Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction

Cellular senescence is the arrest of normal cell division. Oncogenic genes and oxidative stress, which cause genomic DNA damage and generation of reactive oxygen species, lead to cellular senescence. The senescence-associated secretory phenotype is a distinct feature of senescence. Senescence is normally involved in the embryonic development. Senescent cells can communicate with immune cells to invoke an immune response. Senescence emerges during the aging process in several tissues and organs. In fact, increasing evidence shows that cellular senescence is implicated in aging-related diseases, such as nonalcoholic fatty liver disease, obesity and diabetes, pulmonary hypertension, and tumorigenesis. Cellular senescence can also be induced by microbial infection. During cellular senescence, several signaling pathways, including those of p53, nuclear factor-κB (NF-κB), mammalian target of rapamycin, and transforming growth factor-beta, play important roles. Accumulation of senescent cells can trigger chronic inflammation, which may contribute to the pathological changes in the elderly. Given the variety of deleterious effects caused by cellular senescence in humans, strategies have been proposed to control senescence. In this review, we will focus on recent studies to provide a brief introduction to cellular senescence, including associated signaling pathways and pathology.

Cellular senescence: Molecular mechanisms and pathogenicity.

Preconditioning refers to a procedure by which a single noxious stimulus below the threshold of damage is applied to the tissue in order to increase resistance to the same or even different noxious stimuli given above the threshold of damage. Hypoxic preconditioning relies on complex and active defenses that organisms have developed to counter the adverse consequences of oxygen deprivation. The protection it confers against ischemic attack for instance as well as the underlying biological mechanisms have been extensively investigated in animal models. Based on these data, hypoxic conditioning (consisting in recurrent exposure to hypoxia) has been suggested a potential non-pharmacological therapeutic intervention to enhance some physiological functions in individuals in whom acute or chronic pathological events are anticipated or existing. In addition to healthy subjects, some benefits have been reported in patients with cardiovascular and pulmonary diseases as well as in overweight and obese individuals. Hypoxic conditioning consisting in sessions of intermittent exposure to moderate hypoxia repeated over several weeks may induce hematological, vascular, metabolic, and neurological effects. This review addresses the existing evidence regarding the use of hypoxic conditioning as a potential therapeutic modality, and emphasizes on many remaining issues to clarify and future researches to be performed in the field.

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Hypoxic Conditioning as a New Therapeutic Modality

Introduction:
To study the effect of gallic acid (GA) on hippocampal long-term potentiation (LTP) and histological changes in animal model of Alzheimer disease (AD) induced by beta-amyloid (Aβ).

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Effect of Gallic Acid on Dementia Type of Alzheimer Disease in Rats: Electrophysiological and Histological Studies.

Chronic hypoxia has been reported to contribute to the development of Alzheimer's disease (AD). However, the mechanism of hypoxia in the pathogenesis of AD remains unclear. The purpose of this study was to investigate the effects of chronic hypoxia treatment on β-amyloid, tau pathologies, and the behavioral consequences in the double transgenic (APP/PS1) mice. Double transgenic mice (APP/PS1 mice) were treated with hypoxia, and spatial learning and memory abilities of mice were assessed in the Morris water maze. β-amyloid level and plaque level in APP/PS1 double transgenic mice were detected by immunohistochemistry. Protein tau, p35/p25, cyclin-dependent kinase 5 (CDK5), and calpain were detected by western blotting analysis. Chronic hypoxia treatment decreased memory and cognitive function in AD mice. In addition, chronic hypoxia treatment resulted in increased senile plaques, accompanying with increased tau phosphorylation. The hypoxia-induced increase in the tau phosphorylation was associated with a significant increase in the production of p35 and p25 and upregulation of calpain, suggesting that hypoxia induced aberrant CDK5/p25 activation via upregulation of calpain. Our results showed that chronic hypoxia exposure accelerates not only amyloid pathology but also tau pathology via calpain-mediated tau hyperphosphorylation in an AD mouse model. These pathological changes possibly contribute to the hypoxia-induced behavioral change in AD mice.

