Antioxidant SkQ1 delays sarcopenia-associated damage of mitochondrial ultrastructure.

A comparative electron-microscopic study of ultrastructure of mitochondria in skeletal muscles of the 3- and 24-month-old Wistar and OXYS rats revealed age-dependent changes in both general organization of the mitochondrial reticulum and ultrastructure of mitochondria. The most pronounced ultrastructure changes were detected in the OXYS rats suffering from permanent oxidative stress. In the OXYS rats, significant changes in mitochondrial ultrastructure were detected already at the age of 3 months. Among them, there were the appearance of megamitochondria and reduction of cristae resulting in formation of cristae-free regions inside mitochondria. In the 24-month-old OXYS rats, mitochondrial reticulum was completely destroyed. In the isotropic region of muscle fiber, only small solitary mitochondria were present. There appeared regions of lysed myofibrils as well as vast regions filled with autophagosomes. A mitochondrial antioxidant SkQ1 (given to rats with food daily in the dose of 250 nmol/kg of body weight for 5 months beginning from the age of 19 months) prevented development of age-dependent destructive changes in both the Wistar and OXYS rats.

Efficacy of glucosamine alendronate alone & in combination with dihydroquercetin for treatment of osteoporosis in animal model.

BACKGROUND & OBJECTIVES: Considerable efforts are being made to develop new, more effective drugs for osteoporosis, including novel forms of bisphosphonates. The present study was carried out to compare the effect of a novel agent glucosamine alendronate (GA) alone and is combination with dihydroquercetin (DHQ) against the effect of a known drug alendronate (ALN) in the senescence-accelerated OXYS rats as model of osteoporosis. METHODS: Male OXYS and Wistar (control) rats were randomized across four experimental groups (n=15), which received 1.26 mg GA, 0.84 mg ALN, or 1.26 mg GA + 5.06 mg DHQ per kg of body weight. Untreated rats were used as control groups. At the end of treatment, the bone mineral density (BMD), bone biomechanical properties, and the levels of serum osteocalcin, αC-terminal crosslinked telopeptides of type I collagen (α-CTx) and calcium were measured. RESULTS: All treatments increased BMD in rats of both strains, but the improvement was more pronounced in OXYS rats: GA+DHQ increased both the strength of the femur by 20 per cent (P<0.01) and BMD by 7.6 per cent (P<0.023). GA+DHQ and ALN reduced serum α-CTx in OXYS rats. Only GA increased the level of osteocalcin in OXYS rats (P<0.05). ALN increased the cross-sectional area of the femur by 9 per cent (P<0.04) in OXYS and by 12 per cent (P<0.05) in Wistar rats. INTERPRETATION & CONCLUSIONS: The combined treatment with GA+DHQ appears to be more effective at maintaining strength of the femur and BMD in OXYS rats, when compared to the individual drugs GA and ALN.

Effects of the mitochondria-targeted antioxidant SkQ1 on sexually motivated behavior in male rats.

Ample research indicates that age-related neuronal-behavioral decrements are the result of oxidative stress and may be ameliorated by antioxidants. Here we examined effects of mitochondria-targeted antioxidant, SkQ1, on sexual motivation in 12-month-old Wistar and accelerated-senescent OXYS male rats. A change in behavioral activity of a male at a holed transparent partition with a receptive female on the other side was taken as an index of sexual motivation. The social behavior of male in same conditions with ovariectomised (OVXed) female and castrated male was investigated to differentiate sexually and socially motivated behavior. Behavioral response to social stimulus did not depend on age and genotype. No differences were found between 4- and 12-month-old Wistar males when sexual stimulus was presented; however, 12-month-old OXYS males demonstrated a lower propensity for sexual motivation as compared to 4-month-old OXYS rats and 12-month-old Wistar rats. We examined effects of SkQ1 on sexual motivation in 12-month-old male rats following prolonged supplementation begun at 1.5months of age (10, 50 or 250nmol/kg daily), a 45-day supplementation begun at 10.5months of age (50nmol/kg) and a 3-month supplementation begun at 9months of age (250nmol/kg). SkQ1 did not affect locomotor activity; however, it increased the time spent at the partition. A significantly higher measure of the motivational stage of sexual behavior was displayed following chronic preventive treatment at a dose of 50 and 250nmol/kg by OXYS rats. Chronic therapeutic treatment during 3months at a dose of 250nmol/kg was effective in age-accelerated OXYS rats too. These findings suggest an essential role for oxidative stress associated with mitochondrial dysfunction in the decline of sexually motivated behavior of male rats. Recovery from these impairments and/or their prevention enables a fully successful performance of the initial stage of male sexual behavior.

