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PubMed1976

Evidence for two lipoic acid residues per lipoate acetyltransferase chain in the pyruvate dehydrogenase multienzyme complex of Escherichia coli.

The reaction of two maleimides, N-ethylmaleimide and bis-(N-maleimidomethyl) ether, with the pyruvate dehydrogenase multienzyme complex of Escherichia coli in the presence of the substrate, pyruvate, was examined. In both cases, the reaction was demonstrated to be almost exclusively with the lipoate acetyltransferase component, and evidence is presented to show that the most likely sites of reaction are the lipoic acid residues covalently bound to this component. With both reagents the stoicheiometry of the reaction was measured: 2 mol of reagent reacted with each polypeptide chain of lipoate acetyltransferase, implying that each chain bears two functionally active lipolic acid residues. This observation can be reconciled with previous determinations of the lipoic acid content of the complex by allowing for the variability of the subunit polypeptide-chain ratio that can be demonstrated for this multimeric enzyme.

Acetyltransferases↗

PubMed1981

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

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).

Amino Acids↗

PubMed2004

Influence of treatment of diabetic rats with combinations of pycnogenol, beta-carotene, and alpha-lipoic acid on parameters of oxidative stress.

Treatment with antioxidants may act more effectively to alter markers of free radical damage in combinations than singly. This study has determined whether treatment with combinations of pycnogenol, beta-carotene, and alpha-lipoic acid was more effective at reducing oxidative stress in diabetic rats than treatment with these antioxidants alone. It is not feasible, based on this study, to assume that there are interactive effects that make combinations of these antioxidants more effective than any one alone to combat oxidative stress. Female Sprague-Dawley rats, normal and streptozotocin-induced diabetic, were treated (10 mg/kg/day ip for 14 days) with pycnogenol, beta-carotene, pycnogenol + beta-carotene, or pycnogenol + beta-carotene + alpha-lipoic acid; controls were untreated. Concentrations of thiobarbituric acid reactive substances, glutathione and glutathione disulfide, and activities of glutathione reductase, glutathione peroxidase, superoxide dismutase, and catalase were measured in liver, kidney, and heart. Four types of effects were observed: (1) treatment with beta-carotene alone either reversed (cardiac glutathione disulfide) or elevated (cardiac glutathione, hepatic glutathione peroxidase activity) levels seen in diabetic animals; (2) beta-carotene alone produced no effect, but pycnogenol both alone and in combinations elevated (renal glutathione peroxidase and glutathione reductase activities, hepatic glutathione reductase activity and glutathione disulfide) or depressed (cardiac glutathione disulfide) levels seen in untreated diabetic animals; (3) all treatments with antioxidants, either alone or in combination, either normalized (lipid peroxidation in all tissues), elevated (hepatic GSH, cardiac glutathione peroxidase activity), or had no effect on (activities of hepatic catalase and superoxide dismutase in all tissues) levels seen in diabetic animals; (4) in only one case (cardiac glutathione reductase activity) levels in diabetic animals treated with combinations of antioxidants were normal, but elevated in animals treated with either antioxidant alone. Antioxidant effects seem to be dependent on the nature of the antioxidant used and not on combination effects.

Animals↗

PubMed2004

Remedial effect of DL-alpha-lipoic acid against adriamycin induced testicular lipid peroxidation.

Adriamycin (ADR), a cytotoxic antineoplastic drug is used in the treatment of various solid tumors. However, its efficacy continues to be challenged by significant toxicities including testicular toxicity. In the present study, the effect of lipoic acid, a "universal antioxidant" was investigated on ADR induced peroxidative damages in rat testis. Adult male albino rats of Wistar strain were administered ADR (1 mg/kg body weight, i.v.) once a week for 10 weeks. ADR injected rats showed a significant decline in the activities of enzymic antioxidants (catalase, superoxide dismutase, glutathione peroxidase, glutathione reductase and glutathione-S-transferase) and non-enzymic antioxidants (reduced glutathione, Vitamin A, Vitamin C and Vitamin E) with high malondialdehyde levels. The extent of testicular toxicity was evident from the decreased activities of testicular marker enzymes (sorbitol dehydrogenase and glucose-6-phosphate dehydrogenase). Treatment with lipoic acid (35 mg/kg body weight, i.p.) one day prior to ADR administration, maintained near normal activities of the enzymes and significantly reduced lipid peroxidation, thereby proving it to be an effective cytoprotectant.

