Transcriptomic insights into multiple system atrophy from a PLP-α-synuclein transgenic mouse model.

Multiple system atrophy (MSA) is a rare, neurodegenerative disorder with rapid motor and non-motor symptom progression. MSA is characterized by protein aggregations of α-synuclein found in the cytoplasm of oligodendrocytes. Despite this pathological hallmark, there is still little known about the cause of this disease, resulting in poor treatment options and quality of life post-diagnosis. In this study, we investigated differentially expressed genes (DEGs) via RNA-sequencing of brain samples from a validated PLP-α-synuclein transgenic mouse model, identifying a total of 40 DEGs in the PLP group compared to wild-type (WT), with top detected genes being Gm15446, Mcm6, Aldh7a1 and Gm3435. We observed a significant enrichment of immune pathways and endothelial cell genes among the upregulated genes, whereas downregulated genes were significantly enriched for oligodendrocyte and neuronal genes. We then calculated possible overlap of these DEGs with previously profiled human MSA RNA, resulting in the identification of significant downregulation of the Tsr2 gene. Identifying key gene expression profiles specific to MSA patients is crucial to further understanding the cause, and possible prevention, of this rapidly progressive neurodegenerative disorder.

RatDEGdb: a knowledge base of differentially expressed genes in the rat as a model object in biomedical research.

The animal models used in biomedical research cover virtually every human disease. RatDEGdb, a knowledge base of the differentially expressed genes (DEGs) of the rat as a model object in biomedical research is a collection of published data on gene expression in rat strains simulating arterial hypertension, age-related diseases, psychopathological conditions and other human afflictions. The current release contains information on 25,101 DEGs representing 14,320 unique rat genes that change transcription levels in 21 tissues of 10 genetic rat strains used as models of 11 human diseases based on 45 original scientific papers. RatDEGdb is novel in that, unlike any other biomedical database, it offers the manually curated annotations of DEGs in model rats with the use of independent clinical data on equal changes in the expression of homologous genes revealed in people with pathologies. The rat DEGs put in RatDEGdb were annotated with equal changes in the expression of their human homologs in affected people. In its current release, RatDEGdb contains 94,873 such annotations for 321 human genes in 836 diseases based on 959 original scientific papers found in the current PubMed. RatDEGdb may be interesting first of all to human geneticists, molecular biologists, clinical physicians, genetic advisors as well as experts in biopharmaceutics, bioinformatics and personalized genomics. RatDEGdb is publicly available at https://www.sysbio.ru/RatDEGdb.

Signs of early cellular dysfunction in multiple system atrophy.

AIMS: Multiple system atrophy (MSA) is a fatal neurodegenerative disease that belongs to the family of α-synucleinopathies. At post mortem examination, intracellular inclusions of misfolded α-synuclein are found in neurons and oligodendrocytes and are considered to play a significant role in the pathogenesis. However, the early steps of the disease process are unknown and difficult to study in tissue derived from end-stage disease. METHODS: Induced pluripotent stem cells (iPSCs) were generated from patients' and control skin fibroblasts and differentiated into NCAM-positive neural progenitor cells (NPCs). The mitochondrial morphology and function were assessed by immunocytochemistry and high resolution respirometry. The ability to cope with exogenous oxidative stress was tested by exposure to different doses of luperox. The expression of α-synuclein was studied by immunocytochemistry. RESULTS: We identified increased tubulation of mitochondria with preserved respiration profile in MSA-derived NPCs. Exposure of these cells to exogenous oxidative stress even at low doses, triggered an excessive generation of reactive oxygen species (ROS) and cleavage of caspase-3. MSA-derived NPCs did not present changed levels of SNCA gene expression nor intracellular aggregates of α-synuclein. However, we identified disease-related translocation of α-synuclein to the nucleus. CONCLUSIONS: Our results show early cellular dysfunction in MSA-derived NPCs. We identified changes in the redox homeostasis which are functionally compensated at baseline but cause increased susceptibility to exogenous oxidative stress. In addition, nuclear translocation of α-synuclein in MSA-derived NPCs supports an early cellular stress response which may precede the neurodegenerative process in this disorder.

