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Y N Antonenko,
A V Avetisyan,
L E Bakeeva,
B V Chernyak,
V A Chertkov,
L V Domnina,
O Yu Ivanova,
D S Izyumov,
L S Khailova,
S S Klishin, [......],
I V Skulachev,
M V Skulachev,
N V Sumbatyan,
I V Sviryaeva,
V N Tashlitsky,
J M Vassiliev,
M Yu Vyssokikh,
L S Yaguzhinsky,
A A Zamyatnin, V P Skulachev
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Y N Antonenko,
A V Avetisyan,
L E Bakeeva,
B V Chernyak,
V A Chertkov,
L V Domnina,
O Yu Ivanova,
D S Izyumov,
L S Khailova,
S S Klishin, [......],
I V Skulachev,
M V Skulachev,
N V Sumbatyan,
I V Sviryaeva,
V N Tashlitsky,
J M Vassiliev,
M Yu Vyssokikh,
L S Yaguzhinsky,
A A Zamyatnin, V P Skulachev
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[show abstract]
[hide abstract]
ABSTRACT: A protective effect of a mitochondria-targeted antioxidant, a cationic rhodamine derivative linked to a plastoquinone molecule (10-(6'-plastoquinonyl)decylrhodamine-19, SkQR1) was studied in the model of open focal trauma of rat brain sensorimotor cortex. It was found that daily intraperitoneal injections of SkQR1 (100 nmol/kg) for 4 days after the trauma improved performance in a test characterizing neurological deficit and decreased the volume of the damaged cortical area. Our results suggest that SkQR1 exhibits profound neuroprotective effect, which may be explained by its antioxidative activity.
Biochemistry (Moscow) 09/2012; 77(9):996-9. · 1.06 Impact Factor
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E Y Plotnikov,
D N Silachev,
S S Jankauskas,
T I Rokitskaya,
A A Chupyrkina,
I B Pevzner,
L D Zorova,
N K Isaev,
Y N Antonenko, V P Skulachev,
D B Zorov
[show abstract]
[hide abstract]
ABSTRACT: It is generally accepted that mitochondrial production of reactive oxygen species is nonlinearly related to the value of the mitochondrial membrane potential with significant increment at values exceeding 150 mV. Due to this, high values of the membrane potential are highly dangerous, specifically under pathological conditions associated with oxidative stress. Mild uncoupling of oxidative phosphorylation is an approach to preventing hyperpolarization of the mitochondrial membrane. We confirmed data obtained earlier in our group that dodecylrhodamine 19 (C(12)R1) (a penetrating cation from SkQ family not possessing a plastoquinone group) has uncoupling properties, this fact making it highly potent for use in prevention of pathologies associated with oxidative stress induced by mitochondrial hyperpolarization. Further experiments showed that C(12)R1 provided nephroprotection under ischemia/reperfusion of the kidney as well as under rhabdomyolysis through diminishing of renal dysfunction manifested by elevated level of blood creatinine and urea. Similar nephroprotective properties were observed for low doses (275 nmol/kg) of the conventional uncoupler 2,4-dinitrophenol. Another penetrating cation that did not demonstrate protonophorous activity (SkQR4) had no effect on renal dysfunction. In experiments with induced ischemic stroke, C(12)R1 did not have any effect on the area of ischemic damage, but it significantly lowered neurological deficit. We conclude that beneficial effects of penetrating cation derivatives of rhodamine 19 in renal pathologies and brain ischemia may be at least partially explained by uncoupling of oxidation and phosphorylation.
Biochemistry (Moscow) 09/2012; 77(9):1029-37. · 1.06 Impact Factor
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[show abstract]
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ABSTRACT: Using dialkylphospholipid (diphytanyl phosphatidylcholine) instead of the conventional diacylphospholipid (diphytanoyl phosphatidylcholine) in planar lipid bilayer membranes (BLM) led to an increase in the diffusion potential of the penetrating cation plastoquinonyl-decyl-triphenylphosphonium (SkQ1), making it close to the Nernst value, and accelerated translocation of SkQ1 across the BLM as monitored by the kinetics of a decrease in the transmembrane electric current after applying a voltage (current relaxation). The consequences of changing from an ester to an ether linkage between the head groups and the hydrocarbon chains are associated with a substantial reduction in the membrane dipole potential known to originate from dipoles of tightly bound water molecules and carbonyl groups in ester bonds. The difference in the dipole potential between BLM formed of the ester phospholipid and that of the ether phospholipid was estimated to be 100 mV. In the latter case, suppression of SkQ1-mediated proton conductivity of the BLM was also observed.
