Protection of mitochondrial integrity from oxidative stress by the triaminopyridine derivative flupirtine

The suitability of the triaminopyridine derivative flupirtine, an analgesic drug with antioxidative property [Gassen, M., Pergande, G, and Youdim, M.B.H. (1998) Biochem, Pharmacol, 56, 132-1329], for the preservation of mitochondrial integrity from oxidative stress-inducted damage was studied. Rat liver mitochondria were exposed to strong oxidative stress as generated by Fe2+ plus ascorbate, Peroxidation damage of membrane lipids was followed by the measurement of thiobarbituric acid reactive substances. Protein oxidation was estimated by electron spin resonance spectroscopy, after labeling of the 'peroxidized' mitochondria with 4-maleimido-2,2,6,6-tetra-methylpiperidine-1-oxyl. We found that (i) low concentrations of flupirtine (10 mu M) protect lipids and also proteins (with lesser efficiency) from attacks of reactive oxygen species; (ii) flupirtine remarkably delayed the decline of complex mitochondrial functions, such as the respiratory control or the Ca2+ retention capacity of mitochondria, under oxidative stress; and (iii) the ADP/ATP antiporter (ANT), a main component of the oxidative phosphorylation machinery as well as a core component of the permeability transition pore complex, seems to be a membrane protein particularly protected by flupirtine, In conclusion, the preservation of the Ca2+ buffer capacity of mitochondria and of the ANT activity against oxidative stress supports an anti-apoptotic application of flupirtine, (C) 2000 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.