Lipoic Acid Abstracts

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Packer L Witt EH Tritschler HJ

alpha-Lipoic acid as a biological antioxidant.

In: Free Radic Biol Med (1995 Aug) 19(2):227-50

alpha-Lipoic acid, which plays an essential role in mitochondrial dehydrogenase reactions, has recently gained considerable attention as an antioxidant. Lipoate, or its reduced form, dihydrolipoate, reacts with reactive oxygen species such as superoxide radicals, hydroxyl radicals, hypochlorous acid, peroxyl radicals, and singlet oxygen. It also protects membranes by interacting with vitamin C and glutathione, which may in turn recycle vitamin E. In addition to its antioxidant activities, dihydrolipoate may exert prooxidant actions through reduction of iron. alpha-Lipoic acid administration has been shown to be beneficial in a number of oxidative stress models such as ischemia-reperfusion injury, diabetes (both alpha-lipoic acid and dihydrolipoic acid exhibit hydrophobic binding to proteins such as albumin, which can prevent glycation reactions), cataract formation, HIV activation, neurodegeneration, and radiation injury. Furthermore, lipoate can function as a redox regulator of proteins such as myoglobin, prolactin, thioredoxin and NF-kappa B transcription factor. We review the properties of lipoate in terms of (1) reactions with reactive oxygen species; (2) interactions with other antioxidants; (3) beneficial effects in oxidative stress models or clinical conditions.



Muller U Krieglstein J

Prolonged pretreatment with alpha-lipoic acid protects cultured neurons against hypoxic, glutamate-, or iron-induced injury.

In: J Cereb Blood Flow Metab (1995 Jul) 15(4):624-30

The antioxidant dihydrolipoic acid has been shown to reduce hypoxic and excitotoxic neuronal damage in vitro. In the present study, we tested whether pretreatment with alpha-lipoic acid, which presumably allows endogenous formation of dihydrolipoic acid, can protect cultured neurons against injury caused by cyanide, glutamate, or iron ions, using the trypan blue exclusion method to determine neuronal damage. One hour of preincubation with dihydrolipoic acid (1 microM), but not with alpha-lipoic acid, reduced damage of neurons from chick embryo telencephalon caused by 1 mM sodium cyanide or iron ions. alpha-Lipoic acid (1 microM) reduced cyanide-induced neuronal damage when added 24 h before hypoxia, and pretreatment with alpha-lipoic acid for > 24 h enhanced this neuroprotective effect. Both the R- and the S-enantiomer of alpha-lipoic acid exerted a similar neuroprotective effect. Pretreatment with alpha-lipoic acid (1 microM) from the day of plating onward prevented the degeneration of chick embryo telencephalic neurons that had been exposed to Fe2+/Fe3+. alpha-Lipoic acid (1 microM) added to the culture medium the day of plating also reduced neuronal injury induced by 1 mM L-glutamate in rat hippocampal cultures, whereas 30 min of preincubation with alpha-lipoic acid failed to attenuate glutamate-induced neuronal damage. Our results indicate that neuroprotection by prolonged pretreatment with alpha-lipoic acid is probably due to the radical scavenger properties of endogenously formed dihydrolipoic acid.



Ramakrishnan N Wolfe WW Catravas GN

Radioprotection of hematopoietic tissues in mice by lipoic acid.

In: Radiat Res (1992 Jun) 130(3):360-5

Lipoic acid is a lipophilic antioxidant that participates in many enzymatic reactions and is used clinically to treat mushroom poisoning and metal toxicity. In this report the protective effect of lipoic acid (oxidized form) against radiation injury to hematopoietic tissues in mice was assessed by the endogenous and exogenous spleen colony assays and survival (LD50/30) assay. Intraperitoneal administration of lipoic acid at a nonlethal concentration of 200 mg/kg body wt, 30 min before irradiation increased the LD50/30 from 8.67 to 10.93 Gy in male CD2F1 mice. Following a 9-Gy irradiation, the yield of endogenous spleen colony-forming units in mice treated with saline and lipoic acid was 0.75 +/- 0.5 and 8.9 +/- 1.6, respectively. Using the exogenous spleen colony assay, lipoic acid treatment increased the D0 from 0.81 +/- 0.01 to 1.09 +/- 0.01 Gy, yielding a dose modification factor of 1.34 +/- 0.01. Dihydrolipoic acid (reduced form) has no radioprotective effect in CD2F1 mice.



Matalon R Stumpf DA Michals K Hart RD Parks JK Goodman SI

Lipoamide dehydrogenase deficiency with primary lactic acidosis: favorable response to treatment with oral lipoic acid.

In: J Pediatr (1984 Jan) 104(1):65-9

An 8-month-old boy with severe lactic acidosis was found to have lipoamide dehydrogenase deficiency. Treatment with thiamine, biotin, bicarbonate, protein restriction, and ketogenic diet failed to alleviate the lactic acidosis. Oral administration of lipoic acid 25 to 50 mg/kg produced dramatic improvement in lactic and pyruvic acidemia, which has continued for 2 years and which has been accompanied by clinical improvement.