Biochemistry (Moscow) 09/2012; 77(9):1038-43. · 1.06 Impact Factor
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[show abstract]
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ABSTRACT: One of the arguments against aging being programmed is the assumption that variation in the timing of aging-related outcomes is much higher compared to variation in timing of the events programmed by ontogenesis. The main objective of this study was to test the validity of this argument. To this aim, we compared absolute variability (standard deviation) and relative variability (coefficient of variation) for parameters that are known to be determined by the developmental program (age at sexual maturity) with variability of characteristics related to aging (ages at menopause and death). We used information on the ages at sexual maturation (menarche) and menopause from the nationally representative survey of the adult population of the United States (MIDUS) as well as published data for 14 countries. We found that coefficients of variation are in the range of 8-13% for age at menarche, 7-11% for age at menopause, and 16-21% for age at death. Thus, the relative variability for the age at death is only twice higher than for the age at menarche, while the relative variability for the age at menopause is almost the same as for the age at menarche.
Biochemistry (Moscow) 07/2012; 77(7):754-60. · 1.06 Impact Factor
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[show abstract]
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ABSTRACT: The influence of the mitochondria-targeted antioxidant SkQR1 on gentamycin-induced nephrotoxicity and ototoxicity has been analyzed. SkQR1 reduces the death of kidney epithelium cells and decreases the severity of renal failure caused by gentamycin application and also lowers the animals' mortality. Treatment with SkQR1 also decreases gentamycin-induced hearing loss. Mitochondria-targeted antioxidants, such as SkQR1, are new promising agents for preventing negative consequences of therapy with antibiotics.
Biochemistry (Moscow) 06/2012; 77(6):666-70. · 1.06 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Mitochondria-targeted antioxidants of the SkQ family that accumulate in energized mitochondria protect cells from oxidative
stress by increasing the level of reduced glutathione and decreasing cell damage induced by hydrogen peroxide. The exposure
of various human transformed cell lines to SkQR1, a fluorescent member of the SkQ family, showed that SkQR1 was pumped out
of the chemotherapy resistant cells by P-glycoprotein, one of the main transport proteins that determines multidrug resistance
typical for many neoplastic cells. It was also shown that SkQR1 pumping is neutralized by P-glycoprotein inhibitors (verapamil
and pluronic L61). In experiments on K-562 cells, it was found that the subline sensitive to chemotherapy is protected by
SkQR1 from apoptosis induced by hydrogen peroxide. The protection of resistant subline cells is only evident after the inhibition
of P-glycoprotein.
Keywordsmitochondria–antioxidant–oxidative stress–multidrug resistance–P-glycoprotein–SkQ
Cell and Tissue Biology 04/2012; 5(1):37-46.
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ABSTRACT: There are two opposite points of view on aging of organisms. The traditional concept assumes that aging is a stochastic process
consisting in age-dependent accumulation of random injuries in living systems. However, many pieces of evidence are recently
obtained in favor of an alternative scheme suggesting that aging is genetically programmed being the final step of ontogenesis.
The latter concept predicts (i) the existence of non-aging species which have lost the aging program and (ii) that the program
in question can be experimentally interrupted by manipulations with corresponding genes or by small molecules operating as
inhibitors of the execution of aging program. In this paper we summarize observations which are consistent with these two
predictions. In both cases, interruption of the aging program is based upon inhibition of programmed cell death (apoptosis)
mediated by mitochondrial reactive oxygen species (ROS). We argue that the main difference between young and old multicellular
organisms consists in the cellularity, i.e. in number of functional cells in organs or tissues rather than in quality of these cells. The cellularity decreases
due to domination of apoptosis over proliferation in aging organisms. This means that apoptosis appears to be the basis of
aging program. A pharmacological approach to switch off the aging program is considered, and this approach involves mitochondria-targeted
antioxidants and uncouplers. Such compounds prevent mitochondrial oxidative stress which increases with age and stimulates
the age-dependent apoptosis.