[Adult neurogenesis: alterations with aging and Alzheimer's disease development.]

Adult neurogenesis is one of the key mechanisms of the brain plasticity. Increase in the number of cells participating in the rearrangement of the neuronal circuits and synaptic formation facilitates the increase of brain's functional capacity. However, aging as well as neurodegenerative disorders lead to the disruption of the neurogenic niche microenvironment and the loss of molecular control, which in turn results in the significant decline of the neurogenesis. These events may contribute to the cognitive decline and the consequent development of dementia. Alzheimer's disease is a progressive incurable age-related neurodegenerative disorder in the elderly and the most prevalent cause of dementia. Hippocampus and entorhinal cortex are the key neurogenic niches in the adult brain and one of the most vulnerable brain areas during the development of Alzheimer's disease. Thus, neurodegeneration associated with the development of Alzheimer's disease affects adult neurogenesis. However, to date the mechanisms underlying this connection are unclear, and the investigation of these mechanisms is a promising strategy to find the approaches to correct the Alzheimer's disease pathology.

p38 MAPK-dependent alphaB-crystallin phosphorylation in Alzheimer's disease-like pathology in OXYS rats.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder. Development of AD is closely related to alterations of proteostasis including the deposition of amyloid beta (Aß) and hyperphosphorylated tau in the brain. Molecular chaperones such as αB-crystallin (CryaB) can prevent aggregation of proteins and enable their correct refolding. The p38 mitogen-activated protein kinase signaling (MAPK) pathway regulates CryaB activity through phosphorylation of CryaB. Here, we examined CryaB and phospho-(p-)Ser59-CryaB protein amounts in the prefrontal cortex of the senescence-accelerated OXYS rats at different stages of the development of AD-like pathology and in Wistar rats (control). We compared this result with the changes in the expression of genes involved in the p38 MAPK signaling pathway in the prefrontal cortex of both rat strains. Manifestation and progression of AD-like pathology in OXYS rats were accompanied by an increased level of detergent-insoluble p-Ser59-CryaB in the brain cortex, while the CryaB amount did not change. p-Ser59-CryaB was absent in the detergent-soluble protein fraction of the cortex in both rat strains. Immunostaining of brain slices revealed notable colocalization of p-Ser59-CryaB with Aß in 18-month-old OXYS rats. According to RNA sequencing data, the development of AD-like pathology in OXYS rats is accompanied in the cortex by up- and downregulation of genes involved in p38 MAPK signaling. In general, we demonstrated that the manifestation AD-like pathology in OXYS rats occurs against the background of activation of p38 MAPK-dependent CryaB phosphorylation and alterations of the p38 MAPK signaling pathway. The increased p-Ser59-CryaB amount and its colocalization with Aß can be considered a response to the accumulation of protein aggregates and may be an important part of an endogenous mechanism of AD development.

Mitochondria with Morphology Characteristic for Alzheimer's Disease Patients Are Found in the Brain of OXYS Rats.