Matsugo S Yan LJ Han D Trischler HJ Packer L

Elucidation of antioxidant activity of alpha-lipoic acid toward hydroxyl radical.

In: Biochem Biophys Res Commun (1995 Mar 8) 208(1):161-7

The photosensitive organic hydroperoxide, NP-III, which produces hydroxyl radicals on illumination by UVA light, was used to examine the antioxidant activity of alpha-lipoic acid and its derivatives toward hydroxyl radical. Apolipoprotein (apo-B) of human low density lipoprotein (LDL) and bovine serum alubumin (BSA) were irradiated with UVA in the presence of NP-III and alpha-lipoic acid. The oxidation of BSA and the apo-B protein of LDL by NP-III was completely suppressed by alpha-lipoic acid. ESR studies using dimethylpyrroline oxide (DMPO) as a spin trapping reagent also revealed that in the presence of alpha-lipoic acid, the DMPO-OH adduct produced from the irradiation of NP-III and DMPO completely disappeared. DMPO-OH quenching experiments were performed in the presence or absence of desferoxamine but no change in the signal intensity was found. Hence, the quenching activity of alpha-lipoic acid is not due to its chelating activity toward transition metals (ferrous ions). The results lead us to conclude that alpha-lipoic acid is an efficient hydroxyl radical quencher owing to the disulfide bond in the dithiolane ring.



Han D Tritschler HJ Packer L

Alpha-lipoic acid increases intracellular glutathione in a human T-lymphocyte Jurkat cell line.

In: Biochem Biophys Res Commun (1995 Feb 6) 207(1):258-64

The addition of exogenous alpha-lipoic acid to cellular medium causes a rapid increase of intracellular unbound thiols in Jurkat cells, a human T-lymphocyte cell line. The rise of cellular thiols is a result of the cellular uptake and reduction of lipoic acid to dihydrolipoic acid and a rise in intracellular glutathione. Although the level of dihydrolipoic acid is 100-fold lower than glutathione, the cellular concentration of dihydrolipoic acid might be responsible for the modulation of total cellular thiol levels. Rises in glutathione correlate with the levels of intracellular dihydrolipoic acid (p < .01). This increase in glutathione is not the result of expression of new proteins like gamma-glutamylcysteine synthetase, since the rise in glutathione was not inhibited by cycloheximide, a protein synthesis inhibitor. Lipoic acid administration is therefore a potential therapeutic agent in an array of diseases with glutathione anomalies including HIV infection.



Podda M Tritschler HJ Ulrich H Packer L

Alpha-lipoic acid supplementation prevents symptoms of vitamin E deficiency.

In: Biochem Biophys Res Commun (1994 Oct 14) 204(1):98-104

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.



Ou P Tritschler HJ Wolff SP

Thioctic (lipoic) acid: a therapeutic metal-chelating antioxidant?

In: Biochem Pharmacol (1995 Jun 29) 50(1):123-6

Thioctic (alpha-lipoic) acid (TA) is a drug used for the treatment of diabetic polyneuropathy in Germany. It has been proposed that TA acts as an antioxidant and interferes with the pathogenesis of diabetic polyneuropathy. We suggest that one component of its antioxidant activity requiring study is the direct transition metal-chelating activity of the drug. We found that TA had a profound dose-dependent inhibitory effect upon Cu(2+)-catalysed ascorbic acid oxidation (monitored by O2 uptake and spectrophotometrically at 265 nm) and also increased the partition of Cu2+ into n-octanol from an aqueous solution suggesting that TA forms a lipophilic complex with Cu2+. TA also inhibited Cu(2+)-catalysed liposomal peroxidation. Furthermore, TA inhibited intracellular H2O2 production in erythrocytes challenged with ascorbate, a process thought to be mediated by loosely chelated Cu2+ within the erythrocyte. These data, taken together, suggest that prior intracellular reduction of TA to dihydrolipoic acid is not an obligatory mechanism for an antioxidant effect of the drug, which may also operate via Cu(2+)-chelation. The R-enantiomer and racemic mixture of the drug (alpha-TA) generally seemed more effective than the S-enantiomer in these assays of metal chelation.



Constantinescu A Tritschler H Packer L

alpha-Lipoic acid protects against hemolysis of human erythrocytes induced by peroxyl radicals.

In: Biochem Mol Biol Int (1994 Jul) 33(4):669-79

The azo initiator of peroxyl radicals 2,2′-azobis (2-amidinopropane) dihydrochloride (AAPH) induces oxidative hemolysis in human erythrocytes and subsequent hemoglobin oxidation. Using the degree of hemolysis versus time as an indication of the oxidative damage it was found that i) both reduced and oxidized alpha-lipoic acid protected against oxidative damage; ii) simultaneous treatment of erythrocytes with ascorbate and dihydrolipoate or alpha-lipoate has a synergistic tendency to protect cells against hemolysis; iii) glutathione in combination with dihydrolipoic acid or alpha-lipoic acid has an additive effect on hemolysis protection. The spin trapping reagent 5,5-dimethyl-1-pyrroline N-oxide (DMPO) formed an adduct with the peroxyl/alkoxyl radicals produced by thermal decomposition of AAPH in the presence of oxygen. The formation of this adduct was prevented by reduced or oxidized lipoic acid, reduced glutathione or ascorbate. It is concluded that AAPH-peroxyl radicals progressively damage the cells and the released hemoglobin is subsequently oxidized to methemoglobin which might further enhance the oxidative damage. The protective effect of antioxidants is exerted outside the cells by directly scavenging AAPH-alkoxyl radicals.