Hypoxia Increases Aβ-Induced Tau Phosphorylation by Calpain and Promotes Behavioral Consequences in AD Transgenic Mice

We report here studies addressing the possibility of preventing neurodegenerative changes in the brain using adaptation to periodic hypoxia in rats with experimental Alzheimer’s disease induced by administration of the neurotoxic peptide fragment of β-amyloid (Ab) into the basal magnocellular nucleus. Adaptation to periodic hypoxia was performed in a barochamber (4000 m, 4 h per day, 14 days). The following results were obtained 15 days after administration of Ab. 1. Adaptation to periodic hypoxia significantly blocked Ab-induced memory degradation in rats, as assessed by testing a conditioned passive avoidance reflex. 2. Adaptation to periodic hypoxia significantly restricted increases in oxidative stress, measured spectrophotometrically in the hippocampus in terms of the content of thiobarbituric acid-reactive secondary lipid peroxidation products. 3. Adaptation to periodic hypoxia completely prevented the overproduction of NO in the brains of rats with experimental Alzheimer’s disease, as measured in terms of increases in tissue levels of stable NO metabolites, i.e., nitrites and nitrates. 4. The cerebral cortex of rats given Ab injections after adaptation to periodic hypoxia did not contain neurons with pathomorphological changes or dead neurons (Nissl staining), which were typical in animals with experimental Alzheimer’s disease. Thus, adaptation to periodic hypoxia effectively prevented oxidative and nitrosative stress, protecting against neurodegenerative changes and protecting cognitive functions in experimental Alzheimer’s disease.

Prevention of neurodegenerative damage to the brain in rats in experimental Alzheimer's disease by adaptation to hypoxia.

Adaptation to intermittent hypoxia restricts nitric oxide overproduction and prevents beta-amyloid toxicity in rat brain.

Adaptation to intermittent hypoxia prevents rarefaction of the brain vascular net in rats with experimental Alzheimer's disease

Introduction. Patients with Alzheimer’s disease (AD) have reduced cerebral vascular density (VD), which impairs blood flow to neurons and may contribute to progression of AD. Earlier we showed that prior adaptation to intermittent hypobaric hypoxia (IHH) prevented memory loss and degeneration of cortical neurons in rats with experimental AD (EAD). The aim of this study was to test if IHH might prevent EAD-induced vascular rarefaction in rats. Materials and methods. EAD was induced with bilateral injection of neurotoxic beta-amyloid peptide fragment (A) (25–35) into n. basalis magnocellularis. IHH was simulated at a 4,000 m altitude, for 4 hours a day, for 14 days. Brain blood vessels were stained by transcardiac infusion of Indian ink; brain sections were stained with 0.3 % cresyl violet by Nissle method. Vascular density was assessed in the cortex and hippocampus using the Infinity Analysis Software. Results. In the EAD rats, VD was significantly decreased in the hippocampus (13.3±0.9 vs 17.8±1.0 in field of view, FOV, p<0.03) and in the cortex (17.3±1.5 vs 22.3±1.3 in FOV, p<0.03). AIH increased VD in the hippocampus to 27.0±3.5 in FOV (p=0.01) and in cortex to 26.0±1.1 in FOV (p<0.03). In EAD+AIH rats, VD did not differ significantly from the control rats neither in the hippocampus, nor in the cortex. AIH may stimulate angiogenesis through hypoxia inducible factor-1α-mediated expression of vascular endothelial growth factor and/or by increasing expression and activity of antioxidant enzymes. Conclusion. One of the mechanisms of AIH beneficial effect in AD-related neurodegeneration is preserving the capability for compensatory angiogenesis in brain.

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Igor V. Barskov

Papers

Prevention of neurodegenerative damage to the brain in rats in experimental Alzheimer's disease by adaptation to hypoxia.

Adaptation to intermittent hypoxia restricts nitric oxide overproduction and prevents beta-amyloid toxicity in rat brain.

Adaptation to intermittent hypoxia prevents rarefaction of the brain vascular net in rats with experimental Alzheimer's disease

Адаптация к периодической гипоксии предупреждает снижение плотности сосудистой сети мозга крыс при экспериментальной болезни Альцгеймера

Nitric oxide prevents cognitive disorders and neurodegeneration in rats with experimental Alzheimer's disease