Growing evidence suggests that mitochondrial dysfunction is closely linked to the pathogenesis of sporadic Alzheimer's disease (AD). One of the key contributors to various aspects of AD pathogenesis, along with metabolic dysfunction, is mitochondrial dynamics, involving balance between fusion and fission, which regulates mitochondrial number and morphology in response to changes in cellular energy demand. Recently, Zhang et al. ((2016) Sci. Rep., 6, 18725) described a previously unknown mitochondrial phenotype manifesting as elongated chain-linked mitochondria termed "mitochondria-on-a-string" (MOAS) in brain tissue from AD patients and mouse models of AD. The authors associated this phenotype with fission arrest, but implications of MOAS formation in AD pathogenesis remain to be understood. Here we analyze the presence and number of MOAS in the brain of OXYS rats simulating key signs of sporadic AD. Using electron microscopy, we found MOAS in OXYS prefrontal cortex neuropil in all stages of AD-like pathology, including manifestation (5-month-old rats) and progression (12-18-month-old rats). The most pronounced elevation of MOAS content (8-fold) in OXYS rats compared to Wistar controls was found at the preclinical stage (20 days) on the background of decreased numbers of non-MOAS elongated mitochondria. From the age of 20 days through 18 months, the percentage of MOAS-containing neuronal processes increased from 1.7 to 8.3% in Wistar and from 13.9 to 16% in OXYS rats. Our results support the importance of the disruption of mitochondrial dynamics in AD pathogenesis and corroborate the existence of a causal link between impaired mitochondrial dynamics and formation of the distinctive phenotype of "mitochondria-on-a-sting".

Molecular and Cellular Mechanisms of Sporadic Alzheimer's Disease: Studies on Rodent Models in vivo.

In this review, recent data are presented on molecular and cellular mechanisms of pathogenesis of the most widespread (about 95%) sporadic forms of Alzheimer's disease obtained on in vivo rodent models. Although none of the available models can fully reproduce the human disease, several key molecular mechanisms (such as dysfunction of neurotransmitter systems, especially of the acetylcholinergic system, ß-amyloid toxicity, oxidative stress, neuroinflammation, mitochondrial dysfunction, disturbances in neurotrophic systems) are confirmed with different models. Injection models, olfactory bulbectomy, and senescence accelerated OXYS rats are reviewed in detail. These three approaches to in vivo modeling of sporadic Alzheimer's disease have demonstrated a considerable similarity in molecular and cellular mechanisms of pathology development. Studies on these models provide complementary data, and each model possesses its specific advantages. A general analysis of the data reported for the three models provides a multifaceted and the currently most complete molecular picture of sporadic Alzheimer's disease. This is highly relevant also from the practical viewpoint because it creates a basis for elaboration and preclinical studies of means for treatment of this disease.

Impact of Changes in Neurotrophic Supplementation on Development of Alzheimer's Disease-Like Pathology in Oxys Rats.

Alzheimer's disease (AD) is the most common type of age-related dementia. The development of neurodegeneration in AD is closely related to alterations in neurotrophic supplementation of the brain, which may be caused either by disorder of neurotrophin metabolism or by modification of its availability due to changes in the microenvironment of neurons. The underlying mechanisms are not fully understood. In this work, we used senescence-accelerated OXYS rats as a unique model of the sporadic form of AD to examine the relationship of development of AD signs and changes in neurotrophic supplementation of the cortex. Based on comparative analysis of the transcriptome of the frontal cerebral cortex of OXYS and Wistar (control) rats, genes of a neurotrophin signaling pathway with different mRNA levels in the period prior to the development of AD-like pathology in OXYS rats (20 days) and in the period of its active manifestation (5 months) and progression (18 months) were identified. The most significant changes in mRNA levels in the cortex of OXYS rats occurred in the period from 5 to 18 months of age. These genes were associated with neurogenesis, neuronal differentiation, synaptic plasticity, and immune response. The results were compared to changes in the levels of brain-derived neurotrophic factor (BDNF), its receptors TrkB and p75NTR, as well as with patterns of their colocalization, which reveal the balance of proneurotrophins and mature neurotrophins and their receptors. We found that alterations in neurotrophic balance indicating increased apoptosis precede the development of AD-like pathology in OXYS rats. Manifestation of AD-like pathology occurs against a background of activation of compensatory and regenerative processes including increased neurotrophic supplementation. Active progression of AD-like pathology in OXYS rats is accompanied by the suppression of activity of the neurotrophin system. Thus, the results confirm the importance of the neurotrophin system as a potential target for development of new approaches to slow age-related alterations in brain and AD development.

