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PubMed2001

The isolation and characterisation of a Saccharomyces cerevisiae gene (LIP2) involved in the attachment of lipoic acid groups to mitochondrial enzymes.

Lipoic acid is an essential cofactor for a variety of mitochondrial enzymes. We have characterised a gene from Saccharomyces cerevisiae which appears to encode a protein involved in the attachment of lipoic acid groups to the pyruvate dehydrogenase and glycine decarboxylase complexes. The predicted protein product of this gene has significant identity to the lipoyl ligase B of both Escherichia coli and Kluyveromyces lactis. A strain harbouring a null allele of this S. cerevisiae gene is respiratory deficient due to inactive pyruvate dehydrogenase, and is unable to utilise glycine as a sole nitrogen source.

Acyltransferases↗
PubMed2006

Paraquat-induced oxidative stress in drosophila melanogaster: effects of melatonin, glutathione, serotonin, minocycline, lipoic acid and ascorbic acid.

The efficacy of melatonin, glutathione, serotonin, minocycline, lipoic acid and ascorbic acid in counteracting the toxicity of paraquat in Drosophila melanogaster was examined. Male Oregon wild strain flies were fed for 5 days with control food or food containing the test substance. They were transferred in groups of five to vials containing only filter paper soaked with 20 mM paraquat in 5% sucrose solution. Survival was determined 24 and 48 h later. All the substances assayed increased the survival of D. melanogaster. At equimolar concentrations (0.43 mM) melatonin was more effective than serotonin, lipoic acid and ascorbic acid. However, lower concentrations of glutathione (0.22 mM) and minocycline (0.05 mM) were as efficient as melatonin. The highest survival rate (38.6%) after 48 h of paraquat treatment was found with 2.15 mM of lipoic acid. No synergistic effect of melatonin with glutathione, serotonin, minocycline, lipoic acid and ascorbic acid was detected.

Animals↗
PubMed1980

Stable isotope studies on the biosynthesis of lipoic acid in Escherichia coli.

A method has been developed for the gas chromatographic-mass spectrometric (GC-MS) identification of lipoic acid in tissue. The method consists of acid hydrolysis of the tissue to free the bound lipoic acid, methylene chloride extraction of the lipoic acid, and the subsequent chemical derivatization of the lipoic acid as methyl 6,8-bis(benzylthio)octanoate prior to GC-MS analysis. By use of this method of analysis, the incorporation of deuterium into lipoic acid by Escherichia coli growing on [methyl-2H3]acetate has been studied. The results clearly show that the lipoic acid is biosynthesized from octanoic acid with the loss of only one deuterium-containing position at C8. The deuterium incorporated at C6 of octanoic acid from the labeled acetate is retained. Since this deuterium is incorporated in the L configuration during fatty acid biosynthesis and it is known to have the D configuration in lipoic acid, it is concluded that an inversion of configuration occurs at C6 during the sulfur insertion.

Acetates↗
PubMed2005

Protective effect of lipoic acid on micronuclei induction by cyclophosphamide.

The present study investigated the protective efficacy of DL-alpha-lipoic acid on the cyclophosphamide (CP)-induced clastogenicity using the in vivo micronucleus assay. Male Wistar rats of 140 +/- 20 g were categorized into eight groups. Five groups were administered CP (40 mg/kg body weight, intraperitonealy) to induce genotoxicity; four of these groups received a single intraperitoneal injection of lipoic acid at a dose of either 100 or 200 mg/kg body weight, and either 30 or 60 min prior to CP administration. A vehicle-treated control group and lipoic acid control groups were also included. The number of micronucleated polychromatic erythrocytes (MNPCEs) was determined at 24 h after CP administration. In rats injected with CP, the frequency of MNPCEs in bone marrow and peripheral blood was increased significantly in comparison with the controls, and in rats treated with lipoic acid and CP, the number of MNPCEs was decreased significantly in comparison to those given CP alone. The chemoprotective effect was found to be stronger after the administration of lipoic acid at a dose of 200 mg/kg body weight than 100 mg/kg body weight dosage, indicating the dose-dependent protective effect of lipoic acid. However, the protection by lipoic acid was not dependent on the time intervals between lipoic acid and CP administration. Our results illustrate the protective effect of lipoic acid on the in vivo clastogenicity induced by CP.