Sandhya P Mohandass S Varalakshmi P

Role of DL alpha-lipoic acid in gentamicin induced nephrotoxicity.

In: Mol Cell Biochem (1995 Apr 12) 145(1):11-7

The effect of DL alpha-lipoic acid on the nephrotoxic potential of gentamicin was examined. Intraperitoneal injection of gentamicin (100 mg/kg/day) to rats resulted in decreased activity of the glycolytic enzymes-hexokinase, phosphoglucoisomerase, aldolase and lactate dehydrogenase. The two gluconeogenic enzymes–glucose-6-phosphatase and fructose-1,6-diphosphatase, the transmembrane enzymes namely the Na+, K(+)-ATPase, Ca(2+)-ATPase, Mg(2+)-ATPase and the brushborder enzyme alkaline phosphatase, also showed decreased activities. This decrease in the activities of ATPases and alkaline phosphatase suggests basolateral and brush border membrane damage. Decreased activity of the TCA cycle enzymes isocitrate dehydrogenase (ICDH), succinate dehydrogenase (SDH) and malate dehydrogenase (MDH), suggests a loss in mitochondrial integrity. These biochemical disturbances were effectively counteracted by lipoic acid administration. Lipoic acid administration by gastric intubation at two different concentrations (10 mg and 25 mg/kg/day) brought about an increase in the activity of the glycolytic enzymes, ATPases and the TCA cycle enzymes. The gluconeogenic enzymes however showed a further decrease in their activities at both the concentrations of lipoic acid administered. These observations shed light on the nephroprotective action of lipoic acid against experimental aminoglycoside toxicity and the protection afforded at 25 mg/kg/day of lipoic acid was noted to be higher than that at 10 mg level.



Jayanthi S Saravanan N Varalakshmi P

Effect of DL alpha-lipoic acid in glyoxylate-induced acute lithiasis.

In: Pharmacol Res (1994 Oct-Nov) 30(3):281-8

Glyoxylic lithiasis by acute intoxication with sodium glyoxylate, significantly raised the levels of renal tissue calcium and oxalate which has been reflected simultaneously in their urinary levels. Administration of DL alpha-lipoic acid lowered the oxalate levels in the kidney and urine. Sodium glyoxylate administration resulted in enhanced liver glycollate oxidase activity, the major enzyme in endogenous oxalate synthesis. DL alpha-lipoic acid decreased glycollate oxidase activity but did not have any effect on lactate dehydrogenase. The possibility of regulating oxalate metabolism in glyoxylic lithiasis with the use of DL alpha-lipoic acid, by way of inhibiting liver glycollate oxidase, looks attractive.



Suzuki YJ Packer L

Inhibition of NF-kappa B DNA binding by alpha-lipoic acid.

In: Int Conf AIDS (1994 Aug 7-12) 10(2):27 (abstract no. 401A)

NF-kappa B transcription factor regulates HIV activation. Natural and safe compounds which target NF-kappa B action may, therefore, be useful in AIDS therapy to support the actions of antiviral agents. We previously found that alpha-lipoic acid (6,8-dithio-octanoic acid) inhibits NF-kappa B activity induced by tumor necrosis factor (TNF), phorbol esters or HTLV Tax protein in cultured T cells. The present study compared the effects of lipoic acid homologues on NF-kappa B DNA binding activity in vivo and in vitro using band-shift assay. The addition of alpha-lipoic acid in the binding reaction mixtures containing nuclear extracts from stimulated T cells caused inhibition of NF-kappa B DNA binding in vitro. Octanoic acid which lacks the cyclic disulfide also inhibited DNA binding, suggesting that hydrocarbon chain participates in the mechanism of alpha-lipoic acid action. On the other hand, tetranorlipoic acid (2,4-dithio-butanoic acid), which lacks the hydrocarbon chain, was found to be more potent in inhibiting NF-kappa B DNA binding both in vitro and in vivo in TNF-stimulated Jurkat cells. Bisnorlipoic acid (4,6-dithio-hexanoic acid) was found to be less effective than tetranorlipoic acid; moreover, it never caused a complete inhibition of TNF-induced NF-kappa B activity in vivo. This suggests that tetranorlipoic acid affects NF-kappa B action through a distinct mechanism which is suppressed by hydrocarbon chain. Thus, the alpha-lipoic acid molecule contains two structures which can inhibit NF-kappa B action: (1) hydrocarbon chain tail which requires high concentrations and (2) cyclic disulfide head which is potent and whose inhibitory action is suppressed by hydrocarbon chain. Since alpha-lipoic acid is metabolized to tetranorlipoic acid in physiological systems, the dual mechanism of alpha-lipoic acid action may constitute its potential for HIV chemotherapy.



Busse E Zimmer G Schopohl B Kornhuber B

Influence of alpha-lipoic acid on intracellular glutathione in vitro and in vivo.