An attempt to prevent senescence: a mitochondrial approach.

Antioxidants specifically addressed to mitochondria have been studied to determine if they can decelerate senescence of organisms. For this purpose, a project has been established with participation of several research groups from Russia and some other countries. This paper summarizes the first results of the project. A new type of compounds (SkQs) comprising plastoquinone (an antioxidant moiety), a penetrating cation, and a decane or pentane linker has been synthesized. Using planar bilayer phospholipid membrane (BLM), we selected SkQ derivatives with the highest permeability, namely plastoquinonyl-decyl-triphenylphosphonium (SkQ1), plastoquinonyl-decyl-rhodamine 19 (SkQR1), and methylplastoquinonyldecyltriphenylphosphonium (SkQ3). Anti- and prooxidant properties of these substances and also of ubiquinonyl-decyl-triphenylphosphonium (MitoQ) were tested in aqueous solution, detergent micelles, liposomes, BLM, isolated mitochondria, and cell cultures. In mitochondria, micromolar cationic quinone derivatives were found to be prooxidants, but at lower (sub-micromolar) concentrations they displayed antioxidant activity that decreases in the series SkQ1=SkQR1>SkQ3>MitoQ. SkQ1 was reduced by mitochondrial respiratory chain, i.e. it is a rechargeable antioxidant. Nanomolar SkQ1 specifically prevented oxidation of mitochondrial cardiolipin. In cell cultures, SkQR1, a fluorescent SkQ derivative, stained only one type of organelles, namely mitochondria. Extremely low concentrations of SkQ1 or SkQR1 arrested H(2)O(2)-induced apoptosis in human fibroblasts and HeLa cells. Higher concentrations of SkQ are required to block necrosis initiated by reactive oxygen species (ROS). In the fungus Podospora anserina, the crustacean Ceriodaphnia affinis, Drosophila, and mice, SkQ1 prolonged lifespan, being especially effective at early and middle stages of aging. In mammals, the effect of SkQs on aging was accompanied by inhibition of development of such age-related diseases and traits as cataract, retinopathy, glaucoma, balding, canities, osteoporosis, involution of the thymus, hypothermia, torpor, peroxidation of lipids and proteins, etc. SkQ1 manifested a strong therapeutic action on some already pronounced retinopathies, in particular, congenital retinal dysplasia. With drops containing 250 nM SkQ1, vision was restored to 67 of 89 animals (dogs, cats, and horses) that became blind because of a retinopathy. Instillation of SkQ1-containing drops prevented the loss of sight in rabbits with experimental uveitis and restored vision to animals that had already become blind. A favorable effect of the same drops was also achieved in experimental glaucoma in rabbits. Moreover, the SkQ1 pretreatment of rats significantly decreased the H(2)O(2) or ischemia-induced arrhythmia of the isolated heart. SkQs strongly reduced the damaged area in myocardial infarction or stroke and prevented the death of animals from kidney ischemia. In p53(-/-) mice, 5 nmol/kgxday SkQ1 decreased the ROS level in the spleen and inhibited appearance of lymphomas to the same degree as million-fold higher concentration of conventional antioxidant NAC. Thus, SkQs look promising as potential tools for treatment of senescence and age-related diseases.