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lipoic, lipoic acid, alpha lipoic, alpha-lipoic acid, antioxidant

Alpha-Lipoic Acid and metabolism

Lipoic acid increases glutathione production and enhances the effect of mercury in human cell lines.
Hultberg B, Andersson A, Isaksson A.
Department of Clinical Chemistry, Institute of Laboratory Medicine, University Hospital Lund, S-22185 Lund, Sweden.
Toxicology. 2002 Jun 14;175(1-3):103-10.

Thiols are known to influence the metabolism of glutathione. In a previous study (Toxicology 156 (2001) 93) dithiothreitol (DTT) did not show any effect on intra- or extracellular glutathione concentrations in HeLa cell cultures but increased the effects of mercury ions on glutathione concentrations, whereas monothiols such as N-acetylcysteine (NAC) or glutathione did not. In the present study, we have investigated the effects of thiols as well as the interaction between thiols and mercury ions in cultures of both HeLa and hepatoma cells. Furthermore, we have added alpha-lipoic acid (LA) to the previously used test panel of thiols, since it is metabolised intracellularly to a dithiol (dihydrolipoate). The present study shows that LA increased intra- and extracellular concentrations of glutathione in both HeLa and hepatoma cell cultures. In contrast to results for HeLa cells, the presence of DTT increased the intracellular glutathione concentration in hepatoma cells. No increase of glutathione concentrations was observed in hepatoma cell cultures in the presence of the monothiols (NAC, homocysteine or glutathione) tested, in agreement with previous findings in HeLa cell cultures. The presence of dithiols, either DTT or dihydrolipoate (the metabolite of LA), increased the effects of mercury ions on glutathione concentrations in hepatoma cells, whereas monothiols such as NAC or glutathione did not, in agreement with previous findings in HeLa cells. Thus, metabolic effects of mercury ions were observed in hepatoma cells as well as in HeLa cells at a lower concentration than the supposed toxicity threshold for mercury in blood.

Lipoic acid as a means of metabolic therapy of open-angle glaucoma
Filina AA, Davydova NG, Endrikhovskii SN, Shamshinova AM.
Vestn Oftalmol. 1995 Oct-Dec;111(4):6-8.

A total of 45 patients (90 eyes) with stages I and II open-angle glaucoma (OAG) were examined, 26 of these were administered lipoic acid in a daily dose of 0.075 g for 2 months and 19 were given 0.15 g daily for 1 month. Control group consisted of 31 patients with OAG who were administered only local hypotensive therapy. Vision acuity and visual field were checked up, tonometry, tonography, and campimetry carried out, and levels of nonprotein SH-groups and activity of gamma-glutamyl transpeptidase measured in the lacrimal fluid. Improvement of the biochemical parameters, visual function, and of the coefficient of efficacy of liquid discharge was more expressed in the patients administered lipoic acid in a daily dose of 0.15 g. Color campimetry results indicate improved sensitivity of the visual analyzer under the effect of treatment. Improvement was attained in approximately 45-47.5% of examined eyes, and was more often seen in patients with stage II OAG: in 57-58% eyes. The effect of lipoic acid may be explained by its antioxidant properties and direct influence on ocular tissue metabolism.

Differential effects of lipoic acid stereoisomers on glucose metabolism in insulin-resistant skeletal muscle.
Streeper RS, Henriksen EJ, Jacob S, Hokama JY, Fogt DL, Tritschler HJ.

Department of Physiology, University of Arizona, Tucson 85721-0093, USA.

The racemic mixture of the antioxidant alpha-lipoic acid (ALA) enhances insulin-stimulated glucose metabolism in insulin-resistant humans and animals. We determined the individual effects of the pure R-(+) and S-(-) enantiomers of ALA on glucose metabolism in skeletal muscle of an animal model of insulin resistance, hyperinsulinemia, and dyslipidemia: the obese Zucker (fa/fa) rat. Obese rats were treated intraperitoneally acutely (100 mg/kg body wt for 1 h) or chronically [10 days with 30 mg/kg of R-(+)-ALA or 50 mg/kg of S-(-)-ALA]. Glucose transport [2-deoxyglucose (2-DG) uptake], glycogen synthesis, and glucose oxidation were determined in the epitrochlearis muscles in the absence or presence of insulin (13.3 nM). Acutely, R-(+)-ALA increased insulin-mediated 2-DG-uptake by 64% (P < 0.05), whereas S-(-)-ALA had no significant effect. Although chronic R-(+)-ALA treatment significantly reduced plasma insulin (17%) and free fatty acids (FFA; 35%) relative to vehicle-treated obese animals, S-(-)-ALA treatment further increased insulin (15%) and had no effect on FFA. Insulin-stimulated 2-DG uptake was increased by 65% by chronic R-(+)-ALA treatment, whereas S-(-)-ALA administration resulted in only a 29% improvement. Chronic R-(+)-ALA treatment elicited a 26% increase in insulin-stimulated glycogen synthesis and a 33% enhancement of insulin-stimulated glucose oxidation. No significant increase in these parameters was observed after S-(-)-ALA treatment. Glucose transporter (GLUT-4) protein was unchanged after chronic R-(+)-ALA treatment but was reduced to 81 +/- 6% of obese control with S-(-)-ALA treatment. Therefore, chronic parenteral treatment with the antioxidant ALA enhances insulin-stimulated glucose transport and non-oxidative and oxidative glucose metabolism in insulin-resistant rat skeletal muscle, with the R-(+) enantiomer being much more effective than the S-(-) enantiomer.

Alpha-lipoic acid in liver metabolism and disease.
Bustamante J, Lodge JK, Marcocci L, Tritschler HJ, Packer L, Rihn BH. Department of Molecular and Cell Biology, University of California, Berkeley 94720-3200, USA.
Free Radic Biol Med. 1998 Apr;24(6):1023-39.

R-alpha-Lipoic acid is found naturally occurring as a prosthetic group in alpha-keto acid dehydrogenase complexes of the mitochondria, and as such plays a fundamental role in metabolism. Although this has been known for decades, only recently has free supplemented alpha-lipoic acid been found to affect cellular metabolic processes in vitro, as it has the ability to alter the redox status of cells and interact with thiols and other antioxidants. Therefore, it appears that this compound has important therapeutic potential in conditions where oxidative stress is involved. Early case studies with alpha-lipoic acid were performed with little knowledge of the action of alpha-lipoic acid at a cellular level, but with the rationale that because the naturally occurring protein bound form of alpha-lipoic acid has a pivotal role in metabolism, that supplementation may have some beneficial effect. Such studies sought to evaluate the effect of supplemented alpha-lipoic acid, using low doses, on lipid or carbohydrate metabolism, but little or no effect was observed. A common response in these trials was an increase in glucose uptake, but increased plasma levels of pyruvate and lactate were also observed, suggesting that an inhibitory effect on the pyruvate dehydrogenase complex was occurring. During the same period, alpha-lipoic acid was also used as a therapeutic agent in a number of conditions relating to liver disease, including alcohol-induced damage, mushroom poisoning, metal intoxification, and CCl4 poisoning. Alpha-Lipoic acid supplementation was successful in the treatment for these conditions in many cases. Experimental studies and clinical trials in the last 5 years using high doses of alpha-lipoic acid (600 mg in humans) have provided new and consistent evidence for the therapeutic role of antioxidant alpha-lipoic acid in the treatment of insulin resistance and diabetic polyneuropathy. This new insight should encourage clinicians to use alpha-lipoic acid in diseases affecting liver in which oxidative stress is involved. Scientific abstracts from Pubmed