Animals↗
PubMedDate not supplied

[Effect of group B vitamins on 35S-lipoic acid intake by mouse tissues].

Lipoic acid intake following parenteral administration with functionally linked vitamins depends on molar relations between them. It is shown that a combined administration of 35S-lipoate with these vitamins decreases radioactivity 30-120 min after the injection in most of tissues as compared to the control, except for the liver where it does not change or increases (60 min after administration in combination with thiamin or pantothenate). Following 18h thiamin and mixture of vitamins induce an intensified intake of labelled lipoic acid by the brain tissue, a 4-fold increase in case of thiamin and a 2.6-fold increase in case of the vitamins mixture.

Animals↗
PubMed1989

Detection of bacterial lipoic acid. A modified gas-chromatographic-mass-spectrometric procedure.

The detection of bacterial lipoic acid by a modified g.c.-m.s. procedure is reported. Cells were hydrolysed in HCl to release protein-bound lipoic acid, which, after extraction into benzene, was reduced with NaBH4. The dihydrolipic acid so generated was then isolated by covalent chromatography on dithiolspecific p-aminophenylarsenoxide-agarose and, after elution by 2,3-dimercaptopropane-1-sulphonic acid and extraction into benzene, was allowed to O2-oxidize to the disulphide form. The isolated lipoic acid was allowed to react with diazomethane, and the methyl ester so produced was detected by g.c.-m.s. Analysis of the mass spectrum showed the characteristic molecular ion and seven fragmentation ions, which, along with the identification of those ions retaining the two sulphur atoms, allows the definitive detection of lipoic acid. The methodology has been successfully tested with authentic lipoic acid, the 2-oxoglutarate dehydrogenase multienzyme complex and with whole cells of Escherichia coli. In addition, it has been used to search for and identify lipoic acid in the archaebacterium Halobacterium halobium. The significance of this discovery and the possible roles of the cofactor in H. halobium are discussed.

Bacterial Proteins↗
PubMedDate not supplied

Antioxidant adaptive response of human mononuclear cells to UV-B: effect of lipoic acid.

Supplementation of human mononuclear cells with 3 and 6 mM of lipoic acid produces an inhibition of the antioxidant adaptive response triggered by treatment with UV-B light (0.30 W/m2 for 15 min). Supplementation with 1.5 mM of lipoic acid gives no conclusive results. The adaptive response is characterized by an increase in the activities of superoxide dismutase, catalase, glutathione peroxidase and DT-diaphorase. Catalase (5.5 +/- 0.6 pmol/mg prot) increases its activity by up to 22 +/- 3 pmol/mg prot, after irradiation with UV-B. Supplementation with 3 and 6 mM of lipoic acid completely inhibits the adaptive response. The activities of the membrane-bound mitochondrial enzymes succinate dehydrogenase and cytochrome oxidase do not increase after UV-B exposure. Moreover, their activities are found to decrease and the addition of lipoic acid does not prevent this effect. The inhibition of the antioxidant response by lipoic acid in human cells appears as indirect evidence of the existence of oxidative stress in the development of this response. As lipoic acid behaves as an effective antioxidant, it seems that its action decreases the intracellular oxidative signals necessary to develop the adaptive response in human mononuclear cells.

Adult↗
PubMed1992

Determination of lipoic acid in meat of commercial quality.

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.

Animals↗
PubMed2004

Arsenic intoxication-induced reduction of glutathione level and of the activity of related enzymes in rat brain regions: reversal by DL-alpha-lipoic acid.

