Abstract

This is a proposal to investigate the mechanisms by which alpha-lipoic acid prevents changes in cellular redox balance and oxidative damage during oxidative stress. Lipoic acid displays antioxidant effects in vitro and protects against oxidative damage in animal models in vivo. The hypothesis to be tested is that lipoic acid maintains cellular redox balance by acting directly as an antioxidant, by regenerating other cellular antioxidants, and by raising cellular glutathione levels. The first specific aim is to determine how lipoic acid is reduced to the more potent cellular antioxidant dihydrolipoic acid. Studies with cultured cells, subcellular fractions, and purified enzymes are proposed.
The second aim i s to determine the effective concentrations of lipoic acid in vivo. Analyses of lipoic acid and dihydrolipoic acid biokinetics and tissue concentrations are proposed.
The third aim i s to determine how lipoic acid interacts with other cellular antioxidants. This will be addressed by antioxidant turnover studies in vivo.
The fourth aim will employ cell culture studies to determine how lipoic acid increases cellular glutathione. The fifth aim will employ cell culture studies to determine how lipoic acid influences redox sensitive signal transduction pathways. It is proposed that this information will be useful in the study of diseases where glutathione levels are depressed, such as AIDS.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK050430-02
Application #
2458909
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1996-08-01
Project End
1999-07-31
Budget Start
1997-08-01
Budget End
1998-07-31
Support Year
2
Fiscal Year
1997
Total Cost
Indirect Cost

  Institution

Name
University of California Berkeley
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
094878337
City
Berkeley
State
CA
Country
United States
Zip Code
94704

  Publications

Tirosh, O; Guo, Q; Sen, C K et al. (2001) Mitochondrial control of inducible nitric oxide production in stimulated RAW 264.7 macrophages. Antioxid Redox Signal 3:711-9
Korotchkina, L G; Yang, H; Tirosh, O et al. (2001) Protection by thiols of the mitochondrial complexes from 4-hydroxy-2-nonenal. Free Radic Biol Med 30:992-9
Tirosh, O; Sen, C K; Roy, S et al. (2000) Cellular and mitochondrial changes in glutamate-induced HT4 neuronal cell death. Neuroscience 97:531-41
Sen, C K; Packer, L (2000) Thiol homeostasis and supplements in physical exercise. Am J Clin Nutr 72:653S-69S
Hong, Y S; Jacobia, S J; Packer, L et al. (1999) The inhibitory effects of lipoic compounds on mammalian pyruvate dehydrogenase complex and its catalytic components. Free Radic Biol Med 26:685-94
Sen, C K (1999) Glutathione homeostasis in response to exercise training and nutritional supplements. Mol Cell Biochem 196:31-42
Tirosh, O; Sen, C K; Roy, S et al. (1999) Neuroprotective effects of alpha-lipoic acid and its positively charged amide analogue. Free Radic Biol Med 26:1418-26
Marangon, K; Devaraj, S; Tirosh, O et al. (1999) Comparison of the effect of alpha-lipoic acid and alpha-tocopherol supplementation on measures of oxidative stress. Free Radic Biol Med 27:1114-21
Saliou, C; Kitazawa, M; McLaughlin, L et al. (1999) Antioxidants modulate acute solar ultraviolet radiation-induced NF-kappa-B activation in a human keratinocyte cell line. Free Radic Biol Med 26:174-83
Khanna, S; Roy, S; Packer, L et al. (1999) Cytokine-induced glucose uptake in skeletal muscle: redox regulation and the role of alpha-lipoic acid. Am J Physiol 276:R1327-33

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