This impressive array of cellular and molecular functions has raised considerable interest for the use of this substance as a nutritive supplement and also as a therapeutic agent. Unlike GSH, for which only the reduced form is an antioxidant, both the oxidized and reduced forms of LA are powerful antioxidants whose functions include: (1) quenching of reactive oxygen species (ROS), (2) regeneration of exogenous and endogenous antioxidants such as vitamins C and E, and GSH, (3) chelation of metal ions, and (4) reparation of oxidized proteins (5) regulation of gene transcription (6) inhibition of the activation of nuclear factor kapp B (NF-κB Biewenga et al., 1997 Packer, 1998 Zhang and Frei, 2001 Figure 1). In cells containing mitochondria, ALA is reduced in an NADH-dependent reaction with lipoamide dehydrogenase to form dihydrolipoic acid (DHLA), whereas in cells that lack mitochondria, ALA can instead be reduced to DHLA via NADPH with glutathione (GSH) and thioredoxin reductases ( Jones et al., 2002). However, synthetic LA is a racemic mixture of R and S isoforms, where S-LA can prevent the polymerization of R-LA to enhance its bioavailability ( Shay et al., 2009). Only the naturally occurring R isomer is bound to protein and acts as an essential cofactor in biological systems ( Reed, 1998). The presence of an asymmetric carbon produces two optical isomers R-LA and S-LA. ALA acts as a cofactor for pyruvate dehydrogenase and α-keto-glutarate dehydrogenase activity ( Schmidt et al., 1994), and is also required for the oxidative decarboxylation of pyruvate to acetyl-CoA, a critical step bridging glycolysis and the citric acid cycle ( Reed, 1998). It is synthesized enzymatically in plant and animal mitochondria from octanoic acid and cysteine (as a sulfur source). ![]() Lipoic acid (LA) or α-lipoic acid (ALA) is a naturally occurring compound that is also known as 1,2-dithiolane-3-pentanoic acid or thioctic acid ( Busby et al., 1999). It appears that the clearest benefit of lipoic acid supplementation is in patients with diabetic neuropathy. The findings of some of the clinical trials in which lipoic acid administration has been tested in diabetic patients during the last 10 years are summarized. In this review we briefly summarize the known biochemical properties of lipoic acid and then discussed the oxidative mechanisms implicated in diabetic complications and the mechanisms by which lipoic acid may ameliorate these reactions. These diverse actions suggest that lipoic acid acts by multiple mechanisms, many of which have only been uncovered recently. ALA inhibits nuclear factor kappa B and activates AMPK in skeletal muscles, which in turn have a plethora of metabolic consequences. It also boosts antioxidant defense system through Nrf-2-mediated antioxidant gene expression and by modulation of peroxisome proliferator activated receptors-regulated genes. Lipoic acid quenches reactive oxygen species, chelates metal ions, and reduces the oxidized forms of other antioxidants such as vitamin C, vitamin E, and glutathione. Alpha lipoic acid, a naturally occurring dithiol compound which plays an essential role in mitochondrial bioenergetic reactions, has gained considerable attention as an antioxidant for use in managing diabetic complications. ![]() ![]() This has prompted several investigations into the use of antioxidants as a complementary therapeutic approach. Department of Pharmacology and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canadaĭiabetes mellitus is a multi-faceted metabolic disorder where there is increased oxidative stress that contributes to the pathogenesis of this debilitating disease.
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