The purpose of this study was to examine the effects of DL: -alpha-lipoic acid (LA) on arsenic (As) induced alteration of glutathione (GSH) level and of the activity of glutathione-related enzymes-glutathione peroxidase (GSH-Px), glutathione reductase (GR), and glucose-6-phosphate dehydrogenase (G6PDH)-in rat brain regions (cortex, hypothalamus, striatum, cerebellum and hippocampus). Male Wistar rats of 150+/-10 g weight were divided into four groups: control and three experimental groups supplemented with arsenic (sodium arsenite) alone (100 ppm mixed in drinking water), lipoic acid alone (70 mg kg(-1) body weight), arsenic plus lipoic acid (100 ppm arsenic in drinking water plus 70 mg lipoic acid kg(-1) body weight). The arsenic content of brain regions was found to increase with the administration of sodium arsenite. Arsenic exposure elicited a significant decline in glutathione content and in the activity of related enzymes, with the greatest decreases seen in the cortex, striatum, and hippocampus, whereas there were no significant differences between control rats and the group treated with lipoic acid alone. Highly elevated content of the thiobarbituric acid-reactive substance malondialdehyde (MDA) in the brain regions of arsenic-exposed rats reflected extensive lipid peroxidation (LPO) processes. Simultaneous lipoic acid treatment was effective in reducing brain regional arsenic levels and lipid peroxidation and in increasing the glutathione content and the activity of its related enzymes. Lipoic acid, by acting as an alternative sulfhydryl nucleophile to glutathione, prevents its oxidation to glutathione disulfide in detoxifying reactions against reactive oxygen species and consequently increases the activity of glutathione-related enzymes.

Animals↗
PubMed2005

Mitigation of oxidative stress in cyclophosphamide-challenged hepatic tissue by DL-alpha-lipoic acid.

The present study investigated the protective effect of DL-alpha-lipoic acid on the tissue peroxidative damage and abnormal antioxidant levels in cyclophosphamide (CP) induced hepatotoxicity. Male Wistar rats of 140 +/- 20 g were categorized into four groups. Two groups were administered CP (15 mg/kg body weight once a week for 10 weeks by oral gavage) to induce hepatotoxicity; one of these groups received lipoic acid treatment (35 mg/kg body weight intraperitoneally once a week for 10 weeks; 24 h prior to the CP administration). A vehicle (saline) treated control group and a lipoic acid drug control group were also included. The extent of liver damage in CP-induced rats was evident from the increased activities of serum aminotransferases, alkaline phosphatase and lactate dehydrogenase; whereas lipoic acid pretreatment prevented the rise in these marker enzymes. We evaluated the changes in activities/levels of tissue enzymic (superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase, glutathione reductase and glucose-6-phosphate dehydrogenase) and non-enzymic (reduced glutathione, ascorbate and a-tocopherol) antioxidants along with malondialdehyde levels in the experimental groups. In CP-administered rats the antioxidant enzymes showed significantly depressed activities (p < 0.001, p < 0.01) and the antioxidant molecules also showed depleted levels (p < 0.001, p < 0.01), in comparison with the control group. However the extent of lipid peroxidation and the abnormal antioxidant status were normalized in lipoic acid pretreated rats. The present work highlights the efficacy of lipoic acid as a cytoprotectant in CP-induced hepatic oxidative injury.

Animals↗
PubMed1996

Kinetic study of cutaneous and subcutaneous distribution following topical application of [7,8-14C]rac-alpha-lipoic acid onto hairless mice.

To diminish oxidative injury, topically applied antioxidants must reach susceptible cells. alpha-Lipoic acid is a potent thiol antioxidant that might be useful for skin protection; therefore, its skin penetration kinetics were assessed. The cutaneous and subcutaneous distributions of [7,8-14C]rac-alpha-lipoic acid were studied in anesthetized hairless mice after application of a 5% solution in propylene glycol for 0.5 to 4 hr. The mice were killed; then the skin was washed, and the stratum corneum was removed by 10 cellophane tape strippings. A punch biopsy of the frozen, stripped skin was sectioned, and amounts of [14C]-alpha-lipoic acid were determined in strippings and slices of epidermis (4 x 5 microns), dermis, and subcutaneous fat (10 x 10 microns, 20 x 20 microns). The rate of [14C]-alpha-lipoic acid absorption into skin was constant by 30 min (0.10 +/- 0.01 nmol/cm2/min); maximum skin concentrations were reached by 2 hr. The [14C]-alpha-lipoic acid penetration kinetics into the first layer of the stratum corneum predicted its penetration through the stratum corneum and subsequent percutaneous absorption (r2 = 0.96, P < 0.02). Cutaneous absorption of unlabeled alpha-lipoic acid and its reduction to the more potent antioxidant form, dihydrolipoic acid, were also demonstrated, using HPLC analysis with electrochemical detection. In conclusion, alpha-lipoic acid topically applied to skin penetrated readily, and was reduced to dihydrolipoic acid. Thus, alpha-lipoic acid could potentiate skin antioxidant protection.