Animals↗

PubMedDate not supplied

Lipoic acid ameliorates adriamycin-induced testicular mitochondriopathy.

Adriamycin (ADR), an anthracycline antibiotic, which is widely used as an antineoplastic drug in the treatment of various solid tumors, has been shown to induce reproductive abnormalities in males. In the present study, the effect of lipoic acid (LA), a universal antioxidant was investigated on ADR-induced testicular toxicity in rats. Adult male albino rats of Wistar strain were administered ADR (1 mg/kg body weight, i.v.), once a week for 10 weeks. Mitochondrial fractions of the testis were obtained by differential centrifugation. The activities of mitochondrial antioxidant enzymes such as superoxide dismutase, glutathione peroxidase and glutathione reductase were decreased significantly in the animals treated with ADR. The levels of mitochondrial lipid peroxides and hydrogen peroxide were increased in ADR-treated rats. ADR-treated rats also showed decline in the activities of mitochondrial enzymes such as succinate dehydrogenase (SDH), malate dehydrogenase (MDH) and isocitrate dehydrogenase (ICDH). Treatment with lipoic acid (35 mg/kg body weight, i.p.) 1 day prior to ADR administration, maintained near normal activities of the enzymes, thereby proving to be an effective cytoprotectant.

Animals↗

PubMed2005

Lipoic acid modulates adriamycin-induced testicular toxicity.

Adriamycin (ADR), an anthracycline antibiotic, which is widely used as an antineoplastic drug in the treatment of various solid tumors, has been shown to induce reproductive abnormalities in males. In the present study, the effect of lipoic acid (LA) a universal antioxidant was investigated on ADR-induced testicular toxicity in rats. Adult male albino rats of Wistar strain were administered ADR (1mg/kg body weight, i.v.), once a week for 10 weeks. ADR-injected rats showed increased levels of 8-hydroxy-2-deoxyguanosine with high protein carbonyl contents in testicular tissue. These changes were associated with significant increase in DNA damage in the sperm as evidenced by increased single strand breaks in a fluorimetric analysis of DNA unwinding (FADU). The activities of steroidogenic enzymes such as 3beta-hydroxy steroid dehydrogenase and 17beta-hydroxy steroid dehydrogenase, serum testosterone levels were decreased significantly in ADR-treated rats. Flow cytometric evaluation of testicular tissue in ADR-administered rats revealed impaired spermatogenesis and testicular function. Treatment with lipoic acid (35 mg/kg body weight, i.p.) one day prior to ADR administration, maintained near normal steroidogenesis and spermatogenesis, thereby proving it to be an effective cytoprotectant.

17-Hydroxysteroid Dehydrogenases↗

PubMed2001

Electrocatalytic reduction of lipoic acid and electroenzymatic reduction of NAD(P)(+) for integrated dehydrogenase biosensors.

Biosensors for the oxidized substrates of NAD(P)(+)-specific dehydrogenases demand the reductive recycling of the coenzymes. So far, suitable catalysts for the corresponding two-electron transfer are not available. In the present paper, this transport has been realized by a combined electrocatalytical and electroenzymatic process. Lipoic acid has been reduced on graphite electrodes functionalized with Fe(II)-phthalocyanine in 95% yield at-1200 mV in phosphate buffer pH 7.0. With the electrocatalytically reduced product, dihydrolipoic acid, lipoamide dehydrogenase could reduce NAD(+) in 20% yield and thioredoxin reductase NADP(+) in 18.4% yield. So far, the combined electrocatalytic/electroenzymatic system has not yet been realized, mainly because at the potential needed for the lipoic acid reduction, a parallel one-electron reduction of NAD(P)(+) was observed, implying the dimerization of the coenzyme.

