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.

Senescence-accelerated OXYS rats are an experimental model of accelerated aging that was established from wistar stock via selection for susceptibility to cataractogenic effects of a galactose-rich diet and via subsequent inbreeding of highly susceptible rats. Currently, we have the 102nd generation of OXYS rats with spontaneously developing cataract and accelerated senescence syndrome, which means early development of a phenotype similar to human geriatric disorders, including accelerated brain aging. in recent years, our group found strong evidence that OXYS rats are a promising model for studies of the mechanisms of brain aging and neurodegenerative processes similar to those seen in Alzheimer disease (AD). The manifestation of behavioral alterations and learning and memory deficits develop since the fourth week of age, i.e., simultaneously with first signs of neurodegeneration detectable on magnetic resonance imaging and under a light microscope. in addition, impaired long-term potentiation has been demonstrated in OXYS rats by the age of 3 months. with age, neurodegenerative changes in the brain of OXYS rats become amplified. we have shown that this deterioration happens against the background of overproduction of amyloid precursor protein (AβPP), accumulation of β-amyloid (Aβ), and hyperphosphorylation of the tau protein in the hippocampus and cortex. The development of AMDlike retinopathy in OXYS rats is also accompanied by increased accumulation of Aβ in the retina. These published data suggest that the OXYS strain may serve as a spontaneous rat model of AD-like pathology and could help to decipher the pathogenesis of AD.

The amyloid cascade hypothesis posits that deposition of the amyloid β (Aβ) peptide in the brain is a key event in the initiation of Alzheimer's disease (AD). Nonetheless, it now seems increasingly unlikely that amyloid toxicity is the cause of sporadic AD, which leads to cognitive decline. Here, using accelerated-senescence nontransgenic OXYS rats, we confirmed that aggregation of Aβ is a later event in AD-like pathology. We showed that an age-dependent increase in the levels of Aβ1–42 and extracellular Aβ deposits in the brain of OXYS rats occur later than do synaptic losses, neuronal cell death, mitochondrial structural abnormalities, and hyperphosphorylation of the tau protein. We identified the variants of the genes that are strongly associated with the risk of either late-onset or early-onset AD, including App, Apoe4, Bace1, Psen1, Psen2, and Picalm. We found that in OXYS rats nonsynonymous SNPs were located only in the genes Casp3 and Sorl1. Thus, we present proof that OXYS rats may be a model of sporadic AD. It is possible that multiple age-associated pathological processes may precede the toxic amyloid accumulation, which in turn triggers the final stage of the sporadic form of AD and becomes a hallmark event of the disease.

We previously showed that mitochondria-targeted antioxidant SkQ1 (plastoquinonyl-decyltriphenylphosphonium) at nanomolar concentrations is capable of preventing and slowing down some cerebral dysfunctions in accelerated-senescence OXYS rats. Here we demonstrate that OXYS rats develop behavior, learning, and memory deficits against a background of neurodegeneration signs detected by magnetic resonance tomography and amyloid-β (Aβ) pathology similar to those seen in Alzheimer's disease (AD). Long-term treatment with SkQ1 (250 nmol/kg body weight daily from the age of 1.5 to 23 months) reduced the age-related alterations in behavior and spatial memory deficit in Morris water maze in OXYS and Wistar rats. Furthermore, this is the first report that SkQ1 treatment slows down pathological accumulation of AβPP, Aβ, and hyperphosphorylation of tau-protein in OXYS rats, as well as age-dependent changes in healthy Wistar rats. Our results support the possibility of using the OXYS strain as a rat model of AD-like pathology. It seems probable that the mitochondria-targeted antioxidant SkQ1 can be a good prophylactic strategy to maintain brain health and to treat AD.

Translational research on Alzheimer's disease (AD) has often focused on reducing the high cerebral levels of amyloid-β (Aβ) as a key characteristic of AD pathogenesis. There is, however, a growing body of evidence that synaptic dysfunction may be crucial for the development of the most common (sporadic) form of AD. The applicability of melatonin (mainly produced by the pineal gland) to the treatment of AD is actively evaluated, but usually, such studies are based on animal models of early-onset AD, which is responsible for only ~5% of AD cases. We have shown previously that in OXYS rats (an established model of sporadic AD), accumulation of toxic forms of Aβ in the brain occurs later than does the development of signs of neurodegenerative changes and synaptic failure. In this regard, recently, we uncovered beneficial neuroprotective effects of melatonin (prophylactic dietary supplementation) in OXYS rats. Our aim here was to evaluate, starting at the age of active progression of AD-like pathology in OXYS rats, the effects of long-term oral administration of melatonin on the structure of synapses and on neuronal and glial cells of the hippocampus. Melatonin significantly increased hippocampal synaptic density and the number of excitatory synapses, decreased the number of inhibitory synapses, and upregulated pre- and postsynaptic proteins (synapsin I and PSD-95, respectively). Furthermore, melatonin improved the ultrastructure of neuronal and glial cells and reduced glial density. Based on our past and present results, the repair of neuroplasticity by melatonin is a promising strategy against AD.