Animals↗
PubMed2002

Burning mouth syndrome (BMS): an open trial of comparative efficacy of alpha-lipoic acid (thioctic acid) with other therapies.

BACKGROUND: Alpha-lipoic acid (ALA) is a potent antioxidant mitochondrial coenzyme, trometamol salt of thioctic acid, shown in clinical studies to be neuroprotective and in a preliminary study to have an effect on the symptomatology of Burning Mouth Syndrome (BMS). METHODS: We were interested in extending our studies as to whether alpha-lipoic acid might improve the symptomatology in BMS and therefore carried out a larger open controlled clinical study on the effects of alpha-lipoic acid on BMS symptomatology. RESULTS: We have examined the effects on 4 groups of 20 patients with BMS of ALA, compared with bethanecol, Biotene and placebo, and found ALA of remarkable benefit with minimal adverse effects. CONCLUSIONS: These results suggest that double-blind randomized controlled multicenter studies of ALA are indicated.

Administration, Oral↗
PubMed2000

Lipoic acid decreases lipid peroxidation and protein glycosylation and increases (Na(+) + K(+))- and Ca(++)-ATPase activities in high glucose-treated human erythrocytes.

Lipoic acid supplementation has been found to be beneficial in preventing neurovascular abnormalities in diabetic neuropathy. Insufficient (Na(+) + K(+))-ATPase activity has been suggested as a contributing factor in the development of diabetic neuropathy. This study was undertaken to test the hypothesis that lipoic acid reduces lipid peroxidation and glycosylation and can increase the (Na(+) + K(+))- and Ca(++)-ATPase activities in high glucose-exposed red blood cells (RBC). Washed normal human RBC were treated with normal (6 mM) and high glucose concentrations (45 mM) with 0-0.2 mM lipoic acid (mixture of S and R sterioisomers) in a shaking water bath at 37 degrees C for 24 h. There was a significant stimulation of glucose consumption by RBC in the presence of lipoic acid both in normal and high glucose-treated RBC. Lipoic acid significantly lowered the level of glycated hemoglobin (GHb) and lipid peroxidation in RBC exposed to high glucose concentrations. High glucose treatment significantly lowered the activities of (Na(+) + K(+))- and Ca(++)-ATPases of RBC membranes. Lipoic acid addition significantly blocked the reduction in activities of (Na(+) + K(+))- and Ca(++)-ATPases in high glucose- treated RBC. There were no differences in lipid peroxidation, GHb and (Na(+) + K(+))- and Ca(++)-ATPase activity levels in normal glucose-treated RBC with and without lipoic acid. Thus, lipoic acid can lower lipid peroxidation and protein glycosylation, and increase (Na(+) + K(+))- and Ca(++)-ATPase activities in high-glucose exposed RBC, which provides a potential mechanism by which lipoic acid may delay or inhibit the development of neuropathy in diabetes.

Adenosine Triphosphatases↗
PubMed1995

alpha-Lipoic acid as a biological antioxidant.

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.

Animals↗
PubMed1995

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

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.

Animals↗
PubMed2002

Lipoic acid increases glucose uptake by skeletal muscles of obese-diabetic ob/ob mice.