In: Arzneimittelforschung (1992 Jun) 42(6):829-31

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.



Suzuki YJ Aggarwal BB Packer L

Alpha-lipoic acid is a potent inhibitor of NF-kappa B activation in human T cells.

In: Biochem Biophys Res Commun (1992 Dec 30) 189(3):1709-15

Acquired immunodeficiency syndrome (AIDS) results from infection with a human immunodeficiency virus (HIV). The long terminal repeat (LTR) region of HIV proviral DNA contains binding sites for nuclear factor kappa B (NF-kappa 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.



Scott BC Aruoma OI Evans PJ O’Neill C Van der Vliet A Cross CE Tritschler H Halliwell B

Lipoic and dihydrolipoic acids as antioxidants. A critical evaluation.

In: Free Radic Res (1994 Feb) 20(2):119-33

A detailed evaluation of the antioxidant and pro-oxidant properties of lipoic acid (LA) and dihydrolipoic acid (DHLA) was performed. Both compounds are powerful scavengers of hypochlorous acid, able to protect alpha 1-antiproteinase against inactivation by HOCl. LA was a powerful scavenger of hydroxyl radicals (OH.) and could inhibit both iron-dependent OH. generation and peroxidation of ox-brain phospholipid liposomes in the presence of FeCl3-ascorbate, presumably by binding iron ions and rendering them redox-inactive. By contrast, DHLA accelerated iron-dependent OH. generation and lipid peroxidation, probably by reducing Fe3+ to Fe2+. LA inhibited this pro-oxidant action of DHLA. However, DHLA did not accelerate DNA degradation by a ferric bleomycin complex and slightly inhibited peroxidation of arachidonic acid by the myoglobin-H2O2 system. Under certain circumstances, DHLA accelerated the loss of activity of alpha-antiproteinase exposed to ionizing radiation under a N2O/O2 atmosphere and also the loss of creatine kinase activity in human plasma exposed to gas-phase cigarette smoke. Neither LA nor DHLA reacted with superoxide radical (O.2-) or H2O2 at significant rates, but both were good scavengers of trichloromethylperoxyl radical (CCl3O2.). We conclude that LA and DHLA have powerful antioxidant properties. However, DHLA can also exert pro-oxidant properties, both by its iron ion-reducing ability and probably by its ability to generate reactive sulphur-containing radicals that can damage certain proteins, such as alpha 1-antiproteinase and creatine kinase.



Faust A Burkart V Ulrich H Weischer CH Kolb H

Effect of lipoic acid on cyclophosphamide-induced diabetes and insulitis in non-obese diabetic mice.

In: Int J Immunopharmacol (1994 Jan) 16(1):61-6

In an animal model of type I diabetes, the non-obese diabetic (NOD) mouse, the influence of the antioxidant lipoic acid (LA) on the development of diabetes was investigated. Acceleration of diabetes development with cyclophosphamide (CY) resulted in 60% diabetic animals with severely infiltrated islets within 1-3 weeks. Daily administration of lipoic acid for 20 or 30 days around cyclophosphamide treatment suppressed the incidence of diabetes to 30% (P < 0.05) and 33%, respectively. Semiquantitative analysis of islet infiltration showed a reduction of severe intraislet infiltration and an increase in the percentage of islets with mild per-insular and periductular infiltrates (from 8.4 to 29.6 and 25.9%, respectively, P < 0.01) after lipoic acid treatment. These results show that the protective effect of lipoic acid on diabetes development correlates with partial suppression of islet inflammation. The anti-inflammatory action of lipoic acid may be due to its ability to scavenge oxygen radicals and to suppress nitric oxide production.



Stoll S Hartmann H Cohen SA Muller WE

The potent free radical scavenger alpha-lipoic acid improves memory in aged mice: putative relationship to NMDA receptor deficits.

In: Pharmacol Biochem Behav (1993 Dec) 46(4):799-805

alpha-Lipoic acid (alpha-LA) improved longer-term memory of aged female NMRI mice in the habituation in the open field test at a dose of 100 mg/kg body weight for 15 days. In a separate experiment, no such effect could be found for young mice. alpha-LA alleviated age-related NMDA receptor deficits (Bmax) without changing muscarinic, benzodiazepine, and alpha 2-adrenergic receptor deficits in aged mice. The carbachol-stimulated accumulation of inositol monophosphates was not changed by the treatment with alpha-LA. These results give tentative support to the hypothesis that alpha-LA improves memory in aged mice, probably by a partial compensation of NMDA receptor deficits. Possible modes of action of alpha-LA based on its free radical scavenger properties are discussed in relation to the membrane hypothesis of aging.



Filina AA Davydova NG Kolomoitseva EM

[The effect of lipoic acid on the components of the glutathione system in the lacrimal fluid of patients with open-angle glaucoma]

In: Vestn Oftalmol (1993 Oct-Dec) 109(5):5-7 (Published in Russian)

Nonprotein SH groups and gamma-glutamyl transpeptidase were detected in the lacrimal fluid of patients with open-angle glaucoma and senile cataract and in controls (in 82 and 100% of the examinees, respectively). In stage II glaucoma SH group level was found reduced vs. that in stage I or control. Intake of lipoic acid by patients with stage II glaucoma resulted in a reliable increase of lacrimal SH group level. Measurements of lacrimal fluid nonprotein SH groups may be used to monitor antioxidant therapy of patients with open-angle glaucoma.



