox status, N-acetyl-L-cysteine (NAC) and alpha-lipoic acid hold promise for clinical use. A unique advantage of lipoate is that it is able to utilize cellular reducing equivalents, and thus it harnesses the metabolic power of the cell to continuously regenerate its reductive vicinal dithiol form. Because lipoate can be readily recycled in the cell, it has an advantage over N-acetyl-L-cysteine on a concentration:effect basis. Our current knowledge of redox regulated signal transduction has led to the unfolding of the remarkable therapeutic potential of cellular thiol modulating agents.
Shivakumar BR, Ravindranath V. Shivakumar BR, et al. Oxidative stress and thiol modification induced by chronic administration of haloperidol. J Pharmacol Exp Ther. 1993 Jun;265(3):1137-1141.
Abstract: Haloperidol, a widely used neuroleptic, acts through blockade of dopamine receptors leading to increased turnover of dopamine. Increased turnover of dopamine could lead to excessive production of hydrogen peroxide and, thus, generate oxidative stress. The effect of chronic administration of haloperidol on glutathione (GSH)-protein thiol homeostasis and lipid peroxidation was examined in rat brain regions. The oxidized GSH levels increased significantly, though not substantially, in cortex (CT, 15%), striatum (ST, 28%) and midbrain (MB, 27%). Maximal decreases in GSH levels were noted in CT (23%), ST (28%) and MB (20%) after 1 month of haloperidol administration. The GSH levels recovered thereafter, and after 6 months of haloperidol treatment, the GSH levels were not significantly different from control in ST and MB. The depleted GSH was recovered essentially as protein-GSH mixed disulfide with a concomitant decrease in the protein thiol concentration in all the three regions of the brain. The increase in oxidized GSH concentration represented only 1.8, 2.0 and 3.5% of the depleted GSH in the CT, ST and MB after 1 month of haloperidol administration. The concentration of thiobarbituric acid-reactive products increased significantly up to 3 months of haloperidol treatment, but at the end of 6 months, the levels were substantially decreased. The present study demonstrates that haloperidol administration for 1 month results in significant oxidative stress in CT, ST and MB regions of the brain, as demonstrated by alterations in GSH-protein thiol homeostasis and increased lipid peroxidation products. However, after prolonged administration of haloperidol for 6 months, the GSH-protein thiol homeostasis is restored to a large extent, concomitant with the decrease in the concentration of lipid peroxidation products. Administration of haloperidol leads to development of tolerance (supersensitivity of the dopamine autoreceptors) to neuroleptics, which is associated with decreased turnover of dopamine; this may result in overcoming the oxidative stress generated initially due to increased dopamine turnover.
Sigel H, Prijs B, McCormick DB, Shih JCH. Stability of binary and ternary complexes of alpha-lipoate and lipoate derivatives with Mn2+, Cu2+, and Zn2+ in solution. Arch Biochem Biophys 1978;187:208-214.
Streeper RS, Henriksen EJ, Jacob S, Hokama JY, Fogt DL, Tritschler HJ. Differential effects of lipoic acid stereoisomers on glucose metabolism in insulin-resistant skeletal muscle. Am J Physiol 1997 Jul;273(1 Pt 1):E185-191.
