Effect of coenzyme Q10 and vitamin E on brain energy metabolism in the animal model of Huntington's disease.
The neuropathological and clinical symptoms of Huntington's disease (HD) can be simulated in animal model with systemic administration of 3-nitropropionic acid (3-NP). Energy defects in HD could be ameliorated by administration of coenzyme Q(10) (CoQ(10)), creatine, or nicotinamid. We studied the activity of creatine kinase (CK) and the function of mitochondrial respiratory chain in the brain of aged rats administered with 3-NP with and without previous application of antioxidants CoQ(10)+vitamin E. We used dynamic and steady-state methods of in vivo phosphorus magnetic resonance spectroscopy ((31)P MRS) for determination of the pseudo-first order rate constant (k(for)) of the forward CK reaction, the phosphocreatine (PCr) to adenosinetriphosphate (ATP) ratio, intracellular pH(i) and Mg(i)(2+) content in the brain. The respiratory chain function of isolated mitochondria was assessed polarographically; the concentration of CoQ(10) and alpha-tocopherol by HPLC. We found significant elevation of k(for) in brains of 3-NP rats, reflecting increased rate of CK reaction in cytosol. The function of respiratory chain in the presence of succinate was severely diminished. The activity of cytochromeoxidase and mitochondrial concentration of CoQ(10) was unaltered; tissue content of CoQ(10) was decreased in 3-NP rats. Antioxidants CoQ(10)+vitamin E prevented increase of k(for) and the decrease of CoQ(10) content in brain tissue, but were ineffective to prevent the decline of respiratory chain function. We suppose that increased activity of CK system could be compensatory to decreased mitochondrial ATP production, and CoQ(10)+vitamin E could prevent the increase of k(for) after 3-NP treatment likely by activity of CoQ(10) outside the mitochondria. Results of our experiments contributed to elucidation of mechanism of beneficial effect of CoQ(10) administration in HD and showed that the rate constant of CK is a sensitive indicator of brain energy disorder reflecting therapeutic effect of drugs that could be used as a new in vivo biomarker of neurodegenerative diseases.
Kasparová
Svatava
S
Central Laboratory of NMR Spectroscopy, Faculty of Chemical and Food Technology, Slovak University of Technology, Bratislava, Radlinského 9, SK-812 37 Bratislava, Slovakia. kasparov@cvt.stuba.sk
Sumbalová
Zuzana
Z
Bystrický
Peter
P
Kucharská
Jarmila
J
Liptaj
Tibor
T
Mlynárik
Vladimír
V
Gvozdjáková
Anna
A
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000201:enzymology / Q000378:metabolism*; D003067:Coenzymes; D003402:Creatine Kinase / Q000378:metabolism; D004195:Disease Models, Animal; D003576:Electron Transport Complex IV / Q000378:metabolism; D004734:Energy Metabolism; D006816:Huntington Disease / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D010085:Oxidative Phosphorylation; D010725:Phosphocreatine / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000494:pharmacology; D014810:Vitamin E / Q000494:pharmacology*
D003067:Coenzymes; D010725:Phosphocreatine; D014451:Ubiquinone; D014810:Vitamin E; D000255:Adenosine Triphosphate; D003576:Electron Transport Complex IV; D003402:Creatine Kinase; C024989:coenzyme Q10