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.

In: Arzneimittelforschung (1991 Dec) 41(12):1294-8

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.(ABSTRACT TRUNCATED AT 250 WORDS)



Jayanthi S Varalakshmi P

Tissue lipids in experimental calcium oxalate lithiasis and the effect of DL alpha-lipoic acid.

In: Biochem Int (1992 Apr) 26(5):913-21

The function of DL alpha-lipoic acid (6,8-thioctic acid) as a prosthetic group in the oxidative decarboxylation of alpha-keto acids, pyruvate and alpha-ketoglutarate in mitochondria is well known. Its role is well extended to certain reactions in lipid biosynthesis. In addition, lipoic acid has been shown to prevent the induced precipitation of calcium oxalate crystals in the renal tissues of laboratory animals. Here, the effect of alpha-lipoic acid was studied, on altered tissue lipid levels manifested during experimental renal lithiasis. Raised tissue cholesterol, triglyceride and low phospholipid levels were some of the striking significant observations made in calculogenic rats. Lipoic acid treatment reduced tissue cholesterol and triglyceride levels significantly and raised phospholipids. The alterations may have a bearing in relation to calcium oxalate stone formation.



Loginov AS Nilova TV Bendikov EA Petrakov AV

[Preparations of alpha-lipoic acid: the dynamics of their content in the blood and their effect on hemostasis in lesions of the human liver]

In: Farmakol Toksikol (1990 Mar-Apr) 53(2):47-50 (Published in Russian)

The changes in blood coagulating activity before and after treatment with alpha-lipoic acid drugs as compared with blood lipoic acid content were studied in 130 patients with chronic diffuse diseases of the liver of the virus and alcohol etiology. A moderate correlation between the increase in blood alpha-lipoic acid concentration in patients with the liver diseases during the replacement therapy with alpha-lipoic acid drugs and a number of parameters of thrombelastogram was established. It was shown that relief of coenzyme deficit against the background of treatment with lipoic acid is associated with relief of hypocoagulative syndrome and an elevation of the blood ATP level. It is suggested that the ability of the coenzyme to stimulate the bioenergetic protection of hemostasis processes plays the important role in the mechanism of action of alpha-lipoic acid drugs.



Altenkirch H Stoltenburg-Didinger G Wagner HM Herrmann J Walter G

Effects of lipoic acid in hexacarbon-induced neuropathy.

In: Neurotoxicol Teratol (1990 Nov-Dec) 12(6):619-22

The effects of lipoic acid on hexacarbon neurotoxicity in rats were investigated. Rats were exposed by inhalation to n-hexane for 24 hours/day, 7 days/week, up to a total period of 9 weeks. Eight animals were exposed to 700 ppm n-hexane only, and eight animals were exposed to 700 ppm n-hexane and additionally received 100 mumol/kg lipoic acid PO daily. Clinical status of the animals was evaluated by examination of general condition, motor performance tests and neurophysiological measurements of caudal nerve motor conduction velocity. Results showed that animals exposed to 700 ppm n-hexane developed severe motor neuropathy leading to paralysis by the 6th week. Motor distal latencies of these animals were severely prolonged. In contrast, in animals treated with lipoic acid the onset of motor neuropathy was delayed for approximately 3 weeks as could be demonstrated by motor performance tests and measurements of motor distal latencies.



Gregus Z Stein AF Varga F Klaassen CD

Effect of lipoic acid on biliary excretion of glutathione and metals.

In: Toxicol Appl Pharmacol (1992 May) 114(1):88-96

Several metals are excreted in bile as glutathione complexes, and their biliary excretion is facilitated by increased hepatobiliary transport of glutathione. The present study analyzed the effect of lipoic acid (LA; thioctic acid; 37.5-300 mumol/kg, iv), an endogenous disulfide which can be reduced in vivo to a dithiol, on the hepatobiliary disposition of glutathione-related thiols and the biliary excretion of metals (10 mumol/kg, iv) in rats. Administration of LA enhanced the biliary excretion of reduced glutathione in a dose-dependent fashion. Despite increasing glutathione output, LA (150 mumol/kg, iv) did not increase, but rather decreased, the biliary excretion of methylmercury, cadmium, zinc, and copper, which are transported into bile in a glutathione-dependent manner, as indicated by a marked reduction in their biliary excretion after diethyl maleate-induced glutathione depletion. In contrast, biliary excretion of inorganic mercury, which is minimally affected by glutathione depletion, was dramatically enhanced (12- to 37-fold) by LA administration. Following injection of LA, the concentrations of endogenous disulfides in arterial blood plasma (e.g., cystine, glutathione disulfide, cysteine-glutathione, protein-cysteine, and protein-glutathione mixed disulfides) were considerably diminished, while the levels of endogenous thiols (e.g., glutathione and cysteine) were increased. This finding indicates that LA, probably after enzymatic conversion to dihydrolipoic acid, can reduce endogenous disulfides to thiols. It appears that LA induces the transport of glutathione into bile by the temporary formation of dihydrolipoic acid-glutathione mixed disulfide, which after being translocated into bile is cleaved to LA and reduced glutathione. Because the glutathione molecule thus transported into bile cannot complex metals at the thiol group, this might be the mechanism for the observed failure of the LA-induced increase in biliary excretion of glutathione to enhance the hepatobiliary transport of metals that are transported into bile as glutathione complexes (i.e., methylmercury, cadmium, zinc, and copper). The observations also raise the possibility that endogenous dihydrolipoic acid, by forming a stable complex with mercuric ion, may play the role of a carrier molecule in the hepatobiliary transport of inorganic mercury.