Biosensing Techniques↗

PubMed2004

Photoinduced interactions between oxidized and reduced lipoic acid and riboflavin (vitamin B2).

As a powerful natural antioxidant, lipoic acid (LipSS) and its reduced form dihydrolipoic acid (DHLA) exert significant antioxidant activities in vivo and in vitro by deactivation of reactive oxygen and nitrogen species (ROS and RNS). In this study the riboflavin (RF, vitamin B2) sensitized UVA and visible-light irradiation of LipSS and DHLA was studied employing continuous irradiation, fluorescence spectroscopy, and laser flash photolysis (LFP). Our results indicate that LipSS and DHLA quench both the singlet state (1RF*) and the triplet state (3RF*) of RF by electron transfer to produce the riboflavin semiquinone radical (RFH.) and the radical cation of LipSS and DHLA, respectively. The radical cation of DHLA is rapidly deprotonated twice to yield a reducing species, the radical anion of LipSS (LipSS.-). When D2O was used as solvent, it was confirmed that the reaction of LipSS with 3RF* consists of a simple electron-transfer step, while loss of hydrogen occurs in the case of DHLA oxidation. Due to the strong absorption of RFH. and the riboflavin ground state, the absorption of the radical cation and the radical anion of LipSS can not be observed directly by LFP. N,N,N',N'-tetramethyl-p-phenylenediamine (TMPD) and N,N,N',N'-tetramethyl benzidine (TMB) were added as probes to the system. In the case of LipSS, the addition resulted in the formation of the radical cation of TMPD or TMB by quenching of the LipSS radical cation. If DHLA is the reducing substrate, no formation of probe radical cation is observed. This confirms that LipSS.- is produced by riboflavin photosensitization, and that there is no oxidizing species produced after DHLA oxidization.

Antioxidants↗

PubMed1995

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

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.

Antioxidants↗

PubMed2005

Pro-oxidant actions of alpha-lipoic acid and dihydrolipoic acid.

There is strong accumulating evidence that a alpha-lipoic acid (LA) supplement is good insurance, and would markedly improve human health. LA is readily absorbed from the diet, transported to cells and reduced to dihydrolipoic acid (DHLA). Of the two compounds, DHLA evidently has greater antioxidant activity. Much research has focused on the antioxidant properties of these compounds. Aside from its antioxidant role, in vitro and in vivo studies suggest that LA and its reduced form DHLA also act as a pro-oxidant properties. Limited number of studies concerning the pro-oxidant potential of LA and DHLA were performed only in recent years. The ability of LA and/or DHLA to function as either anti- or pro-oxidants, at least in part, is determined by the type of oxidant stress and the physiological circumstances. These pro-oxidant actions suggest that LA and DHLA act by multiple mechanisms, many of which are only now being explored. LA has been reported to have a number of potentially beneficial effects in both prevention and treatment of oxygen-related diseases. Selection of appropriate pharmacological doses of LA for use in oxygen-related diseases is critical. On the other hand, much of the discussion in clinical studies has been devoted to the pro-oxidant role of LA. This aspect remains to be elucidated. In further studies, careful evaluation will be necessary for the decision in the biological system whether LA administration is beneficial or harmful.

Biological Availability↗

PubMed1999

Lipoic acid acutely induces hypoglycemia in fasting nondiabetic and diabetic rats.

