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Research Articles
Alpha-Lipoic Acid
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Toxicol Appl Pharmacol 2002 Jul
1;182(1):84-90 |
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Antioxidant and prooxidant activities of alpha-lipoic acid and
dihydrolipoic acid.
Moini H, Packer L, Saris NE.
Department of Applied Chemistry and Microbiology, PB 56 Viikki
Biocenter, FIN-00014, University of Helsinki, Helsinki, Finland.
hmoini@usc.edu
Reactive oxygen (ROS) and nitrogen oxide (RNOS) species are produced
as by-products of oxidative metabolism. A major function for ROS and
RNOS is immunological host defense. Recent evidence indicate that
ROS and RNOS may also function as signaling molecules. However, high
levels of ROS and RNOS have been considered to potentially damage
cellular macromolecules and have been implicated in the pathogenesis
and progression of various chronic diseases. alpha-Lipoic acid and
dihydrolipoic acid exhibit direct free radical scavenging properties
and as a redox couple, with a low redox potential of -0.32 V, is a
strong reductant. Several studies provided evidence that alpha-lipoic
acid supplementation decreases oxidative stress and restores reduced
levels of other antioxidants in vivo. However, there is also
evidence indicating that alpha-lipoic acid and dihydrolipoic acid
may exert prooxidant properties in vitro. alpha-Lipoic acid and
dihydrolipoic acid were shown to promote the mitochondrial
permeability transition in permeabilized hepatocytes and isolated
rat liver mitochondria. Dihydrolipoic acid also stimulated
superoxide anion production in rat liver mitochondria and
submitochondrial particles. alpha-Lipoic acid was recently shown to
stimulate glucose uptake into 3T3-L1 adipocytes by increasing
intracellular oxidant levels and/or facilitating insulin receptor
autophosphorylation presumably by oxidation of critical thiol groups
present in the insulin receptor beta-subunit. Whether alpha-lipoic
acid and/or dihydrolipoic acid-induced oxidative protein
modifications contribute to their versatile effects observed in vivo
warrants further investigation.
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Free Radic Biol Med 1999
Nov;27(9-10):1114-21 |
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Comparison of the effect of alpha-lipoic acid and alpha-tocopherol
supplementation on measures of oxidative stress.
Marangon K, Devaraj S, Tirosh O, Packer L, Jialal I.
Department of Pathology, University of Texas Southwestern Medical
Center at Dallas, 75235-9073, USA.
In vitro studies have shown that alpha-lipoic acid (LA) is an
antioxidant. There is a paucity of studies on LA supplementation in
humans. Therefore, the aim of this study was to assess the effect of
oral supplementation with LA alone and in combination with alpha-tocopherol
(AT) on measures of oxidative stress. A total of 31 healthy adults
were supplemented for 2 months either with LA (600 mg/d, n = 16), or
with AT (400 IU/d, n = 15) alone, and then with the combination of
both for 2 additional months. At baseline, after 2 and 4 months of
supplementation, urine for F2-isoprostanes, plasma for protein
carbonyl measurement and low-density lipoprotein (LDL) oxidative
susceptibility was collected. Plasma oxidizability was assessed
after incubation with 100 mM 2,2'-azobis (2-amidinopropane)
hydrochloride (AAPH) for 4 h at 37 degrees C. LDL was subjected to
copper- and AAPH-catalyzed oxidation at 37 degrees C over 5 h and
the lag time was computed. LA significantly increased the lag time
of LDL lipid peroxide formation for both copper-catalyzed and AAPH-induced
LDL oxidalion (p < .05), decreased urinary F2-isoprostanes levels (p
< .05), and plasma carbonyl levels after AAPH oxidation (p < .001).
AT prolonged LDL lag time of lipid peroxide formation (p < .01 ) and
conjugated dienes (p < .01) after copper-catalyzed LDL oxidation,
decreased urinary F2-isoprostanes (p < .001), but had no effect on
plasma carbonyls. The addition of LA to AT did not produce an
additional significant improvement in the measures of oxidative
stress. In conclusion, LA supplementation functions as an
antioxidant, because it decreases plasma- and LDL-oxidation and
urinary isoprostanes.
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Free Radic Biol Med 1998
Apr;24(6):1023-39 |
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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.
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.
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Diabetes Care 1995
Aug;18(8):1160-7 |
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Lipoic acid improves nerve blood flow, reduces oxidative stress,
and improves distal nerve conduction in experimental diabetic
neuropathy.
Nagamatsu M, Nickander KK, Schmelzer JD, Raya A, Wittrock DA,
Tritschler H, Low PA.
Department of Neurology, Mayo Foundation, Rochester, Minnesota
55905, USA.
OBJECTIVE--To determine whether lipoic acid (LA) will reduce
oxidative stress in diabetic peripheral nerves and improve
neuropathy. RESEARCH DESIGN AND METHODS--We used the model of
streptozotocin-induced diabetic neuropathy (SDN) and evaluated the
efficacy of LA supplementation in improving nerve blood flow (NBF),
electrophysiology, and indexes of oxidative stress in peripheral
nerves affected by SDN, at 1 month after onset of diabetes and in
age-matched control rats. LA, in doses of 20, 50, and 100 mg/kg, was
administered intraperitoneally five times per week after onset of
diabetes. RESULTS--NBF in SDN was reduced by 50%; LA did not affect
the NBF of normal nerves but improved that of SDN in a
dose-dependent manner. After 1 month of treatment, LA-supplemented
rats (100 mg/kg) exhibited normal NBF. The most sensitive and
reliable indicator of oxidative stress was reduction in reduced
glutathione, which was significantly reduced in streptozotocin-induced
diabetic and alpha-tocopherol-deficient nerves; it was improved in a
dose-dependent manner in LA-supplemented rats. The conduction
velocity of the digital nerve was reduced in SDN and was
significantly improved by LA. CONCLUSIONS--These studies suggest
that LA improves SDN, in significant part by reducing the effects of
oxidative stress. The drug may have potential in the treatment of
human diabetic neuropathy.
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Can J Appl Physiol 2001;26
Suppl:S4-12 |
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Update on thiol status and supplements in physical exercise.
Sen CK.
Laboratory of Molecular Medicine, Department of Surgery, 512 Heart
and Lung Research Institute, The Ohio State University Medical
Center, Columbus, OH 43210, USA.
Strenuous physical exercise represents a condition that is often
associated with increased production of reactive oxygen species in
various tissues. One of the most reliable indices of
exercise-induced oxidant production is tissue glutathione oxidation.
In humans, exercise-induced blood glutathione oxidation is rapid and
subject to control by antioxidant supplementation. The objective of
this brief review is to provide an update of our current
understanding of cellular thiols and thiol antioxidants. Cellular
thiols are critically important in maintaining the cellular
antioxidant defense network. In addition, thiols play a key role in
regulating redox-sensitive signal transduction process. Lipoic acid
is a highly promising thiol antioxidant supplement. Recent studies
have clarified that while higher levels of oxidants may indeed
inflict oxidative damage, oxidants are not necessarily deleterious.
Under certain conditions oxidants may function as cellular
messengers that regulate a multitude of signal transduction
pathways. In light of this, the significance of oxidants in various
aspects of biology needs to be revisited.
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