The influence of changes in expression of redox-sensitive genes on the development of retinopathy in rats.

Age-related macular degeneration (AMD) is a complex multifactorial disease of the elderly, with unclear pathogenesis; AMD is the leading cause of blindness. One of the destructive processes in AMD is oxidative stress, which leads to an imbalance in the processes responsible for production and detoxification of reactive oxygen species. The aryl hydrocarbon receptor (AhR) signaling pathway can participate in the development of oxidative stress, but the main regulator of antioxidant defense is nuclear factor, erythroid derived 2 (Nrf2). AhR-dependent oxidative stress can be attenuated by activation of Nrf2, and defects in the Nrf2 signaling pathway can increase sensitivity of the cell to oxidative stress. Our aim was to determine the role of the pro-oxidant (AhR-dependent) and antioxidant (Nrf2-dependent) systems in the pathogenesis of AMD using rats of OXYS strain and of OXYSb substrain with signs of AMD-like retinopathy of varying severity. We compared the retinal levels of mRNA expression of Nrf2- and AhR-dependent redox-sensitive systems between 1-, 3-, and 12- month-old senescence-accelerated OXYS rats (have been shown to be a valid experimental model of AMD) and the rat substrain OXYSb, which shows low morbidity of AMD. We uncovered interstrain differences in the expression of Nrf2 and Nrf2-dependent genes (glutathione S-reductase [Gsr] and heme oxygenase 1 [Hmox1]), in the expression of AhR-dependent genes (cytochrome P450 1A2 [Cyp1a2] and cytochrome P450 1B1 [Cyp1b1]), and in the NADPH-quinone oxidoreductase (Nqo1) expression, which is controlled by both AhR and Nrf2. Binding of AhR and Nrf2 proteins to the regulatory regions of AhR and Nrf2 genes, respectively, was detected by chromatin immunoprecipitation in the retina of 1-, 3-, and 12-month-old OXYS, OXYSb, and Wistar (control) rats. We compared the strength of DNA-protein interactions of AhR and Nrf2 with regulatory sequences and found that the level of autoupregulation of the AhR gene was higher in the retina of 1-month-old OXYSb rats in comparison with OXYS rats. An imbalance between pro-oxidant (AhR-dependent) and antioxidant (Nrf2-dependent) systems may play a crucial role in the onset and/or progression of AMD.

Review: Multiple system atrophy: emerging targets for interventional therapies.

Multiple system atrophy (MSA) is a fatal orphan neurodegenerative disorder that manifests with rapidly progressive autonomic and motor dysfunction. The disease is characterized by the accumulation of α-synuclein fibrils in oligodendrocytes that form glial cytoplasmic inclusions, a neuropathological hallmark and central player in the pathogenesis of MSA. Here, we summarize the current knowledge on the etiopathogenesis and neuropathology of MSA. We discuss the role of α-synuclein pathology, microglial activation, oligodendroglial dysfunction and putative cell death mechanisms as candidate therapeutic targets in MSA.

Characteristic of a force sensing guide wire for minimally invasive cardiac surgery.

In minimal invasive cardiac surgery (MICS), the surgeon is missing haptic feedback of the guide wire for navigation through the vessels. A wide range of guide wires with various properties and performance characteristics are available to reduce the risk of complications during the intervention. This paper presents a force sensing guide wire for cardiac catheterization, which provides the surgeon a haptic feedback on the guide wire tip. Three conventional wires for the recanalization of chronic total coronary occlusions (CTO) are investigated and general design requirements for the force sensing guide wire are determined. A comparison of the developed with the conventional guide wires concerning the tip force is conducted. The measured tip force of the force sensing guide wire is 50 mN, which is slightly lower than two of the compared conventional wires. As a result, the guide wire offers a good compromise between a soft, low-traumatic and hard guide wire tip.