Mattulat A Baltes W

Determination of lipoic acid in meat of commercial quality.

In: Z Lebensm Unters Forsch (1992 Apr) 194(4):326-9

For the quantitative determination of lipoic acid in meat a sensitive GC/MS method in the chemical ionisation mode with methane as reactant gas has been developed. Firstly, the cleavage of protein-bound lipoic acid from the epsilon-amino group of lysine residues was optimized by hydrolysing the synthesized model compound epsilon-lipoyllysine with several organic and inorganic acids and proteolytic enzymes. The concentrations of lipoyllysine and lipoic acid during this test hydrolysis were monitored by HPLC. Optimum hydrolytic conditions were heating at 120 degrees C in 2 mol H2SO4 for seven hours. After tissue hydrolysis, the lipoic acid in the hydrolysate was separated by a diethylether/sodium bicarbonate/diethylether extraction and then derivatised for GC with MBDSTFA. The highest amounts of lipoic acid in meat of commercial quality were detected in liver, heart and kidney whereas in muscle tissues its content was lower.



Gao TL Huang YZ

[Effects of lipoic acid on reperfusion induced arrhythmias and myocardiac action potential alterations induced by free radical generating system]

In: Sheng Li Hsueh Pao (1991 Apr) 43(2):149-55 (Published in Chinese)

By means of Langendorff method the isolated rat heart was perfused with Krebs Henseleit solution. Following ligation of the left descending coronary artery for 10 min the heart was reperfused for 3 min. The incidence of ventricular fibrillation in the reperfusion period was 100%, and the normal sinus rhythm time was shortened to 29 s within 3 min of reperfusion. Administration of lipoic acid (6.8 X 10(-6)-1.7 X 10(-4) mol/L) to the perfusate significantly reduced the incidence of ventricular fibrillation to 33-50% and prolonged the normal sinus rhythm time to 97-107 s. APA, RP, and Vmax recorded from the guinea pig papillary muscle were depressed due to the deleterious effect of xanthine oxidase and hypoxanthine free radical generating system. Under the treatment of lipoic acid (3.5 X 10(-5) mol/L), the depression of APA, RP, and Vmax were significantly relieved. This confirms that lipoic acid treatment, owing to its free radical scavenger effect, is able to protect myocardium from free radical induced electrophysiological abnormalities, and consequently decrease the incidence of malignant arrhythmias.



Bast A Haenen GR

Interplay between lipoic acid and glutathione in the protection against microsomal lipid peroxidation.

In: Biochim Biophys Acta (1988 Dec 16) 963(3):558-61

Reduced glutathione (GSH) delays microsomal lipid peroxidation via the reduction of vitamin E radicals, which is catalyzed by a free radical reductase (Haenen, G.R.M.M. et al. (1987) Arch. Biochem. Biophys. 259, 449-456). Lipoic acid exerts its therapeutic effect in pathologies in which free radicals are involved. We investigated the interplay between lipoic acid and glutathione in microsomal Fe2+ (10 microM)/ascorbate (0.2 mM)-induced lipid peroxidation. Neither reduced nor oxidized lipoic acid (0.5 mM) displayed protection against microsomal lipid peroxidation, measured as thiobarbituric acid-reactive material. Reduced lipoic acid even had a pro-oxidant activity, which is probably due to reduction of Fe3+. Notably, protection against lipid peroxidation was afforded by the combination of oxidized glutathione (GSSG) and reduced lipoic acid. It is shown that this effect can be ascribed completely to reduction of GSSG to GSH by reduced lipoic acid. This may provide a rationale for the therapeutic effectiveness of lipoic acid.



Loginov AS Nilova TV Bendikov EA Petrakov AV

[Pharmacokinetics of preparations of lipoic acid and their effect on ATP synthesis, processes of microsomal and cytosol oxidation in hepatocytes in liver damage in man]

In: Farmakol Toksikol (1989 Jul-Aug) 52(4):78-82 (Published in Russian)

The features of the pharmacokinetics of preparations of alpha-lipoic acid (lipoic acid, thioctacide) as compared with their pharmacodynamic effects were studied in 125 patients with chronic diffuse diseases of the liver of viral and alcohol etiology. After a single administration of the preparations, the authors found an elevation of the maximal blood concentrations and an increase of alpha-lipoic acid elimination half-life in patients with liver cirrhosis as compared with chronic hepatitis patients. During the replacement therapy and elimination of alpha-lipoic acid deficiency by using the preparations containing lipoic acid, there is commonly an increase ATP content, an elevation of functioning mass of hepatocytes and activation of liver detoxifying function according to the data of the tests of galactose cytosol oxidation, microsomal oxidation of antipyrine and conjugation of bilirubin.