Keywordsapoptosis–aging–mitochondria-targeted antioxidants
04/2012; 1(1):16-27.
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I. A. Mufazalov,
D. N. Penkov,
B. V. Chernyak,
O. Y. Pletjushkina,
M. Y. Vyssokikh,
R. V. Chertkova,
M. P. Kirpichnikov,
D. A. Dolgikh,
A. A. Kruglov,
D. V. Kuprash, V. P. Skulachev,
S. A. Nedospasov
[show abstract]
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ABSTRACT: Mouse embryonic fibroblasts (MEF) with point mutation in somatic cytochrome C gene were generated and characterized. It was
shown that the substitution of lysine for tryptophan in position 72 (K72W) decreased the proapoptotic functions of cytochrome
C in response to staurosporin treatment without disrupting its respiratory functions. The presence of this mutation did not
affect the pattern of cytochrome C gene expression or its localization inside the cell. These cell lines therefore represent
an interesting model for the study of apoptotic signaling and physiological functions of cytochrome C.
Molecular Biology 04/2012; 43(4):596-603. · 0.66 Impact Factor
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V. N. Anisimov,
L. E. Bakeeva,
P. A. Egormin,
O. F. Filenko,
E. F. Isakova,
V. N. Manskikh,
V. M. Mikhelson,
A. A. Panteleeva,
E. G. Pasyukova,
D. I. Pilipenko, [......],
T. A. Samoylova,
A. V. Semenchenko,
M. V. Skulachev,
I. M. Spivak,
E. A. Tsybul’ko,
M. L. Tyndyk,
M. Yu. Vyssokikh,
M. N. Yurova,
M. A. Zabezhinsky, V. P. Skulachev
[show abstract]
[hide abstract]
ABSTRACT: Very low (nano- and subnanomolar) concentrations of 10-(6′-plastoquinonyl) decyltriphenylphosphonium (SkQ1) were found to
prolong lifespan of a fungus (Podospora anserina), a crustacean (Ceriodaphnia affinis), an insect (Drosophila melanogaster), and a mammal (mouse). In the latter case, median lifespan is doubled if animals live in a non-sterile vivarium. The lifespan
increase is accompanied by rectangularization of the survival curves (an increase in survival is much larger at early than
at late ages) and disappearance of typical traits of senescence or retardation of their development. Data summarized here
and in the preceding papers of this series suggest that mitochondria-targeted antioxidant SkQ1 is competent in slowing down
execution of an aging program responsible for development of age-related senescence.
Biochemistry (Moscow) 04/2012; 73(12):1329-1342. · 1.06 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Addition of 200 nM β-amyloid 1-42 (Abeta) to a rat hippocampal slice impairs the induction of a long-term post-tetanic potentiation (LTP) of population spike (PS) in pyramidal neurons of the CA1 field of hippocampus. Intraperitoneal injection into the rat of the mitochondria-targeted plastoquinone derivative SkQR1 (1 µmol/kg of weight given 24 h before the slices were made) abolishes the deleterious effect of Abeta on LTP. These data demonstrate that SkQR1 therapy is able to compensate the Abeta-induced impairments of long-term synaptic plasticity in the hippocampus, which are the main cause of loss of memory and other cognitive functions associated with Alzheimer's disease.
