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PubMed2005

Dietary supplementation with (R)-alpha-lipoic acid reverses the age-related accumulation of iron and depletion of antioxidants in the rat cerebral cortex.

Accumulation of divalent metal ions (e.g. iron and copper) has been proposed to contribute to heightened oxidative stress evident in aging and neurodegenerative disorders. To understand the extent of iron accumulation and its effect on antioxidant status, we monitored iron content in the cerebral cortex of F344 rats by inductively coupled plasma atomic emission spectrometry (ICP-AES) and found that the cerebral iron levels in 24-28-month-old rats were increased by 80% (p<0.01) relative to 3-month-old rats. Iron accumulation correlated with a decline in glutathione (GSH) and the GSH/GSSG ratio, indicating that iron accumulation altered antioxidant capacity and thiol redox state in aged animals. Because (R)-alpha-Lipoic acid (LA) is a potent chelator of divalent metal ions in vitro and also regenerates other antioxidants, we monitored whether feeding LA (0.2% [w/w]; 2 weeks) could lower cortical iron and improve antioxidant status. Results show that cerebral iron levels in old LA-fed animals were lower when compared to controls and were similar to levels seen in young rats. Antioxidant status and thiol redox state also improved markedly in old LA-fed rats versus controls. These results thus show that LA supplementation may be a means to modulate the age-related accumulation of cortical iron content, thereby lowering oxidative stress associated with aging.

Aging↗
PubMed2005

Proteomic analysis of specific brain proteins in aged SAMP8 mice treated with alpha-lipoic acid: implications for aging and age-related neurodegenerative disorders.

Free radical-mediated damage to neuronal membrane components has been implicated in the etiology of Alzheimer's disease (AD) and aging. The senescence accelerated prone mouse strain 8 (SAMP8) exhibits age-related deterioration in memory and learning along with increased oxidative markers. Therefore, SAMP8 is a suitable model to study brain aging and, since aging is the major risk factor for AD and SAMP8 exhibits many of the biochemical findings of AD, perhaps as a model for and the early phase of AD. Our previous studies reported higher oxidative stress markers in brains of 12-month-old SAMP8 mice when compared to that of 4-month-old SAMP8 mice. Further, we have previously shown that injecting the mice with alpha-lipoic acid (LA) reversed brain lipid peroxidation, protein oxidation, as well as the learning and memory impairments in SAMP8 mice. Recently, we reported the use of proteomics to identify proteins that are expressed differently and/or modified oxidatively in aged SAMP8 brains. In order to understand how LA reverses the learning and memory deficits of aged SAMP8 mice, in the current study, we used proteomics to compare the expression levels and specific carbonyl levels of proteins in brains from 12-month-old SAMP8 mice treated or not treated with LA. We found that the expressions of the three brain proteins (neurofilament triplet L protein, alpha-enolase, and ubiquitous mitochondrial creatine kinase) were increased significantly and that the specific carbonyl levels of the three brain proteins (lactate dehydrogenase B, dihydropyrimidinase-like protein 2, and alpha-enolase) were significantly decreased in the aged SAMP8 mice treated with LA. These findings suggest that the improved learning and memory observed in LA-injected SAMP8 mice may be related to the restoration of the normal condition of specific proteins in aged SAMP8 mouse brain. Moreover, our current study implicates neurofilament triplet L protein, alpha-enolase, ubiquitous mitochondrial creatine kinase, lactate dehydrogenase B, and dihydropyrimidinase-like protein 2 in process associated with learning and memory of SAMP8 mice.

Aging↗
PubMed1996

Direct determination of glutathione in human blood by micellar electrokinetic chromatography: simultaneous determination of lipoamide and lipoic acid.

A reproducible, rapid procedure for the determination of glutathione in human blood by micellar electrokinetic chromatography has been developed. Whole blood samples were deproteinized with 5% w/v sulfosalicylic acid (final concentration). After centrifugation, the supernatant was directly injected for analysis, without further derivatization. Separations were performed by using an uncoated capillary of 30 cm effective length and 50 microns internal diameter (ID), 50 mM Tris-HCl, 30 mM sodium dodecyl sulfate (SDS), pH 7.00, as running buffer, and 10-20 kV. On-line detection was carried out at 214 nm and a detection limit in the range of femtomoles was achieved. Under the same experimental conditions, we resolved a mixed standard solution containing glutathione in its oxidize and reduced forms, lipoamide and alpha-lipoic acid. The corresponding migration times were reproducible. The present method allows rapid determination of these compounds, which play a critical role in oxidative stress, in cellular defense against injurious agents and whose levels are related to the toxicology and metabolism of several toxins and drugs, such as antineoplastic agents.

