Inhibitory effect of alpha-lipoic acid and its positively charged amide analogue on nitric oxide production in RAW 264.7 macrophages.
The aim of this study was to investigate the effect of the mitochondrial cofactor alpha-lipoic acid [R (+) LA] or its lipoamide analogue, 2-(N,N-dimethylamine) ethylamido lipoate [R (+) LA-plus], on nitric oxide (NO) production in RAW 264.7 macrophages. NO production from RAW 264.7 cells stimulated with 10 microg/mL of lipopolysaccharide and 50 U/mL of interferon-gamma was measured directly by electron spin resonance using spin-trapping techniques. R (+) LA or R (+) LA-plus was found to inhibit NO production at pharmacologically relevant concentrations. However, in a cell-free chemical system, neither R (+) LA nor R (+) LA-plus was able to directly scavenge NO. Furthermore, in the presence of 2.5 or 25 mM glucose, the inhibitory effects of R (+) LA and R (+) LA-plus on NO production were decreased markedly, while they showed more potent inhibitory effects in the presence of 2 microM rotenone or 5 microg/mL of antimycin A, inhibitors of mitochondrial complex I and complex III, respectively. Glucose, rotenone, or antimycin A alone resulted in an increase of NO production. These results suggest that NO production in macrophages can be regulated by glucose and mitochondrial respiration, and that modulation of NO production by lipoic acid or lipoamide analogues in inflammatory situations is attributed not to their radical scavenging activity but to their redox properties.
Department of Molecular and Cell Biology, University of California, 251 Life Sciences Addition, Berkeley, CA 94720-3200, USA.
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D000577:Amides / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002460:Cell Line; D004347:Drug Interactions; D004578:Electron Spin Resonance Spectroscopy; D016166:Free Radical Scavengers / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D010084:Oxidation-Reduction; D008063:Thioctic Acid / Q000494:pharmacology*
D000577:Amides; D000975:Antioxidants; D016166:Free Radical Scavengers; D009569:Nitric Oxide; D008063:Thioctic Acid; D005947:Glucose