Mitochondria-Targeted Plastoquinone Derivatives as Tools to Interrupt Execution of the Aging Program.
2. Treatment of Some ROS- and Age-Related Diseases (Heart Arrhythmia, Heart Infarctions, Kidney Ischemia, and Stroke)

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L. E. Bakeeva¹, I. V. Barskov², M. V. Egorov³, N. K. Isaev^1,2, V. I. Kapelko⁴, A. V. Kazachenko⁵, V. I. Kirpatovsky⁵, S. V. Kozlovsky³, V. L. Lakomkin⁴, S. B. Levina², O. I. Pisarenko⁴, E. Y. Plotnikov¹, V. B. Saprunova¹, L. I. Serebryakova⁴, M. V. Skulachev³, E. V. Stelmashook², I. M. Studneva⁴, O. V. Tskitishvili⁴, A. K. Vasilyeva¹, I. V. Victorov⁶, D. B. Zorov¹, and V. P. Skulachev^1,3,7*

¹Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia; fax: (495) 939-0338; E-mail: skulach@belozersky.msu.ru

²Department of Brain Research, Institute of Neurology, Russian Academy of Medical Sciences, Pereulok Obukha 5, 105064 Moscow, Russia

³Center for Mitoengineering, Lomonosov Moscow State University, 119991 Moscow, Russia

⁴Institute of Experimental Cardiology, Cardiology Research Center, 3-ya Cherepkovskaya ul. 15A, 121552 Moscow, Russia

⁵Institute of Urology, 3-ya Parkovaya ul. 51, 105425 Moscow, Russia

⁶Serbsky State Research Center of Social and Forensic Psychiatry, Kropotkinsky Pereulok 23, 119992 Moscow, Russia

⁷Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119991 Moscow, Russia

^* To whom correspondence should be addressed.

Received December 29, 2007; Revision received August 14, 2008

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Effects of 10-(6´-plastoquinonyl) decyltriphenylphosphonium (SkQ1) and 10-(6´-plastoquinonyl) decylrhodamine 19 (SkQR1) on rat models of H₂O₂- and ischemia-induced heart arrhythmia, heart infarction, kidney ischemia, and stroke have been studied ex vivo and in vivo. In all the models listed, SkQ1 and/or SkQR1 showed pronounced protective effect. Supplementation of food with extremely low SkQ1 amount (down to 0.02 nmol SkQ1/kg per day for 3 weeks) was found to abolish the steady heart arrhythmia caused by perfusion of isolated rat heart with H₂O₂ or by ischemia/reperfusion. Higher SkQ1 (125-250 nmol/kg per day for 2-3 weeks) was found to decrease the heart infarction region induced by an in vivo ischemia/reperfusion and lowered the blood levels of lactate dehydrogenase and creatine kinase increasing as a result of ischemia/reperfusion. In single-kidney rats, ischemia/reperfusion of the kidney was shown to kill the majority of the animals in 2-4 days, whereas one injection of SkQ1 or SkQR1 (1 µmol/kg a day before ischemia) saved lives of almost all treated rats. Effect of SkQR1 was accompanied by decrease in ROS (reactive oxygen species) level in kidney cells as well as by partial or complete normalization of blood creatinine and of some other kidney-controlled parameters. On the other hand, this amount of SkQ1 (a SkQ derivative of lower membrane-penetrating ability than SkQR1) saved the life but failed to normalize ROS and creatinine levels. Such an effect indicates that death under conditions of partial kidney dysfunction is mediated by an organ of vital importance other than kidney, the organ in question being an SkQ1 target. In a model of compression brain ischemia/reperfusion, a single intraperitoneal injection of SkQR1 to a rat (1 µmol/kg a day before operation) effectively decreased the damaged brain area. SkQ1 was ineffective, most probably due to lower permeability of the blood-brain barrier to this compound.

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KEY WORDS: mitochondria-targeted antioxidant, plastoquinone, arrhythmia, heart, kidney, infarction, stroke

DOI: 10.1134/S000629790812002X

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