Biochemistry (Moscow) 12/2011; 76(12):1367-70. · 1.06 Impact Factor
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M. V. Skulachev,
Y. N. Antonenko,
V. N. Anisimov,
B. V. Chernyak,
D. A. Cherepanov,
V. A. Chistyakov,
M. V. Egorov,
N. G. Kolosova,
G. A. Korshunova,
K. G. Lyamzaev, [......],
A. Y. Savchenko,
I. I. Severina,
F. F. Severin,
T. P. Shkurat,
V. N. Tashlitsky,
K. M. Shidlovsky,
M. Y. Vyssokikh,
A. A. Zamyatnin,
D. B. Zorov, V. P. Skulachev
[show abstract]
[hide abstract]
ABSTRACT: Plastoquinone, a very effective electron carrier and antioxidant of chloroplasts, was conjugated with decyltriphenylphosphonium to obtain a cation easily penetrating through membranes. This cation, called SkQ1, is specifically targeted to mitochondria by electrophoresis in the electric field formed by the mitochondrial respiratory chain. The respiratory chain also regenerates reduced SkQ1H2 from its oxidized form that appears as a result of the antioxidant activity of SkQ1H2. SkQ1H2 prevents oxidation of cardiolipin, a mitochondrial phospholipid that is especially sensitive to attack by reactive oxygen species (ROS). In cell cultures, SkQ1 and its analog plastoquinonyl decylrhodamine 19 (SkQR1) arrest H2O2-induced apoptosis. When tested in vivo, SkQs (i) prolong the lifespan of fungi, crustaceans, insects, fish, and mice, (ii) suppress appearance of a large number of traits typical for age-related senescence (cataract, retinopathies, achromotrichia, osteoporosis, lordokyphosis, decline of the immune system, myeloid shift of blood cells, activation of apoptosis, induction of β-galactosidase, phosphorylation of H2AX histones, etc.) and (iii) lower tissue damage and save the lives of young animals after treatments resulting in kidney ischemia, rhabdomyolysis, heart attack, arrhythmia, and stroke. We suggest that the SkQs reduce mitochondrial ROS and, as a consequence, inhibit mitochondriamediated apoptosis, an obligatory step of execution of programs responsible for both senescence and fast “biochemical suicide” of an organism after a severe metabolic crisis.
Current Drug Targets 05/2011; 12(6):800-826. · 3.55 Impact Factor
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M V Skulachev,
Y N Antonenko,
V N Anisimov,
B V Chernyak,
D A Cherepanov,
V A Chistyakov,
M V Egorov,
N G Kolosova,
G A Korshunova,
K G Lyamzaev, [......],
A Y Savchenko,
I I Severina,
F F Severin, T P Shkurat,
V N Tashlitsky,
K M Shidlovsky,
M Y Vyssokikh,
A A Zamyatnin,
D B Zorov,
V P Skulachev
[show abstract]
[hide abstract]
ABSTRACT: Plastoquinone, a very effective electron carrier and antioxidant of chloroplasts, was conjugated with decyltriphenylphosphonium to obtain a cation easily penetrating through membranes. This cation, called SkQ1, is specifically targeted to mitochondria by electrophoresis in the electric field formed by the mitochondrial respiratory chain. The respiratory chain also regenerates reduced SkQ1H(2) from its oxidized form that appears as a result of the antioxidant activity of SkQ1H(2). SkQ1H(2) prevents oxidation of cardiolipin, a mitochondrial phospholipid that is especially sensitive to attack by reactive oxygen species (ROS). In cell cultures, SkQ1 and its analog plastoquinonyl decylrhodamine 19 (SkQR1) arrest H(2)O(2)-induced apoptosis. When tested in vivo, SkQs (i) prolong the lifespan of fungi, crustaceans, insects, fish, and mice, (ii) suppress appearance of a large number of traits typical for age-related senescence (cataract, retinopathies, achromotrichia, osteoporosis, lordokyphosis, decline of the immune system, myeloid shift of blood cells, activation of apoptosis, induction of β-galactosidase, phosphorylation of H2AX histones, etc.) and (iii) lower tissue damage and save the lives of young animals after treatments resulting in kidney ischemia, rhabdomyolysis, heart attack, arrhythmia, and stroke. We suggest that the SkQs reduce mitochondrial ROS and, as a consequence, inhibit mitochondria-mediated apoptosis, an obligatory step of execution of programs responsible for both senescence and fast "biochemical suicide" of an organism after a severe metabolic crisis.
Current drug targets 01/2011; 12(6):800-26. · 3.93 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Mitochondria-targeted antioxidants of the SkQR1 family, being accumulated in energized mitochondria, protect cells from oxidative stress by increasing the level of reduced glutathione and decreasing the cell-damaging effect induced by hydrogen peroxide. Using various human transformed cell lines and SkQR1 (a fluorescent member of the SkQ family), we show that SkQRI is ejected from chemotherapy-resistant cells by P-glycoprotein - one of the main transport proteins determining multidrug resistance typical for many neoplastic cells. It is also shown that SkQR1 ejection is neutralized by P-glycoprotein inhibitors (verapamil and pluronic L61). In experiments on K562 cells, it was found that the subline sensitive to chemotherapy is protected by SkQRI from apoptotic action of hydrogen peroxide. Protection of the resistant subline occurs only after inhibition of P-glycoprotein.