Abstract: The racemic mixture of the antioxidant alpha-lipoic acid (ALA) enhances insulin-stimulated glucose metabolism in insulin-resistant humans and animals. We determined the individual effects of the pure R-(+) and S-(-) enantiomers of ALA on glucose metabolism in skeletal muscle of an animal model of insulin resistance, hyperinsulinemia, and dyslipidemia: the obese Zucker (fa/fa) rat. Obese rats were treated intraperitoneally acutely (100 mg/kg body wt for 1 h) or chronically [10 days with 30 mg/kg of R-(+)-ALA or 50 mg/kg of S-(-)-ALA]. Glucose transport [2-deoxyglucose (2-DG) uptake], glycogen synthesis, and glucose oxidation were determined in the epitrochlearis muscles in the absence or presence of insulin (13.3 nM). Acutely, R-(+)-ALA increased insulin-mediated 2-DG-uptake by 64% (P < 0.05), whereas S-(-)-ALA had no significant effect. Although chronic R-(+)-ALA treatment significantly reduced plasma insulin (17%) and free fatty acids (FFA; 35%) relative to vehicle-treated obese animals, S-(-)-ALA treatment further increased insulin (15%) and had no effect on FFA. Insulin-stimulated 2-DG uptake was increased by 65% by chronic R-(+)-ALA treatment, whereas S-(-)-ALA administration resulted in only a 29% improvement. Chronic R-(+)-ALA treatment elicited a 26% increase in insulin-stimulated glycogen synthesis and a 33% enhancement of insulin-stimulated glucose oxidation. No significant increase in these parameters was observed after S-(-)-ALA treatment. Glucose transporter (GLUT-4) protein was unchanged after chronic R-(+)-ALA treatment but was reduced to 81 +/- 6% of obese control with S-(-)-ALA treatment. Therefore, chronic parenteral treatment with the antioxidant ALA enhances insulin-stimulated glucose transport and non-oxidative and oxidative glucose metabolism in insulin-resistant rat skeletal muscle, with the R-(+) enantiomer being much more effective than the S-(-) enantiomer.
Strodter D, Lehmann E, Lehmann U, et al. The influence of thioctic acid on metabolism and function of the diabetic heart. Diabetes Res Clin Pract 1995;29:19-26.
Sumathi R, Baskaran G, Varalakshmi P. Relationship between glutathione and DL alpha-lipoic acid against cadmium-induced hepatotoxicity. Jpn J Med Sci Biol 1996;49:39-48.
Sumathi R, Devi VK, Varalakshmi P. DL alpha-lipoic acid protection against cadmium-induced tissue lipid peroxidation. Med Sci Res 1994;22:23-25.
Suzuki YJ, Aggarwal BB, Packer L. Alpha-lipoic acid is a potent inhibitor of NF-kappa B activation in human T cells. Biochem Biophys Res Commun 1992 Dec 30;189(3):1709-1715.
Abstract: 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 B), 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.
Suzuki YJ, Tsuchiya M, Packer L. Thiotic acid and dihydrolipoic acid are novel antioxidants which interact with reactive oxygen species. Free Rad Res Comms 1991;15:255-263.
Tran Ba Huy P, Deffrennes D. Aminoglycoside ototoxicity: influence of dosage regimen on drug uptake and correlation between membrane binding and some clinical features. Acta Otolaryngol [Stockh] 1988;105:511-515.
Whiteman M, Tritschler H, Halliwell B. Protection against peroxynitrite-dependent tyrosine nitration and alpha 1-antiproteinase inactivation by oxidized and reduced lipoic acid. FEBS Lett 1996 Jan 22;379(1):74-76.
Abstract: Peroxynitrite, formed by combination of superoxide radical with nitric oxide, is a reactive tissue-damaging species apparently involved in the pathology of several human diseases. Peroxynitrite nitrates tyrosine residues and inactivates alpha 1-antiproteinase. We show that both lipoic acid and dihydrolipoic acid efficiently protect against damage by peroxynitrite. By contrast, other disulphides tested did not. The biological antioxidant effects of lipoate/dihydrolipoate may involve scavenging of reactive nitrogen species as well as reactive oxygen species.
Wolz P, Krieglstein J. Neuroprotective effects of alpha-lipoic acid and its enantiomers demonstrated in rodent models of focal cerebral ischemia. Neuropharmacology 1996;35:369-375.
Xu DP, Wells WW. alpha-lipoic acid dependent regeneration of ascorbic acid from dehydroascorbic acid in rat liver mitochondria. J Bioenerg Biomembr 1996;28:77-85.
Zempleni J, Trusty TA, Mock DM. Lipoic acid reduces the activities of biotin-dependent carboxylases in rat liver. J Nutr 1997 Sep;127(9):1776-1781.