Muller L

Protective effects of DL-alpha-lipoic acid on cadmium-induced deterioration of rat hepatocytes.

In: Toxicology (1989 Oct 2) 58(2):175-85

The suitability of DL-alpha-lipoic acid (LA) to serve as an antidote in cadmium (Cd) toxicity in rat hepatocytes was investigated. Isolated hepatocytes were exposed to 200 and 450 microM Cd in the presence of 0.2, 1.0 and 5.0 mM LA, respectively. After 30 min of incubation various criteria of cell viability were monitored. Lipoic acid markedly diminished Cd uptake. Concomitantly, Cd-induced membrane injury, as reflected by the leakage of aspartate aminotransferase and sorbitol dehydrogenase (SDH) was decreased. Moreover, LA protected against intracellular toxic responses to Cd, such as a decrease in cellular SDH activity, a decrease in cellular acid soluble thiols, especially in total glutathione, a decrease in cellular urea and an increase in thiobarbituric acid (TBA) reactants, as a measure of lipid peroxidation. Most protective effects were seen in hepatocytes challenged with the lower Cd concentration and coincubated with 5 mM LA. In contrast, at 450 microM Cd even the highest LA concentration applied either did only reverse Cd-effects incompletely (SDH-response, TBA-reactants) or did not protect at all (Cd uptake, enzyme leakage, loss of glutathione). The data indicate that DL-alpha-lipoic acid serves as a protective tool against Cd-induced membrane damage and cell dysfunction in hepatocytes. This stands as long as Cd exposure is low enough to permit interaction with LA prior to interaction with cell structures.



Ohmori H Yamauchi T Yamamoto I

Augmentation of the antibody response by lipoic acid in mice. II. Restoration of the antibody response in immunosuppressed mice.

In: Jpn J Pharmacol (1986 Oct) 42(2):275-80

Lipoic acid (Lip) was examined for its effect on the in vivo antibody response in mice. It was found that Lip significantly restored the suppressed antibody response to sheep erythrocytes (SRBC) in cyclophosphamide-injected mice when it was orally administered at 25 mg/kg twice a day for 4 consecutive days after immunization. On the other hand, Lip-administration did not affect the antibody response in normal mice immunized with SRBC. Normal or cyclophosphamide-treated mice were primed with horse erythrocytes (HRBC) and were given either saline or Lip for 3 consecutive days. HRBC-specific helper T cell activity of their spleen cells were compared by coculturing these cells with trinitrophenyl (TNP)-keyhole limpet hemocyanin-primed spleen cells in the presence of TNP-HRBC as the antigen. A significant restoration of the suppressed helper T cell activity was observed in the Lip-administered group. However, the helper T cell activity was not affected significantly by Lip-administration in normal mice. Lip could also partially restore the helper T cell activities that were suppressed by the treatment with hydrocortisone or X-ray irradiation.



Ohmori Hnt Yamauchi T Yamamoto I

Augmentation of the antibody response by lipoic acid in mice. I. Analysis of the mode of action in an in vitro cultures system.

In: Jpn J Pharmacol (1986 Sep) 42(1):135-40

Lipoic acid (Lip), a naturally occurring disulfide compound, was found to augment markedly in vitro antibody responses to sheep erythrocytes (SRBC), dinitrophenyl-Ficoll and trinitrophenyl-lipopolysaccharide (TNP-LPS) as effectively as 2-mercaptoethanol (2-ME) in murine lymphocytes. The mitogenic response to LPS or concanavalin A (Con A) was augmented by Lip only slightly. 2-ME has been reported to facilitate cystine utilization by the lymphocytes, but Lip did not, indicating that the mode of action of Lip is different from that of 2-ME. Lip-augmentation of anti-SRBC response was markedly abrogated when murine lymphocytes were depleted of T cells and cultured in the presence of Con A-conditioned medium containing T cell-replacing factor. The effect of Lip was also diminished in the response to TNP-LPS when the spleen cells were depleted of T cells. These observations suggest that Lip could augment the antibody response by stimulating a T cell subpopulation. This idea was confirmed by the experiment that Lip could enhance helper T cell activity which was induced by culturing murine lymphocytes with the antigen.



Gershon H Shanks L

Reversal of fungitoxicity of 8-quinolinols and their copper(II) bischelates. II. Reversal of the action of 8-quinolinol by DL-alpha- lipoic acid.

In: Can J Microbiol (1981 Jun) 27(6):612-26

The effect of amino acids and derivatives, Krebs cycle acids and related compounds, fatty acids, and vitamins and related compounds on the toxicity of 8-quinolinol and bis(8-quinolinolato)copper(II) to Aspergillus oryzae (ATCC 1011) was studied. Only aliphatic thiol-containing compounds (cysteine, glutathione, dithioerythritol, and dithiothreitol) and DL-alpha-lipoic acid protected against 8-quinolinol but not its copper(II) bischelate. It is suggested that 8-quinolinol inhibits lipoic acid biosynthesis, and the mode of fungitoxicity of 8-quinolinol is different from that of bis(8-quinolinolato)copper(II).