[MORPHOLOGICAL CHARACTERIZATION OF OXYS AND WISTAR RAT HIPPOCAMPUS IN THE AGING PROCESS].

Using light and electron microscopy, the structural changes in the hippocampus of senescence-accelerated OXYS rats (n = 20) and Wistar (n = 20) were examined in the age aspect. By light microscopy, the neurons with the signs of chromatolysis and hyperchromatic neurons were detected in CA1, CA3 fields and the dentate gyrus of the hippocampus, suggesting the presence of the signs of degeneration already in 4 month-old OXYS rats. By the age of 18 months, severe structural changes occured in all the regions of the hippocampus of OXYS rats. Ultramicroscopically, in 4 month-old OXYS rats the. initial manifestation of destruction of mitochondria and accumulation of lipofuscin granules were found. These changes were shown to progress with age; 18-month-old animals were characterized by more significant degradation of organelles. These findings indicate more pronounced age-related changes of neurons in OXYS rats as compared to those in in Wistar rats.

Influence of Antioxidant SkQ1 on Accumulation of Mitochondrial DNA Deletions in the Hippocampus of Senescence-Accelerated OXYS Rats.

Reduction of efficiency of oxidative phosphorylation associated with aging and the development of neurodegenerative diseases including Alzheimer's disease is thought to be linked to the accumulation of deletions in mitochondrial DNA (ΔmtDNA), which are seen as a marker of oxidative damage. Recently, we have shown that mitochondria-targeted antioxidant SkQ1 (10-(6'-plastoquinonyl)decyltriphenylphosphonium) can slow the development of signs of Alzheimer's disease in senescence-accelerated OXYS rats. The purpose of this study was to explore the relationship between the development of neurodegenerative changes in the brain of OXYS rats and changes in the amount of mtDNA and the 4834-bp mitochondrial DNA deletion (ΔmtDNA4834) as well as the effect of SkQ1. We studied the relative amount of mtDNA and ΔmtDNA4834 in the hippocampus of OXYS and Wistar (control) rats at ages of 1, 2, 6, 10, and 20 days and 3, 6, and 24 months. During the period crucial for manifestation of the signs of accelerated aging of OXYS rats (from 1.5 to 3 months of age), we evaluated the effects of administration of SkQ1 (250 nmol/kg) and vitamin E (670 mmol/kg, reference treatment) on the amount of mtDNA and ΔmtDNA4834 and on the formation of the behavioral feature of accelerated senescence in OXYS rats - passive type of behavior in the open field test. In OXYS rats, the level of ΔmtDNA4834 in the hippocampus is increased compared to the Wistar rats, especially at the stage of completion of brain development in the postnatal period. This level remains elevated not only at the stages preceding the manifestation of the signs of accelerated brain aging and the development of pathological changes linked to Alzheimer's disease, but also during their progression. However, at age of 24 months, there were no detectable differences between the two strains. SkQ1 treatment reduced the level of ΔmtDNA4834 in the hippocampus of Wistar and OXYS rats and slowed the formation of passive behavior in OXYS rats. These results support the possible use of SkQ1 for prophylaxis of brain aging.

[Metformin reduces the signs of sarcopenia in old OXYS rats].

The increasing prevalence of sarcopenia (with the gradually aging population) necessitates the development of effective prophylactic strategies. As promising geroprotectors that comprehensively influence the processes of aging, mimetics of caloric restriction are being actively studied, for example, the antidiabetic agent biguanide Metformin (MF). We tested the influence of MF on the signs of sarcopenia in senescence-accelerated OXYS rats during oral administration (100 or 300 mg per kilogram of body weight per day, with feed) from age 19 to 24 months: the period when the signs of sarcopenia are present. We analyzed the effects of MF on muscular strength of the rats and on structural and functional parameters of skeletal muscle by means of light microscopy. MF slowed down the age-related atrophy of muscle fiber bundles because it slowed the necrosis of some fibers, sclerotic changes in skeletal muscle, and hypertrophy of connective tissue of the perimysium (with a greater effect on the endomysium). MF also substantially improved the blood supply and metabolism in the fibers. As a result of MF treatment, the structure of skeletal muscle of OXYS rats approached that of Wistar rats (healthy control) in terms of qualitative and quantitative parameters; this improvement increased the muscle strength of OXYS rats and abrogated the weight loss that is characteristic of old age.