Abstract: In the past, lipoic acid has been administered to patients and test animals as therapy for diabetic neuropathy and various intoxications. Lipoic acid and the vitamin biotin have structural similarities. We sought to determine whether the chronic administration of lipoic acid affects the activities of biotin-dependent carboxylases. For 28 d, rats received daily intraperitoneal injections of one of the following: 1) a small dose of lipoic acid [4.3 micromol/( kg.d)]; 2) a large dose of lipoic acid [15.6 micromol/(kg.d)]; or 3) a large dose of lipoic acid plus biotin [15.6 and 2.0 micromol/(kg.d), respectively]. Another group received n-hexanoic acid [14.5 micromol/(kg.d)], which has structural similarities to lipoic acid and biotin and thus served as a control for the specificity of lipoic acid. A fifth group received phosphatidylcholine in saline injections and served as the vehicle control. The rat livers were assayed for the activities of acetyl-CoA carboxylase, pyruvate carboxylase, propionyl-CoA carboxylase, and beta-methylcrotonyl-CoA carboxylase. Urine was analyzed for lipoic acid; serum was analyzed for indicators of liver damage and metabolic aberrations. The mean activities of pyruvate carboxylase and beta-methylcrotonyl-CoA carboxylase were 28-36% lower in the lipoic acid-treated rats compared with vehicle controls (P < 0.05). Rats treated with lipoic acid plus biotin had normal carboxylase activities. Carboxylase activities in livers of n-hexanoic acid-treated rats were normal despite some evidence of liver injury. Propionyl-CoA carboxylase and acetyl-CoA carboxylase were not significantly affected by administration of lipoic acid. This study provides evidence consistent with the hypothesis that chronic administration of lipoic acid lowers the activities of pyruvate carboxylase and beta-methylcrotonyl-CoA carboxylase in vivo by competing with biotin.
Ziegler D, Gries FA. Alpha-lipoic acid in the treatment of diabetic peripheral and cardiac autonomic neuropathy. Diabetes 1997 Sep;46 Suppl 2:S62-66.
Abstract: 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.
Ziegler D, Hanefield M, Ruhnau KJ, et al. Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant alpha-lipoic acid. A 3-week multicenter randomized controlled trial (ALADIN Study). Diabetologia 1995;38:1425-1433.
Ziegler D, Schatz H, Conrad F, Gries FA, Ulrich H, Reichel G. 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). Deutsche Kardiale Autonome Neuropathie. Diabetes Care 1997 Mar;20(3):369-373.
Abstract: OBJECTIVE: To evaluate the efficacy and safety of oral treatment with the antioxidant alpha-lipoic acid (ALA) in NIDDM patients with cardiac autonomic neuropathy (CAN), assessed by heart rate variability (HRV). RESEARCH DESIGN AND METHODS: In a randomized, double-blind placebo-controlled multicenter trial (Deutsche Kardiale Autonome Neuropathie [DEKAN] Study), NIDDM patients with reduced HRV were randomly assigned to treatment with daily oral dose of 800 mg ALA (n = 39) or placebo (n = 34) for 4 months. Parameters of HRV at rest included the coefficient of variation (CV), root mean square successive difference (RMSSD), and spectral power in the low-frequency (LF; 0.05-0.15 Hz) and high-frequency (HF; 0.15-0.5 Hz) bands. In addition, cardiovascular autonomic symptoms were assessed. RESULTS: Seventeen patients dropped out of the study (ALA n = 10; placebo n = 7). Mean blood pressure and HbA1 levels did not differ between the groups at baseline and during the study, but heart rate at baseline was higher in the group treated with ALA (P < 0.05). RMSSD increased from baseline to 4 months by 1.5 ms (-37.6 to 77.1) [median (minimum-maximum)] in the group given ALA and decreased by -0.1 ms (-19.2 to 32.8) in the placebo group (P < 0.05 for ALA vs. placebo). Power spectrum in the LF band increased by 0.06 bpm2 (-0. 09 to 0.62) in ALA, whereas it declined by -0.01 bpm2 (-0.48 to 1.86) in placebo (P < 0.05 for ALA vs. placebo). Furthermore, there was a trend toward a favorable effect of ALA versus placebo for the CV and HF band power spectrum (P = 0.097 and P = 0.094 for ALA vs. placebo). The changes in cardiovascular autonomic symptoms did not differ significantly between the groups during the period studied. No differences between the groups were noted regarding the rates of adverse events. CONCLUSIONS: These findings suggest that treatment with ALA using a well-tolerated oral dose of 800 mg/day for 4 months may slightly improve CAN in NIDDM patients.