Lipoic acid (LA) is a unique antioxidant that increases peripheral glucose utilization in diabetic patients. This study was conducted to investigate whether the inhibition of glucose production could be an additional mechanism for the action of LA. Intravenous (i.v.) LA injection (100 or 60 mg/kg body weight) to fasting nondiabetic or streptozotocin (STZ)-induced diabetic rats caused a rapid reduction in blood glucose with no effect on circulating insulin levels. In vivo conversion of fructose to glucose was not inhibited by LA, whereas the gluconeogenesis flux from alanine was completely prevented. Reduced liver pyruvate carboxylase (PC) activity in vivo is suggested by the finding that LA induced a decrease in liver coenzyme A (CoA) content (44% and 28% reduction in nondiabetic and diabetic rats, respectively, compared with vehicle-treated animals) and liver acetyl CoA content (80% and 67% reduction in nondiabetic and diabetic rats, respectively). A reduction in plasma free carnitine (42% and 22% in nondiabetic and diabetic rats, respectively) was observed in LA-treated animals, and acylcarnitine levels were increased twofold. This could be attributed to elevated levels of C16 and C18 acylcarnitine, without a detectable accumulation of lipoylcarnitine. Under such conditions, a significant increase in the plasma free fatty acid (FFA) concentration (204% in nondiabetic and 151% in diabetic animals) with no elevation in beta-hydroxybutyrate levels was noted. In conclusion, this study suggests that short-term administration of LA at high dosage to normal and diabetic rats causes an inhibition of gluconeogenesis secondary to an interference with hepatic fatty acid oxidation. This may render LA an antihyperglycemic agent for the treatment of diabetic subjects, who display glucose overproduction as a major metabolic abnormality.

3-Hydroxybutyric Acid↗

PubMed2003

Randomized, placebo-controlled, double blind study on the clinical efficacy of a cream containing 5% alpha-lipoic acid related to photoageing of facial skin.

BACKGROUND: alpha-lipoic acid (LA) or the reduced form dihydrolipoate (DHLA) is a potent scavenger with anti-inflammatory properties. Previous uncontrolled studies with topical treatment with 5% LA-containing creams indicate a beneficial effect on photoageing skin. OBJECTIVE: The purpose of this study was to investigate whether a cream containing 5% LA showed any advantages concerning a number of the criteria associated with ageing of the facial skin, compared with an identical cream lacking LA. MATERIAL AND METHODS: Thirty-three women, mean age 54.4 years, were included in this controlled study. After randomization half the face was treated twice daily for 12 weeks with the LA cream and the other half with the control cream. The following methods of assessment were used: self-evaluation by the test subjects, clinical evaluation, photographic evaluation and laser profilometry. Profilometry was performed before the start of treatment and at the end. RESULTS: All four methods of assessment showed a statistically significant improvement on the LA-treated half of the face. Laser profilometry, the most objective method used, showed an average decrease in skin roughness of 50.8% (44.9-54.0) on the LA-treated side, compared with 40.7% (32.4-48.7) on the placebo-treated half of the face P < 0.001 (Wilcoxon matched pairs test). CONCLUSIONS: It is indicated that 12 weeks of treatment with a cream containing 5% LA improves clinical characteristics related to photoageing of facial skin.

Administration, Cutaneous↗

PubMed2002

The neuroprotective antioxidant alpha-lipoic acid induces detoxication enzymes in cultured astroglial cells.

alpha-Lipoic acid (LA), an antioxidant with broad neuroprotective capacity, is thought to act by scavenging reactive oxygen species and stimulation of glutathione synthesis. LA shows structural resemblance to dithiolethiones, like anethole dithiolethione (ADT). ADT protects against oxidative damage, primarily by induction of phase II detoxication enzymes, in particular NAD(P)H:quinone oxidoreductase (NQO1) and glutathione-S-transferase (GST). Therefore, we investigated whether LA, like ADT, is capable also of inducing these protective enzymes. Our data show that LA, like ADT, induces a highly significant, time- and concentration dependent, increase in the activity of NQO1 and GST in C6 astroglial cells. The LA or ADT mediated induction of NQO1 was further confirmed by quantitative PCR and western blot analysis. This work for the first time unequivocally demonstrates LA mediated upregulation of phase II detoxication enzymes, which may highly contribute to the compounds' neuroprotective potential. Moreover, the data support the notion of a common mechanism of action of LA and ADT.