Benzenesulfonates↗
PubMed1997

Neuroprotection by the metabolic antioxidant alpha-lipoic acid.

Reactive oxygen species are thought to be involved in a number of types of acute and chronic pathologic conditions in the brain and neural tissue. The metabolic antioxidant alpha-lipoate (thioctic acid, 1, 2-dithiolane-3-pentanoic acid; 1, 2-dithiolane-3 valeric acid; and 6, 8-dithiooctanoic acid) is a low molecular weight substance that is absorbed from the diet and crosses the blood-brain barrier. alpha-Lipoate is taken up and reduced in cells and tissues to dihydrolipoate, which is also exported to the extracellular medium; hence, protection is afforded to both intracellular and extracellular environments. Both alpha-lipoate and especially dihydrolipoate have been shown to be potent antioxidants, to regenerate through redox cycling other antioxidants like vitamin C and vitamin E, and to raise intracellular glutathione levels. Thus, it would seem an ideal substance in the treatment of oxidative brain and neural disorders involving free radical processes. Examination of current research reveals protective effects of these compounds in cerebral ischemia-reperfusion, excitotoxic amino acid brain injury, mitochondrial dysfunction, diabetes and diabetic neuropathy, inborn errors of metabolism, and other causes of acute or chronic damage to brain or neural tissue. Very few neuropharmacological intervention strategies are currently available for the treatment of stroke and numerous other brain disorders involving free radical injury. We propose that the various metabolic antioxidant properties of alpha-lipoate relate to its possible therapeutic roles in a variety of brain and neuronal tissue pathologies: thiols are central to antioxidant defense in brain and other tissues. The most important thiol antioxidant, glutathione, cannot be directly administered, whereas alpha-lipoic acid can. In vitro, animal, and preliminary human studies indicate that alpha-lipoate may be effective in numerous neurodegenerative disorders.

Animals↗
PubMed1999

Cytokine-induced glucose uptake in skeletal muscle: redox regulation and the role of alpha-lipoic acid.

In L6 myotubes, glucose uptake stimulated by interferon (IFN)-gamma or lipopolysaccharides (LPS) and a combination of LPS, IFN-gamma, and tumor necrosis factor (TNF)-alpha was inhibited by the antioxidant pyrrolidinedithiocarbamate and potentiated in reduced glutathione (GSH)-deficient cells. Also, the stimulatory effect of LPS and IFN-gamma individually, and of a combination of LPS, IFN-gamma, and TNF-alpha, on glucose uptake was associated with an increased level of intracellular oxidants (dichlorofluorescein assay) and loss of intracellular GSH. Study of the individual effects of LPS, IFN-gamma, and TNF-alpha as well as of a combination of the three activators provided evidence against a role of nitric oxide in mediating the stimulatory effect of the above-mentioned agents on glucose uptake. We also observed that the insulin-mimetic nutrient alpha-lipoic acid (LA; R-enantiomer) is able to stimulate glucose uptake in cytokine-treated cells that are insulin resistant. This study shows that cytokine-induced glucose uptake in skeletal muscle cells is redox sensitive and that, under conditions of acute infection that is accompanied with insulin resistance, LA may have therapeutic implications in restoring glucose availability in tissues such as the skeletal muscle.

Animals↗
PubMed1998

Vitamin E and lipoic acid, but not vitamin C improve blood oxygenation after high-energy IMPULSE noise (BLAST) exposure.

Exposure to high energy impulse noise (BLAST) caused by explosions, result in structural and functional damage to the hollow organs, especially to the respiratory and auditory systems. Lung damage includes alveolar wall rupture, edema and hemorrhage, and may be fatal. Previous observations at the molecular level using the rat model, suggested that secondary free radical-mediated oxidative stress occurs post exposure resulting in antioxidant depletion and hemoglobin (Hb) oxidation. This study examined whether a short period of pre-exposure supplementation with antioxidants would protect Hb from the effects of BLAST exposure. Six groups of male Sprague-Dawley rats (8/group) were gavaged with 800 IU vitamin E (VE) in 2 ml corn oil, 1000 mg vitamin C (VC) in 2 ml distilled water or 25 mg or (-lipoic acid (LA) in 2 ml corn oil for 3 days. Matched control groups were gavaged with the respective vehicles. On day 4, rats were deeply anesthetized and exposed to a simulated BLAST wave with an average peak pressure of 62 +/- 2 kPa. Rats were euthanized one hour post exposure and blood samples were obtained by cardiac puncture and analyzed using a hemoximeter. Post exposure oxygenation states (HbO2, O2 saturation, and O2 content) were markedly decreased, while reduced-Hb was increased. Supplementation with VE and LA reversed the trend and increased Hb oxygenation, but VC did not. This suggests that a brief dietary loading with pharmacological doses of VE or LA, but not VC shortly before BLAST exposure may be beneficial. Moreover, measurement of blood oxygenation may function as a simple semi-invasive biomarker of BLAST-induced injury applicable to humans.