[The senescence-accelerated oxys rats--a genetic model of premature aging and age-dependent degenerative diseases].

The genetic model of accelerated senescence and the associated diseases--the OXYS strain of rats--was created using selection and inbreeding of Wistar rats sensitive to cataractogenic effects of galactose. In the first 5 generations, the development of cataract was induced by galactose overconsumption, and after that, the rats were selected for early spontaneous cataract. Genetically linked with the latter was a set of features of accelerated senescence, which were inherited by the subsequent generations of the animals. At present, we have a 103rd generation of OXYS rats, who at young age develop retinopathy (similar to age-related macular degeneration in humans), osteoporosis, arterial hypertension, accelerated thymus involution, sarcopenia, and neurodegenerative changes in the brain (with the features characteristic of Alzheimer's disease), besides the cataract. This review discusses possible mechanisms of the accelerated senescence: the results of comparison of retinal transcriptomes between OXYS and Wistar(control) rats at different ages, studies of the markers of Alzheimer's disease in the retina and in certain brain regions, and the outcome of the efforts to develop congenic strains of animals via a transfer of several quantitative trait loci (QTLs) of chromosome 1 from OXYS to WAG rats that are associated with the signs of accelerated senescence. The uniqueness of OXYS rats lies in the complex composition of manifestations of the traits; accordingly, this rat model can be used not only for studies of the mechanisms of aging and pathogenesis of the age-related diseases but also for objective evaluation of new methods of treatment and prevention.

Expression of genes for AhR and Nrf2 signal pathways in the retina of OXYS rats during the development of retinopathy and melatonin-induced changes in this process.

Modulation of oxidative stress is one of the experimental approaches to the therapy of age-related macular degeneration. Melatonin holds much promise in this respect. It was hypothesized that the efficiency of melatonin in age-related macular degeneration is associated with its ability to modulate gene expression for the AhR and Nrf2 signal pathways. Experiments were performed on premature aging OXYS rats, which serve as a reliable model of age-related macular degeneration in humans. We studied the effect of melatonin on gene mRNA for the AhR and Nrf2 signal pathways. Melatonin was shown to decrease the level of mRNA for AhR-dependent genes of CYP1A2 and CYP1B1 cytochromes in the retina, but had no effect on the content of mRNA for Nrf2-dependent genes in OXYS rats.

Cell proliferation in in vivo-like three-dimensional cell culture is regulated by sequestration of ERK1/2 to lipid rafts.

OBJECTIVES: Regulatory mechanisms of cell proliferation have been extensively studied as they represent major challenges when dealing with pathologies such as fibrosis, tumourigenesis or tissue regeneration. Numerous in vitro studies still exploit conventional, two-dimensional cell cultures where cells are forced to adhere to unnaturally stiff and flat surfaces of culture dishes. In the living organism, however, each cell is in contact with components of the extracellular matrix and/or neighbouring cells, thus creating a complex three-dimensional (3D) tissue structure. The current paper describes a native 3D culture of cells, based on the GD25ß1 fibroblast cell line, and its use for investigating cell proliferation in in vivo-like conditions. MATERIALS AND METHODS: Four-day post-confluent culture of GD25ß1 fibroblasts resulted in formation of a 3D system of cells embedded in naturally synthesized extracellular matrix. Morphological characterization of the culture was performed by histochemistry, immunohistochemistry and immunofluorescence. Viability/proliferation was assayed by MTT testing, FACS analysis and Western blotting for determination of expression levels and activation status of the relevant signalling molecules. RESULTS: GD25b1 fibroblasts, grown as 3D culture, gave rise to tissue-like structures characterized by low level of apoptosis, low senescence and development of 3D matrix adhesions, typical of living tissues. Transition to three-dimensionality led to a switch from exponential to linear culture growth, accompanied by accumulation of activated ERK1/2 into caveolin-containing raft domains. Disruption of raft domains as well as reverse transition from 3D back to monolayer culture led to release of phosphorylated ERK1/2 from rafts, activation of cyclin D1 expression and increase in proliferation levels. CONCLUSIONS: These results imply that under in vivo-like conditions, cells might achieve reduction of their proliferation level by sequestering activated ERK1/2 to lipid rafts.