Vodoevich VP

[Effect of lipoic acid, biotin and pyridoxine on blood content of saturated and unsaturated fatty acids in ischemic heart disease and hypertension]

In: Vopr Pitan (1983 Sep-Oct)(5):14-6 (Published in Russian)

Gas liquid chromatography was used to examine the effect of treatment on the blood content of saturated and unsaturated fatty acids in 75 patients with coronary heart disease and essential hypertension. There were three groups of patients. The first group (30 subjects) received lipoic acid, whereas the second one (30 subjects) were given biotin nd pyridoxine. Fifteen patients (controls) did not receive any vitamins. Lipoic acid was found to raise the content of linoleic and arachidonic acids and to decrease the content of myristic acid. Meanwhile administration of biotin and pyridoxine led to an increase in the content of eicosatriene and arachidonic acids and to a reduction in the concentration of myristic and stearic acids. In the 15 patients who did not receive any vitamins, the blood content of fatty acids remained unchanged. Comparatively, the preference is given to lipoic acid that raises the blood content of linoleic acid playing an important part in the prophylaxis of atherosclerosis.



Marnett LJ Wilcox CL

Stimulation of prostaglandin biosynthesis by lipoic acid.

In: Biochim Biophys Acta (1977 Apr 26) 487(1):222-30

Enzyme preparations from sheep seminal vesicles display an enhanced ability to synthesize prostaglandins, particularly prostaglandin F from polyunsaturated fatty acids if alpha-lipoic acid is present in the incubation mixture prior to the addition of fatty acid. The stimulation by lipoate is reversible, time dependent, and involves modifications of V and Km for oxygenase activity. Product studies, structure vs. activity studies, and purification data indicate that lipoate exerts it effect by a mechanism distinct from a glutathione-like metabolism of the endoperoxide linkage in prostaglandin G and prostaglandin H. In addition, product studies suggest that lipoate is not a cofactor for the endoperoxide isomerase component of prostaglandin synthetase. Purification of the endoperoxide synthesizing activity by ion-exchange chromatography and isoelectric focusing yields preparations which are more responsive to lipoate than microsomal preparations.



Maesaka H Komiya K Misugi K Tada K

Hyperalaninemia hyperpyruvicemia and lactic acidosis due to pyruvate carboxylase deficiency of the liver; treatment with thiamine and lipoic acid.

In: Eur J Pediatr (1976 May 4) 122(2):159-68

A 16-month-old female infant with severe mental and motor retardation, clinically diagnosed as Leigh’s encephalomyelopathy, forms the basis of this study. This infant was found to have lactic acidosis, low cerebrospinal fluid glucose, hyperalaninemia, and increased levels of urine lactate, pyruvate and alanine. These laboratory studies suggested an inborn error in gluconeogenesis. Further investigation revealed a low level of hepatic pyruvate carboxylase activity. The patient’s elder sister who also had mental and motor deterioration was then also found to have an elevated blood lactate. These two siblings clinically and biochemically showed improvement with treatment consisting of thiamine and lipoic acid.



Klein W

[Treatment of diabetic neuropathy with oral alpha-lipoic acid (author’s transl)]

In: MMW Munch Med Wochenschr (1975 May 30) 117(22):957-8 (Published in German)

100 patients were treated with Thioctacid orally for diabetic neuropathy. A successful assessment was possible with sufficient certainty in 89 patients. Of these, 29 received 2 X 50 mg and 60 patients 2 X 100 mg Thioctacid daily. In the first group the treatment was successful in 23 patients, and in 51 of the second group. According to these findings, administration of thiotic acid is effective in diabetic neuropathy just as frequently orally as intravenously.



Baur A Harrer T Peukert M Jahn G Kalden JR Fleckenstein B

Inhibition of HIV-infectivity and replication by alpha-lipoic acid.

In: Int Conf AIDS (1991 Jun 16-21) 7(1):110 (abstract no. M.A.1075)

OBJECTIVE: To study the antiviral activity of alpha-lipoic acid, a naturally occurring disulfide compound, that has been applied for years for the treatment of polyneuropathies and hepatic disorders. METHODS: Acutely and persistently infected T cells were treated with various doses of alpha-lipoic acid. Reduction of viral expression and activity was determined by plaque titration and RT-activity. Viral markers were assessed in HIV-infected patients before and during treatment with alpha-lipoic acid. RESULTS: In vitro, alpha-lipoic acid significantly inhibits CPE, RT-activity and plaque forming units (PFU) in acutely and persistently infected cells. At lower doses of the compound, mainly the PFU were reduced, suggesting that the compound affects the infectivity of virus particles. First virological data from patients treated with alpha-lipoic acid indicate that antiviral effects are also seen in vivo. A reduction of infectious viral titers was observed as predicted from the in-vitro experiments. CONCLUSION: Alpha-lipoic acid may be suitable for the treatment of HIV-infection.