Anethole Trithione↗

PubMed2006

Lipoic acid supplementation prevents cyclosporine-induced hypertension and nephrotoxicity in spontaneously hypertensive rats.

BACKGROUND: Cyclosporine (CsA) has significantly improved long-term survival after organ transplantations. Hypertension and nephrotoxicity are common side effects during CsA treatment and are aggravated by high salt intake. OBJECTIVE: To examine whether lipoic acid (LA), a natural antioxidant that scavenges reactive oxygen species and regenerates/recycles endogenous antioxidants, could prevent CsA-induced hypertension and nephrotoxicity. METHODS: Six-week-old spontaneously hypertensive rats (SHR) on a high-sodium diet (NaCl 6%) received CsA [5 mg/kg subcutaneously (s.c.)] alone or in combination with LA (0.5% w/w) for 6 weeks. Blood pressure, arterial functions, and tissue morphology were determined. Immunohistochemistry, quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and high-pressure liquid chromatography were used for kidney and heart samples. RESULTS: CsA induced severe hypertension, cardiac hypertrophy, endothelial dysfunction, and pronounced albuminuria. Histologically, the kidneys showed severe thickening of the media of the afferent arteries with fibrinoid necrosis, perivascular monocyte/macrophage infiltration and nitrotyrosine overexpression. CsA induced the expression of fibrogenic connective tissue growth factor both in the heart and kidneys. The detrimental effects of CsA were associated with upregulation of myocardial atrial natriuretic peptide (ANP) mRNA expression, paradoxical activation of the renin-angiotensin system (RAS), induction of renal reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase, and overexpression of oxidative stress-induced transcription factor NRF2. LA lowered blood pressure, ameliorated cardiac hypertrophy and endothelial dysfunction, and totally normalized albuminuria. In LA-treated rats, renal and cardiac morphologies were indistinguishable from those of SHR controls. CsA-induced myocardial ANP and connective tissue growth factor (CTGF) mRNA overexpression, RAS activation, NADPH oxidase induction, and NRF2 overexpression were prevented by LA. LA induced the mRNA expression of gamma-glutamylcysteine ligase, the rate-limiting enzyme in glutathione synthesis, and markedly increased hepatic cysteine and glutathione concentrations. CONCLUSIONS: Our findings suggest a salutary role for lipoic acid supplementation in the prevention of CsA-induced hypertension and nephrotoxicity, and underscore the importance of increased oxidative stress in the pathogenesis of CsA toxicity.

Animals↗

PubMed2005

Alpha-lipoic acid inhibits TNF-alpha-induced apoptosis in human bone marrow stromal cells.

UNLABELLED: TNF-alpha is an important mediator of bone loss. In the HS-5 hBMSC, TNF-alpha and H2O2 increased intracellular ROS levels and induced cell apoptosis through activation of caspases, JNK and NF-kappaB. alpha-Lipoic acid prevented these changes induced by TNF-alpha and H2O2, suggesting its potential therapeutic applications in attenuating bone loss. INTRODUCTION: Oxidative stress is an important mediator of bone loss. TNF-alpha, which plays a critical role in the bone loss after menopause, has been shown to increase intracellular oxidative stress. Because oxidative stress is associated with cell death, we analyzed the apoptotic effects of TNF-alpha and H2O2 on human bone marrow stromal cells (hBMSCs). We also examined the protective effects of an important biological thiol antioxidant, alpha-lipoic acid (alpha-LA), against TNF-alpha- and H2O2-induced apoptosis. MATERIALS AND METHODS: Using the HS-5 hBMSC cell line, we tested whether TNF-alpha-induced apoptosis was mediated by the generation of excessive reactive oxygen species (ROS). Apoptosis was determined by 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide (MTT) assay, trypan blue exclusion assay, quantitation of histone-associated DNA fragments in cytosol, and the activation of caspases. The mechanisms mediating these apoptotic effects were determined by Western blotting and enzyme immunoassay. RESULTS: Both TNF-alpha and H2O2 increased intracellular ROS levels, reduced total cellular glutathione levels, activated caspases-3, -9, and -8, and enhanced hBMSC apoptosis. The activation of c-jun N-terminal kinase (JNK) and NF-kappaB mediated these apoptotic effects. Pretreatment of cells with alpha-LA prevented these changes induced by TNF-alpha and H2O2. CONCLUSIONS: Our data show that TNF-alpha increases intracellular ROS in hBMSC and that TNF-alpha and H2O2 induce apoptosis in hBMSC through the activation of JNK and NF-kappaB. Our findings also suggest that alpha-LA may have therapeutic applications in halting or attenuating bone loss associated with increased oxidative stress.