AIM: Alpha-lipoic acid has been reported to increase glucose disposal in diabetic states. This study has examined the effect of alpha-lipoic acid on glucose uptake by cultured L6 muscle cells and different types of skeletal muscles in normal lean (+/+) and severely insulin-resistant, obese-diabetic (ob/ob) mice. METHODS: Glucose uptake was measured in L6 muscle cells using the non-metabolized glucose analogue 2-deoxy-d-glucose (2DG), and in isolated muscles by glucose disappearance from the incubation medium. RESULTS: In L6 muscle cells, short-term incubations (2-12 h) with 10(-3) m alpha-lipoic acid increased glucose uptake by 40-80%, approximately the same extent as 10(-6) m insulin. Combination of the two agents produced a slightly greater increase (120% at 12 h) than either alone. Red quadriceps (mainly type 1 fibres), diaphragm (similar proportions of type 1 and 2 fibres) and abdominal muscle (mainly type 2 fibres) from normal mice incubated with 10(-3) m alpha-lipoic acid showed increased glucose uptake to a similar extent as 10(-6) m insulin in each of the three muscles. Muscles from ob/ob mice, which showed little response to insulin, showed a substantial increase (approximately 300%, p < 0.05-0.01) in glucose uptake when 10(-3) m alpha-lipoic acid was added in the presence of insulin. The alpha-lipoic acid also increased glucose uptake in red quadriceps (approximately 300%, p < 0.01) from ob/ob mice without added insulin. CONCLUSION: The results suggest that alpha-lipoic acid can increase glucose uptake by a range of normal muscle types and improve the response to insulin by insulin-resistant skeletal muscles of ob/ob mice.

Animals↗
PubMed2005

Lipoic acid decreases exhaled nitric oxide concentrations in anesthetized endotoxemic rats.

We recently demonstrated that lipoic acid suppresses endotoxin-stimulated expression of inducible nitric oxide synthase and nitric oxide production in mouse macrophages. In this study, we tested whether lipoic acid suppresses these inflammatory mediators in the lungs of rats. Rats were assigned to receive either no special treatment, endotoxin alone, or pretreatment with lipoic acid followed by endotoxin. After anesthetizing the rats and injecting them intraperitoneally with lipoic acid (100 mg/kg) at 4 h and again at 1 h before treatment, the rats then received either endotoxin (0.01 mg/kg) or its vehicle solution. Exhaled gas was sampled every 15 min and concentrations of nitric oxide in the samples were measured using a chemiluminescence analyzer. After 150 min of exposure to endotoxin, the lungs were harvested and snap-frozen in liquid nitrogen for subsequent analysis. Lipoic acid attenuated endotoxin-induced increases in exhaled nitric oxide concentrations (P<0.001) and iNOS (P<0.05). These findings support the hypothesis that lipoic acid inhibits endotoxin-stimulated formation of intrapulmonary nitric oxide.

Anesthesia↗
PubMed2003

Alpha-lipoic acid decreases thiol reactivity of the insulin receptor and protein tyrosine phosphatase 1B in 3T3-L1 adipocytes.

Alpha-lipoic acid is known to increase insulin sensitivity in vivo and to stimulate glucose uptake into adipose and muscle cells in vitro. In this study, alpha-lipoic acid was demonstrated to stimulate the autophosphorylation of insulin receptor and glucose uptake into 3T3-L1 adipocytes by reducing the thiol reactivity of intracellular proteins. To elucidate mechanism of this effect, role of protein thiol groups and H(2)O(2) in insulin receptor autophosphorylation and glucose uptake was investigated in 3T3-L1 adipocytes following stimulation with alpha-lipoic acid. Alpha-lipoic acid or insulin treatment of adipocytes increased intracellular level of oxidants, decreased thiol reactivity of the insulin receptor beta-subunit, increased tyrosine phosphorylation of the insulin receptor, and enhanced glucose uptake. Alpha-lipoic acid or insulin-stimulated glucose uptake was inhibited (i) by alkylation of intracellular, but not extracellular, thiol groups downstream of insulin receptor activation, and (ii) by diphenylene iodonium at the level of the insulin receptor autophosphorylation. alpha-Lipoic acid also inhibited protein tyrosine phosphatase activity and decreased thiol reactivity of protein tyrosine phosphatase 1B. These findings indicate that oxidants produced by alpha-lipoic acid or insulin are involved in activation of insulin receptor and in inactivation of protein tyrosine phosphatases, which eventually result in elevated glucose uptake into 3T3-L1 adipocytes.

3T3 Cells↗