Tsitologiia 01/2011; 53(6):488-97.
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V P Skulachev
[show abstract]
[hide abstract]
ABSTRACT: Recently M. E. Rumpho and coworkers (USA) established that the marine slug Elysia chlorotica, a gastropod mollusk that feeds on the eukaryotic filamentous yellow-green alga Vaucheria litorea, recruits chloroplasts from the alga and transports them from the digestive apparatus into a special organ of the slug that resembles a green leaf and is an approximately 100-fold increased parapodium-an outgrowth of the slug's body. The chloroplasts survive inside the slug for up to 10 months and perform active photosynthesis accompanied by assimilation of CO2. Under conditions of starvation, this photosynthesis becomes for the animal the only source of energy and fixed carbon. For functioning, chloroplasts have to constantly import some short-lived proteins that are encoded in the nucleus of the photosynthesizing organism. Therefore, the authors supposed that a transfer of the corresponding genes must have occurred between the algal and mollusk nuclei. This hypothesis was experimentally confirmed for two genes encoding proteins of the photosynthesizing apparatus. The questions arise of what mechanism was responsible for the transfer of these genes and how the slug created its photosynthesizing organ resembling the leaf of a higher plant rather than the primitive filamentous algal structure which was the source of the acquired chloroplasts and the photosynthesis genes.
Biochemistry (Moscow) 12/2010; 75(12):1498-9. · 1.06 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Oxidative stress-related renal pathologies apparently include rhabdomyolysis and ischemia/reperfusion phenomenon. These two pathologies were chosen for study in order to develop a proper strategy for protection of the kidney. Mitochondria were found to be a key player in these pathologies, being both the source and the target for excessive production of reactive oxygen species (ROS). A mitochondria-targeted compound which is a conjugate of a positively charged rhodamine molecule with plastoquinone (SkQR1) was found to rescue the kidney from the deleterious effect of both pathologies. Intraperitoneal injection of SkQR1 before the onset of pathology not only normalized the level of ROS and lipid peroxidized products in kidney mitochondria but also decreased the level of cytochrome c in the blood, restored normal renal excretory function and significantly lowered mortality among animals having a single kidney exposed to ischemia/reperfusion. The SkQR1-derivative missing plastoquinone (C12R1) possessed some, although limited nephroprotective properties and enhanced animal survival after ischemia/reperfusion. SkQR1 was found to induce some elements of nephroprotective pathways providing ischemic tolerance such as an increase in erythropoietin levels and phosphorylation of glycogen synthase kinase 3β in the kidney. SkQR1 also normalized renal erythropoietin level lowered after kidney ischemia/reperfusion and injection of a well-known nephrotoxic agent gentamicin.
Biochimica et Biophysica Acta 09/2010; 1812(1):77-86. · 4.66 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Lifelong treatment of mice with the effective mitochondria-targeted antioxidant SkQ1 [10-(6'-plastoquinonyl) decyltriphenylphosphonium] does not affect hematopoietic stem cells (HSC) and more differentiated hematopoietic progenitors but significantly decelerates age-dependent changes in peripheral blood. During the first 13 months, SkQ1 (0.9 or 28.8 nmol/kg day) prevents age-dependent myeloid shift (increase in the proportion of granulocytes and decrease in the proportion of lymphocytes). During the next year of treatment the effect disappears, and the hemogram of 2-year-old treated mice does not differ from the control. The number of mesenchymal stem cells (MSC) in the bone marrow does not change during 2 years of treatment with SkQ1, but the concentration of MSC progeny fibroblast colony-forming units (CFU-F) increases with dose of SkQ1. The concentration of CFU-F after 1 and 2 years treatment with SkQ1 is twice higher than in young mice. Our data indicate that the stromal environment of hematopoietic cells could be the primary target of age-dependent changes mediated by reactive oxygen species produced in mitochondria. The anti-aging effects of SkQ1 described here are in perfect agreement with the inhibitory effects of this antioxidant on aging observed in the other models.
