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At least 19 recordsLinked to original sources
PubMed1975

[A possible essential metabolite of linoleic acid: lipoic acid, the universal coenzyme of alpha-keto acid oxidation].

The metabolism of [14C-U] linoleci acid (LI) and [14C-U] oleic acid were compared by injecting these fatty acids into growing rats and then homogenizing livers into a three phase system (chloroform/methanol/water). The radioactivities of these phases were equilibrated by extracting them X times with the same solvents. The lipid lower phase was discarded and the analysis was carried out on the evaporated hydroalcoholic upper phase. The residue was extracted again with methanol and hydrolyzed (HCl 6N). The acidic solution was evaporated, treated with HCl/methanol, extracted with chloroform and analysed by thin layer chromatography. One of the most radioactive intermediates detected after injecting LI was purified again and identified as lipoic acid, on the basis of: a. retention time in gas-liquid chromatography; b. Rf in thin layer chromatography; c. molecular weight as determined by mass spectrometry. Thus, the most important fate of essential fatty acids (except for their part in the prostaglandin synthesis and membrane formation) seems to be that of a precursor for this covalently bound alpha keto-acid dehydrogenation coenzyme--the link between lipid and carbohydrate metabolisms.

Animals↗
PubMed1992

Radioprotection of hematopoietic tissues in mice by lipoic acid.

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.

Animals↗
PubMed2002

[Biologic properties of lipoic acid].

Lipoic acid is a prostetic group of H-protein of the glycine cleavage system and the dihydrolipoamide acyltransferases (E2) of the pyruvate, alpha-ketoglutarate and branched-chain alpha-keto acid dehydrogenase complexes. Lipoic acid and its reduced form, dihydrolipoic acid, reacts with oxygen reactive species. This paper reviews the beneficial effects in oxidative stress models or clinical conditions.

Acquired Immunodeficiency Syndrome↗
PubMed1977

Nonenzymatic reduction of prostaglandin H by lipoic acid.

Lipoic acid has recently been found to stimulate prostaglandin biosynthesis by sheep vesicular gland microsomes (Marnett, L. J., and Wilcox, C. L. (1977). Biochim. Biophys. Acta 487, 222). The increase in oxygenated products is predominantly in the formation of prostaglandin F and its structure has been verified by gas chromatography-mass spectrometry. Endoperoxide trapping experiments employing reduced glutathione show that the conversion of prostaglandin H to prostaglandin F is slow in lipoate containing incubation mixtures. Therefore, the net effect of the addition of lipoic acid to vesicular gland microsomes is the stimulation of prostaglandin endoperoxide biosynthesis. Further experiments reveal that the reduction of prostaglandin H to prostaglandin F by lipoate is nonenzymatic and occurs after the termination of biosynthesis in the work-up mixture. The reduction takes place preferentially in the organic phase of a Folch extract (chloroform-methanol-2% formic acid 8:4:3). Authentic prostaglandin H2 is reduced by lipoic acid to prostaglandin F 2alpha in high yield under these conditions.

Animals↗
PubMed2000

Fatty acid and lipoic acid biosynthesis in higher plant mitochondria.

Fatty acid and lipoic acid biosynthesis were investigated in plant mitochondria. Although the mitochondria lack acetyl-CoA carboxylase, our experiments reveal that they contain the enzymatic equipment necessary to transform malonate into the two main building units for fatty acid synthesis: malonyl- and acetyl-acyl carrier protein (ACP). We demonstrated, by a new method based on a complementary use of high performance liquid chromatography and mass spectrometry, that the soluble mitochondrial fatty-acid synthase produces mainly three predominant acyl-ACPs as follows: octanoyl(C8)-, hexadecanoyl(C16)-, and octadecanoyl(C18)-ACP. Octanoate production is of primary interest since it has been postulated long ago to be a precursor of lipoic acid. By using a recombinant H apoprotein mutant as a potential acceptor for newly synthesized lipoic acid, we were able to detect limited amounts of lipoylated H protein in the presence of malonate, several sulfur donors, and cofactors. Finally, we present a scheme outlining the new biochemical pathway of fatty acid and lipoic acid synthesis in plant mitochondria.

Acyl-Carrier Protein S-Malonyltransferase↗
PubMed1994

Lipoic acid favors thiolsulfinate formation after hypochlorous acid scavenging: a study with lipoic acid derivatives.