Animals↗
PubMed2003

Vascular endothelial dysfunction in aging: loss of Akt-dependent endothelial nitric oxide synthase phosphorylation and partial restoration by (R)-alpha-lipoic acid.

Aging is the single largest risk factor for cardiovascular diseases, which in turn are the leading cause of death of individuals over the age of 65 years. In part, this risk is due to a profound loss of vasomotor function of the major conduit arteries, primarily because of lower levels of endothelial-derived nitric oxide. The mechanisms involved in vascular dysfunction are not entirely understood, but age-related alterations in eNOS (endothelial nitric oxide synthase) activity appear to be a likely source of the aging lesion. However, age-related changes in cell signalling that ultimately affect eNOS phosphorylation and its activity have not been explored. Results in our laboratory indicate that levels of eNOS phosphorylation in aortas from aged F344xBN rats (28-30 months old) are almost 50% lower than in aortas from young animals (3 months old). Lower eNOS phosphorylation is directly attributable to loss of constitutive Akt/protein kinase B activity. The decline in eNOS phosphorylation can be partially restored by treating old rats with (R)-alpha-lipoic acid. These results thus suggest that age-related changes in eNOS phosphorylation may be a significant factor in the overall loss of vasomotor function in the elderly.

Aging↗
PubMed2004

Decline in transcriptional activity of Nrf2 causes age-related loss of glutathione synthesis, which is reversible with lipoic acid.

Glutathione (GSH) significantly declines in the aging rat liver. Because GSH levels are partly a reflection of its synthetic capacity, we measured the levels and activity of gamma-glutamylcysteine ligase (GCL), the rate-controlling enzyme in GSH synthesis. With age, both the catalytic (GCLC) and modulatory (GCLM) subunits of GCL decreased by 47% and 52%, respectively (P < 0.005). Concomitant with lower subunit levels, GCL activity also declined by 53% (P < 0.05). Because nuclear factor erythroid2-related factor 2 (Nrf2) governs basal and inducible GCLC and GCLM expression by means of the antioxidant response element (ARE), we hypothesized that aging results in dysregulation of Nrf2-mediated GCL expression. We observed an approximately 50% age-related loss in total (P < 0.001) and nuclear (P < 0.0001) Nrf2 levels, which suggests attenuation in Nrf2-dependent gene transcription. By using gel-shift and supershift assays, a marked reduction in Nrf2/ARE binding in old vs. young rats was noted. To determine whether the constitutive loss of Nrf2 transcriptional activity also affects the inducible nature of Nrf2 nuclear translocation, old rats were treated with (R)-alpha-lipoic acid (LA; 40 mg/kg i.p. up to 48 h), a disulfide compound shown to induce Nrf2 activation in vitro and improve GSH levels in vivo. LA administration increased nuclear Nrf2 levels in old rats after 12 h. LA also induced Nrf2 binding to the ARE, and, consequently, higher GCLC levels and GCL activity were observed 24 h after LA injection. Thus, the age-related loss in GSH synthesis may be caused by dysregulation of ARE-mediated gene expression, but chemoprotective agents, like LA, can attenuate this loss.

Aging↗
PubMed2001

Effect of DL-alpha-lipoic acid on glutathione metabolic enzymes in aged rats.