Antioxidants↗

PubMed1997

The synthesis of (R)-(+)-lipoic acid using a monooxygenase-catalysed biotransformation as the key step.

2-(2-Acetoxyethyl)cyclohexanone (4) was converted into the lactone (-)-(5) regio- and enantioselectively using 2-oxo-delta 3-4,5,5-trimethylcyclopentenyl acetyl-CoA monooxygenase, an NADPH-dependent Baeyer-Villiger monooxygenase from camphor grown Pseudomonas putida NCIMB 10007. The lactone (-)-(5) was converted into (R)-(+)-lipoic acid in six steps. In contrast cyclopentanone monooxygenase, an NADPH-dependent Baeyer-Villiger monooxygenase from cyclopentanol-grown Pseudomonas sp. NCIMB 9872 selectively oxidized the (S)-enantiomer of the ketone (4) giving better access to optically enriched, naturally occurring lipoic acid.

Biotransformation↗

PubMed2004

The role of lipoic acid in the regulation of the redox status of wheat irrigated with 20% sea water.

The effect of irrigation with 20% sea water was studied in 14 and 21-day-old seedlings of durum wheat (Triticum durum, cv. Ofanto). Comparisons between control (Hoagland's 2 solution) and treated (20% sea water in Hoagland's solution) plants included, besides HPLC determination of reduced (DHLA) and oxidised (LA) forms of lipoic acid, ascorbate and glutathione contents, their redox status, the activity of ascorbate peroxidase (APX, EC 1.11.1.11.) and glutathione reductase (GR, EC 1.6.4.2.). The results indicated a more relevant presence of lipoic acid in the roots in comparison to the shoots. An involvement of its reduced form in the regeneration of the reduced glutathione, at least at 14 days of treatment, suggested, besides its role as dehydrogenase enzyme cofactor, a role in the recycling of the other antioxidants. The amount of LA always increased with growth in shoots and decreased in roots, while DHLA remained constant in control and increased in treated plants. Besides, the oxidised form always decreased with sea water while the reduced form decreased in shoots and increased in roots. The ascorbate pool exerted its positive influence especially in the shoots, while APX and GR activities resulted differently modulated by the salinity level.

Antioxidants↗

PubMed2000

Alpha lipoic acid: a novel treatment for depression.

Insulin resistance has been associated with people diagnosed with depression. Conversely, it has also been documented that diabetics have an increased risk of depression. Evidence suggests that insulin activity plays a role in serotonergic activity by increasing the influx of tryptophan into the brain. This increased influx of tryptophan has been shown to result in an increase in serotonin synthesis. In accordance with the serotonin theory of depression, it may be possible to treat depression by increasing insulin activity. The antioxidant alpha lipoic acid has been shown to increase insulin sensitivity and is used to treat people with diabetes. Therefore, the nutrient alpha lipoic acid should be clinically tested as an adjunct treatment for depression.

Antidepressive Agents↗