[Potential of melatonin for prevention of age-related macular degeneration: experimental study].

Decline with age of the content of melatonin is considered as one of the leading mechanisms of aging and development of associated diseases, including age-related macular degeneration (AMD)--the disease, which becomes the most common cause of blindness and acuity of vision deterioration in elderly. The prospects of the use of melatonin in the prevention of AMD is being actively discussed, but as a rule on the basis of the results of the experiments on cells in retinal pigment epithelium (RPE). We showed previously that the senescence-accelerated OXYS rat is an adequate animal model of AMD, already used for identifying the relevant therapeutic targets. Here we have investigated the effect of Melatonin (Melaksen, 0,004 mg per kg--a dose equivalent to the recommended one for people) on the development of retinopathy similar to AMD in OXYS rats. Ophthalmoscopic examinations show that Melatonin supplementation decreased the incidence and severity of retinopathy and improved some (but not all) histological abnormalities associated with retinopathy. Thus, melatonin prevented the structural and functional changes in RPE cells, reduced the severity of microcirculatory disorders. Importantly, Melatonin prevented destruction of neurosensory cells, associative and gangliolar neurons in the retina. Taken together, our data suggest the therapeutic potential of Melatonin for treatment and prevention of AMD.

The therapeutic effect of mitochondria-targeted antioxidant SkQ1 and Cistanche deserticola is associated with increased levels of tryptophan and kynurenine in the rat lens.

Supplementation of senescence-accelerated OXYS rats with the mitochondria-targeted antioxidant SkQ1 and with the powder from Cistanche deserticola results in the deceleration of the cataract development and even in the improvement of lens transparency. The therapeutic effect of these preparations correlates with a significant elevation of tryptophan and kynurenine levels in the lens. This finding is attributed to a deceleration of the tryptophan and kynurenine oxidation due to antioxidant-assisted reduction of oxidative stress in the lens.

Brain proteoglycans in postnatal development and during behavior decline in senescence-accelerated OXYS rats.

Proteoglycans (PG) are involved in the brain development as well as in the pathogenesis of age-related neurodegenerative disorders but underlying mechanism remains poorly understood. We showed that senescence-accelerated OXYS rats are suitable model of age-related cerebral dysfunctions. Here the content and composition of PG in the postnatal development and during behavioral decline were examined in the brain of OXYS and Wistar(control) rats at the ages of 1, 7, 14 days and 1, 2 and 14 months. Thereafter behavior in open field (OF) and elevated plus maze (EPM) was investigated. Data confirmed the absence of differences in the performance in tasks between Wistar and OXYS rats at the age of 1 month and showed faster age-related anxiety-like behavior decline in OXYS rats. The distribution of PG and the extent of their sulfation undergo dramatic and rapid changes in the brain during postnatal development both in Wistar and OXYS rats. Significant differences in these parameters appeared in the period of development of behavioral decline in OXYS rats. In contrast, no interstrain differences were revealed in the content and composition of PG in 14-month-old rats when behavior deteriorations are already developed. The results suggest that behavioral deterioration in OXYS rats occurs against the background of altered composition, quantity and glycosaminoglycans (GAG) sulfation.