Ageing is characterized by a failure to maintain homeostasis under conditions of physiological stress, with an increasing susceptibility to disease and death. The accumulation of errors committed by faulty biochemical reactions over a vast period generates the cumulative effect observed during ageing. The most notable among the effects of ageing are the age-related disorders where free radicals are the major cause. When the level of free radicals increases because of diet, lifestyle, environment or other influences, it results in subsequent reduction of antioxidants. Reduced glutathione is one of the most fascinating molecules virtually present in all animal cells in often quite higher concentrations. An essential mechanism that accounts for most of the metabolic and cell regulatory properties of glutathione is the thiol disulfide exchange equilibria. We evaluated the age-associated alterations in glutathione dependent enzymes, glutathione and hydroxyl radicals in young and aged rats with respect to lipoate supplementation. In aged rats, activities of glutathione peroxidase, glutathione reductase, glutathione-S-transferase and glucose-6-phosphate dehydrogenase and the level of glutathione were low, whereas the level of hydroxyl radical was higher than in the young ones. Administration of DL-alpha-lipoic acid, a thiol antioxidant intraperitoneally to the aged rats, led to a time-dependent reduction in hydroxyl radicals and elevation in the activities/level of glutathione systems. Hence it can be suggested that lipoate, a dithiol prevents the oxidation of reduced glutathione and protects its related enzymes from peroxidative damage.

Aging↗
PubMed2004

Alpha-lipoic acid mitigates insulin resistance in Goto-Kakizaki rats.

Impaired glucose uptake and metabolism by peripheral tissues is a common feature in both type I and type II diabetes mellitus. This phenomenon was examined in the context of oxidative stress and the early events within the insulin signalling pathway using soleus muscles derived from non-obese, insulin-resistant type II diabetic Goto-Kakizaki (GK) rats, a well-known genetic rat model for human type II diabetes. Insulin-stimulated glucose transport was impaired in soleus muscle from GK rats. Oxidative and non-oxidative glucose disposal pathways represented by glucose oxidation and glycogen synthesis in soleus muscles of GK rats appear to be resistant to the action of insulin when compared to their corresponding control values. These diabetes-related abnormalities in glucose disposal were associated with a marked diminution in the insulin-mediated enhancement of protein kinase B (Akt/PKB) and insulin receptor substrate-1 (IRS-1)-associated phosphatidylinostol 3-kinase (PI 3-kinase) activities; these two kinases are key elements in the insulin signalling pathway. Moreover, heightened state of oxidative stress, as indicated by protein bound carbonyl content, was evident in soleus muscle of GK diabetic rats. Chronic administration of the hydrophobic/hydrophilic antioxidant alpha -lipoic-acid (ALA, 100 mg/kg, i.p.) partly ameliorated the diabetes-related deficit in glucose metabolism, protein oxidation as well as the activation by insulin of the various steps of the insulin signalling pathway, including the enzymes Akt/PKB and PI-3 kinase. Overall, the current investigation illuminates the concept that oxidative stress may indeed be involved in the pathogenesis of certain types of insulin resistance. It also harmonizes with the notion of including potent antioxidants such as ALA in the armamentarium of antidiabetic therapy.

Animals↗
PubMed1990

Primary biliary cirrhosis. Inhibition of pyruvate dehydrogenase complex activity by autoantibodies specific for E1 alpha, a non-lipoic acid containing mitochondrial enzyme.

Antimitochondrial antibodies (AMA) are serologically characteristic of patients with PBC. Four Ag recognized by AMA have been recently identified, including protein X and the acyltransferases of three related multienzyme complexes: the pyruvate dehydrogenase complex (PDC), the branched-chain alpha-ketoacid dehydrogenase complex, and the alpha-ketoglutarate dehydrogenase complex. Each of these enzymes contains one or more lipoyl moieties as part of a major functional site. In addition, epitope mapping has suggested that the AMA target is this lipoic acid-binding region. In this report we demonstrate that sera from patients with PBC also recognize the E1 component (pyruvate dehydrogenase, EC 1.2.4.1) of PDC. PDC-E1 is composed of alpha and beta-chains. Reactivity with the 41 kD alpha chain was detected in 80 of 120 (66%) PBC sera by immunoblotting against purified PDC-E1; 2 of 120 sera also demonstrated reactivity with the 34 kD beta chain. In contrast, sera from patients with SLE, chronic active hepatitis, or progressive sclerosing cholangitis as well as sera from healthy volunteers did not react with PDC-E1. Furthermore, affinity-purified PBC sera against PDC-E1 alpha were able to inhibit PDC enzyme activity, whereas control sera could not. PDC-E1 alpha is now the fifth mitochondrial autoantigen of PBC to be identified. Similar to the four previously identified autoantigens, AMA appear to be directed to a functional site of PDC-E1 alpha inasmuch as they are able to inhibit enzyme function. However, PDC-E1 alpha is also unique in that it is the first identified mitochondrial autoantigen which does not contain lipoic acid.

Antigen-Antibody Reactions↗