Lipoic acid, the oxidized form of 6,8-dimercapto-octanoic acid has a strained cyclic disulfide in a 1,2-dithiolane ring. Recently its antioxidant activity gained attention. Hypochlorous acid (HOCl) is an oxidant produced by neutrophils. A prominent effect of HOCl is the inactivation of alpha-1-antiproteinase. Due to this inactivation, the ability of alpha-1-antiproteinase to inhibit elastase is lost. The resulting higher activity of elastase is held responsible for tissue damage in lung emphysema. We studied the HOCl scavenging capability of three metabolites of lipoic acid: tetranor-, bisnor-, and beta-lipoic acid. To obtain some insight on the molecular basis of HOCl scavenging 1,2-dithiane-4,5-diol, cystine, lipoic acid methyl ester, and lipoamide were also included in the study. The extent of alpha-1-antiproteinase inactivation by HOCl in the presence of scavenger was taken as a parameter to quantify the scavenging activity. It was found that lipoic acid, tetranor- and bisnorlipoic acid, lipoic acid methyl ester, and lipoamide all showed the same activity toward HOCl. beta-Lipoic acid, 1,2-dithiane-4,5-diol and cystine were less active. The products of lipoic acid after reaction with HOCl were studied using GC/MS. Indications for thiolsulfinate formation were found by comparing these products with the GC/MS profile of beta-lipoic acid. Thiolsulfinate formation may also be suggested in the reaction of tetranor- and bisnorlipoic acid and lipoic acid methyl ester with HOCl. The present results show an antioxidant activity of the metabolites tetranor- and bisnorlipoic acid. The 1,2-dithiolane ring may enhance the reactivity toward HOCl compared to less strained disulfides, resulting in the formation a thiolsulfinate.

Free Radical Scavengers↗
PubMed1996

Decomposition of alpha-lipoic acid derivatives by photoirradiation-formation of dihydrolipoic acid from alpha-lipoic acid-.

Due to its strained five-membered ring, alpha-lipoic acid (LA) has an absorption band around 330 nm, which is used to quantify its concentration. In order to obtain information for the homolytic rupture of the S-S bond and the formation of dihydrolipoic acid (DHLA), the photochemical reaction of lipoic acid was examined in the presence or absence of ascorbic acid upon exposure to UVA light. The absorption band of alpha-lipoic acid at around 330 nm disappeared by photoirradiation, which corresponds to the rupture of S-S bond of the 1,2-dithiolane ring in lipoic acid. HPLC-Electrochemical Detection (ECD) analysis of lipoic acid showed significant formation of dihydrolipoic acid and other thiols. The formation of thiols from the photoreaction of lipoic acid was also confirmed by the Ellman method. The formation of thiols from lipoic acid was completely time-dependent and the formation of the thiols increased upto 55%. Similar results were obtained in the photochemical reactions of short-chain analogues, bisnor- and tetranor-lipoic acid. On the other hand, beta-lipoic acid was quite stable, no photodecomposition of beta-lipoic acid was observed in the UV region. The formation of thiols including dihydrolipoic acid from lipoic acid can be explained by considering the rupture of S-S bond, which results in the formation of the dithiyl radicals of alpha-lipoic acid. It is proposed that intra- and intermolecular hydrogen abstraction of the dithyl radical produces thiols including dihydrolipoic acid as final products.

Antioxidants↗
PubMed1999

Metabolic effects of gamma-linolenic acid-alpha-lipoic acid conjugate in streptozotocin diabetic rats.

Data suggesting the involvement of increased oxidative stress in the pathophysiology of diabetes has raised interest in the potential therapeutic benefit of antioxidants. Although beneficial metabolic effects of antioxidant supplementation have been suggested, an antioxidant mode of action, particularly in skeletal muscle, has not been documented. In the present study, we evaluate the metabolic effects of a gamma-linolenic acid-alpha-lipoic acid conjugate (GLA-LA) in streptozotocin-induced diabetic rats, and assess its potential mode of action by comparing its effects with equimolar administration of LA and GLA alone. Ten days of oral supplementation of 20 mg/kg body weight GLA-LA, but not LA or GLA alone, caused a mild reduction in fasting blood glucose concentration as compared with vehicle-treated diabetic rats (375 +/- 11 vs. 416 +/- 16 mg/dl, p = 0.03), with no change in fasting plasma insulin levels. A peripheral insulin-sensitizing effect could be observed with GLA-LA, LA, and GLA treatments, as demonstrated by a significant (p < 0.04) 23%, 13%, and 10% reduction, respectively, in the area under the glucose curve following an intravenous insulin tolerance test. This effect was associated with a 67% and 50% increase in GLUT4 protein content in the membranes of gastrocnemius muscle of GLA-LA and LA-treated animals, respectively; however, no change was observed with GLA treatment alone. Interestingly, both GLA-LA and LA treatments corrected a diabetes-related decrease in the gastrocnemius muscle low-molecular-weight reduced thiols content. These data demonstrate insulin-sensitizing properties of the GLA-LA conjugate by distinct mechanisms attributable to each of its components, which are associated with antioxidant effects.