Mechanisms of ageing and development 06/2010; 131(6):415-21. · 4.18 Impact Factor
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V P Skulachev
[show abstract]
[hide abstract]
ABSTRACT: Much evidence has recently been reported suggesting that reactive oxygen species (ROS) produced in mitochondria play a crucial role in the programmed senescence of organisms. In particular, it has been shown that antioxidants addressed to mitochondria slow down the appearance of symptoms of senescence and development of senile diseases and increase the median lifespan of various organisms from fungi to mammals. At the biochemical level, the mechanism of action of such rechargeable antioxidants as plastoquinonyldecyltriphenyl phosphonium (SkQ1) includes, in particular, prevention of oxidation of mitochondrial cardiolipin by ROS. The hormone melatonin also exhibits a number of such effects, and decrease in its level with age could explain the weakening of antioxidant protection upon aging. According to Moosmann et al., there exists a natural mechanism of antioxidant protection that, like SkQ1, is localized in the internal mitochondrial membrane and is rechargeable. It involves methionine residues in the surface regions of proteins encoded by mitochondrial DNA. It appears that in organisms with high respiratory metabolism the genetic code in the mitochondrial system of protein biosynthesis has changed. In these organisms (including some yeasts, insects, crustaceans, and vertebrates), the AUA codon codes for methionine rather than isoleucine, as in the case of synthesis of proteins encoded either in the nucleus or in mitochondria of organisms with lower rates of metabolism (other yeast species, sponges, and echinoderms). Methionine quenches ROS, being converted to methionine sulfoxide, which is re-reduced to the initial methionine by NADPH.
Biochemistry (Moscow) 12/2009; 74(12):1400-3. · 1.06 Impact Factor
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V V Neroev,
M M Archipova,
L E Bakeeva,
A Zh Fursova,
E N Grigorian,
A Yu Grishanova,
E N Iomdina,
Zh N Ivashchenko,
L A Katargina,
I P Khoroshilova-Maslova, [......],
V B Saprunova,
I I Senin,
M V Skulachev,
L F Sotnikova,
N A Stefanova,
N K Tikhomirova,
I V Tsapenko,
A I Shchipanova,
R A Zinovkin, V P Skulachev
[show abstract]
[hide abstract]
ABSTRACT: Mitochondria-targeted cationic plastoquinone derivative SkQ1 (10-(6'-plastoquinonyl) decyltriphenylphosphonium) has been investigated as a potential tool for treating a number of ROS-related ocular diseases. In OXYS rats suffering from a ROS-induced progeria, very small amounts of SkQ1 (50 nmol/kg per day) added to food were found to prevent development of age-induced cataract and retinopathies of the eye, lipid peroxidation and protein carbonylation in skeletal muscles, as well as a decrease in bone mineralization. Instillation of drops of 250 nM SkQ1 reversed cataract and retinopathies in 3-12-month-old (but not in 24-month-old) OXYS rats. In rabbits, experimental uveitis and glaucoma were induced by immunization with arrestin and injections of hydroxypropyl methyl cellulose to the eye anterior sector, respectively. Uveitis was found to be prevented or reversed by instillation of 250 nM SkQ1 drops (four drops per day). Development of glaucoma was retarded by drops of 5 microM SkQ1 (one drop daily). SkQ1 was tested in veterinarian practice. A totally of 271 animals (dogs, cats, and horses) suffering from retinopathies, uveitis, conjunctivitis, and cornea diseases were treated with drops of 250 nM SkQ1. In 242 cases, positive therapeutic effect was obvious. Among animals suffering from retinopathies, 89 were blind. In 67 cases, vision returned after SkQ1 treatment. In ex vivo studies of cultivated posterior retina sector, it was found that 20 nM SkQ1 strongly decreased macrophagal transformation of the retinal pigmented epithelial cells, an effect which might explain some of the above SkQ1 activities. It is concluded that low concentrations of SkQ1 are promising in treating retinopathies, cataract, uveitis, glaucoma, and some other ocular diseases.
Biochemistry (Moscow) 01/2009; 73(12):1317-28. · 1.06 Impact Factor
