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, 1323-1329], for the preservation of mitochondrial integrity from oxidative stress-induced damage was studied. Rat liver mitochondria were exposed to strong oxidative stress as generated by Fe(2+) 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-tetramethylpiperidine-1-oxyl. We found that (i) low concentrations of flupirtine (10 microM) 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 Ca(2+) 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 Ca(2+) buffer capacity of mitochondria and of the ANT activity against oxidative stress supports an antiapoptotic application of flupirtine.
Schlüter
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Institute for Biochemistry, Medical Faculty, Otto-von-Guericke-University, Magdeburg, Germany.
Struy
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Schönfeld
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D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D017920:Antiporters / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001205:Ascorbic Acid / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D019069:Cell Respiration / Q000187:drug effects; D004578:Electron Spin Resonance Spectroscopy; D005260:Female; D017665:Hydroxyl Radical / Q000378:metabolism; D007473:Ion Channels; D007501:Iron / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008563:Membrane Lipids / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D016877:Oxidants / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D010085:Oxidative Phosphorylation / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D013113:Spin Labels; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
D000631:Aminopyridines; D017920:Antiporters; D007473:Ion Channels; D008563:Membrane Lipids; D008565:Membrane Proteins; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D016877:Oxidants; D017382:Reactive Oxygen Species; D013113:Spin Labels; D017392:Thiobarbituric Acid Reactive Substances; D017665:Hydroxyl Radical; D007501:Iron; C034161:flupirtine; D001205:Ascorbic Acid; D002118:Calcium