Animals↗
PubMed2001

The effect of gamma-linolenic acid-alpha-lipoic acid on functional deficits in the peripheral and central nervous system of streptozotocin-diabetic rats.

Diabetes mellitus can lead to functional and structural deficits in both the peripheral and central nervous system. The pathogenesis of these deficits is multifactorial, probably involving, among others, microvascular dysfunction and oxidative stress. The present study examined the effects of 12 weeks of treatment with a conjugate of the essential fatty acid gamma-linolenic acid and the anti-oxidant alpha-lipoic acid (GLA-LA) on functional deficits in the peripheral and central nervous system in streptozotocin-diabetic rats. Treatment was initiated 16 weeks after diabetes induction. Sciatic nerve motor and sensory conduction velocity, brainstem auditory evoked potentials and visual evoked potentials were measured in control, untreated and GLA-LA treated diabetic rats. Also, long-term potentiation, a form of synaptic plasticity used as a model for learning and memory at the cellular level, was examined in hippocampal slices. GLA-LA treatment (50 mg/kg/day) did not reverse established deficits in nerve conduction velocity or in evoked potential latencies in diabetic rats. However, GLA-LA treatment did improve long-term potentiation in the hippocampus. It is concluded that GLA-LA, which is known to improve early deficits in peripheral nerve conduction in diabetic rats, is unable to reverse late deficits. However, the compound does reverse established deficits in long-term potentiation, suggesting that at least part of its activity is specifically directed at synaptic plasticity.

Animals↗
PubMed2003

Interactions of conjugated linoleic acid and lipoic acid on insulin action in the obese Zucker rat.

The fatty acid conjugated linoleic acid (CLA) and the antioxidant R-(+)-alpha-lipoic acid (R-ALA) individually enhance glucose tolerance and insulin action on skeletal muscle glucose transport in the insulin-resistant obese Zucker rat. To date, no study has assessed the potential interactions between these 2 interventions in treating insulin resistance. The present study was designed to determine whether chronic treatment with CLA and R-ALA in combination would enhance skeletal muscle glucose transport to a greater extent than either intervention individually. CLA, R-ALA, or a combination treatment of R-ALA and CLA were administered to female obese Zucker rats for 20 days at low or high doses. Whereas low-dose R-ALA (10 mg/kg body weight) alone did not alter muscle glucose transport, low-dose CLA (0.3 g/kg) induced a significant increase (38%, P <.05) in insulin-mediated glucose transport in epitrochlearis, but not in soleus. Low-dose combination therapy brought about the greatest enhancement of insulin-mediated glucose transport in epitrochlearis (77%) and soleus (54%), with the latter effect being associated with a 50% reduction in protein carbonyls (an index of tissue oxidative stress) and a 33% diminution in muscle triglycerides. High-dose treatments with CLA (1.5 g/kg), R-ALA (50 mg/kg), and the combination of CLA and R-ALA elicited increases in insulin-mediated glucose transport in epitrochlearis (57%, 58%, and 77%) and soleus (32%, 35%, and 54%). However, whereas the individual high-dose treatments with CLA and R-ALA reduced protein carbonyls (63% and 49%) and triglycerides (29% and 28%) in soleus, no further reductions were observed with the high-dose combination treatment groups. These findings support a significant interaction between low doses of CLA and R-ALA for enhancement of insulin action on skeletal muscle glucose transport, possibly via reductions in muscle oxidative stress and in lipid storage.

Animals↗
PubMed1999

Treatment of diabetic polyneuropathy with the antioxidant thioctic acid (alpha-lipoic acid): a two year multicenter randomized double-blind placebo-controlled trial (ALADIN II). Alpha Lipoic Acid in Diabetic Neuropathy.

Short-term trials with the antioxidant thioctic acid (TA) appear to improve neuropathic symptoms in diabetic patients, but the long-term response remains to be established. Therefore, Type 1 and Type 2 diabetic patients with symptomatic polyneuropathy were randomly assigned to three treatment regimens: (1) 2 x 600(mg of TA (TA 1200), (2) 600)mg of TA plus placebo (PLA) (TA 600) or (3) placebo and placebo (PLA). A trometamol salt solution of TA of 1200 or 600 mg or PLA was intravenously administered once daily for five consecutive days before enrolling the patients in the oral treatment phase. The study was prospective, PLA-controlled, randomized, double-blind and conducted for two years. Severity of diabetic neuropathy was assessed by the Neuropathy Disability Score (NDS) and electrophysiological attributes of the sural (sensory nerve conduction velocity (SNCV), sensory nerve action potential (SNAP)) and the tibial (motor nerve conduction velocity (MNCV), motor nerve distal latency (MNDL)) nerve. Statistical analysis was performed after independent reviewers excluded all patients with highly variable data allowing a final analysis of 65 patients (TA 1200: n = 18, TA 600: n = 27; PLA: n = 20). At baseline no significant differences were noted between the groups regarding the demographic variables and peripheral nerve function parameters for these 65 patients. Statistically significant changes after 24 months between TA and PLA were observed (mean +/- SD) for sural SNCV: +3.8 +/- 4.2 m/s in TA 1200, +3.0+/-3.0m/s in TA 600, -0.1+/-4.8m/s in PLA (p < 0.05 for TA 1200 and TA 600 vs. PLA); sural SNAP: +0.6+/-2.5 microV in TA 1200, +0.3+/-1.4 microV in TA 600, -0.7 +/- 1.5 microV in PLA (p = 0.076 for TA 1200 vs. PLA and p < 0.05 for TA 600 vs. PLA), and in tibial MNCV: +/- 1.2 +/- 3.8 m/s in TA 1200, -0.3 +/- 5.2 m/s in TA 600, 1.5 +/- 2.9 m/s in PLA (p < 0.05 for TA 1200 vs. PLA). No significant differences between the groups after 24 months were noted regarding the tibial MNDL and the NDS. We conclude that in a subgroup of patients after exclusion of patients with excessive test variability throughout the trial, TA appeared to have a beneficial effect on several attributes of nerve conduction.

Action Potentials↗
PubMed1993

Biosynthesis of lipoic acid: characterization of the lipoic acid auxotrophs Escherichia coli W1485-lip2 and JRG33-lip9.

The abilities of the Escherichia coli lipoic acid auxotrophs W1485-lip2 and JRG33-lip9 to grow on succinate medium in the presence of octanoate, 8-mercaptooctanoate, or 6-mercaptooctanoate have been determined. Both organisms are mutated in lipA. Neither organism can use octanoate or 6-mercaptooctanoate for production of lipoate, but the lip2 allele can use 8-mercaptooctanoate. Chromosomal DNA from the auxotrophs was amplified by PCR using primers derived from the DNA sequence of wild-type lipA and then sequenced. Both mutants contain single G/C to A/T mutations in lipA, resulting in conversion of Ser307 into Phe in W1485-lip2 and Glu195 into Lys in JRG33-lip9. These results support the hypothesis that lipA is involved in the sulfur insertion step(s) of lipoate biosynthesis and indicate that it is possible to selectively block formation of the C8-S bond through suitable mutation in lipA.

Amino Acid Sequence↗
PubMed1998

Biosynthesis of lipoic acid in Arabidopsis: cloning and characterization of the cDNA for lipoic acid synthase.

Lipoic acid is a coenzyme that is essential for the activity of enzyme complexes such as those of pyruvate dehydrogenase and glycine decarboxylase. We report here the isolation and characterization of LIP1 cDNA for lipoic acid synthase of Arabidopsis. The Arabidopsis LIP1 cDNA was isolated using an expressed sequence tag homologous to the lipoic acid synthase of Escherichia coli. This cDNA was shown to code for Arabidopsis lipoic acid synthase by its ability to complement a lipA mutant of E. coli defective in lipoic acid synthase. DNA-sequence analysis of the LIP1 cDNA revealed an open reading frame predicting a protein of 374 amino acids. Comparisons of the deduced amino acid sequence with those of E. coli and yeast lipoic acid synthase homologs showed a high degree of sequence similarity and the presence of a leader sequence presumably required for import into the mitochondria. Southern-hybridization analysis suggested that LIP1 is a single-copy gene in Arabidopsis. Western analysis with an antibody against lipoic acid synthase demonstrated that this enzyme is located in the mitochondrial compartment in Arabidopsis cells as a 43-kD polypeptide.

Amino Acid Sequence↗