4-hydroxy-2-nonenal and Cognitive-Dysfunction

Vascular dementia (VaD) is a progressive cognitive impairment caused by a reduced blood supply to the brain. Chronic cerebral hypoperfusion (CCH) is one cause of VaD; it induces oxidative stress, neuroinflammation, and blood-brain barrier (BBB) disruption, damaging several brain regions. Vitamin C plays a vital role in preventing oxidative stress-related diseases induced by reactive oxygen species, but it is easily oxidized and loses its antioxidant activity. To overcome this weakness, we have developed a vitamin C/DNA aptamer complex (NXP031) that increases vitamin C's antioxidant efficacy. Aptamers are short single-stranded nucleic acid polymers (DNA or RNA) that can interact with their corresponding target with high affinity. We established an animal model of VaD by permanent bilateral common carotid artery occlusion (BCCAO) in 12 week old Wistar rats. Twelve weeks after BCCAO, we injected NXP031 into the rats intraperitoneally for two weeks at moderate (200 mg/4 mg/kg) and high concentrations (200 mg/20 mg/kg). NXP031 administration alleviates cognitive impairment, microglial activity, and oxidative stress after CCH. NXP031 increased the expression of basal lamina (laminin), endothelial cell (RECA-1, PECAM-1), and pericyte (PDGFRβ); these markers maintain the BBB integrity. We found that NXP031 administration activated the Nrf2-ARE pathway and increased the expression of SOD-1 and GSTO1/2. These results suggest that this new aptamer complex, NXP031, could be a therapeutic intervention in CCH-induced VaD.

Topics: Aldehydes; Animals; Blood-Brain Barrier; Brain; Chronic Disease; Cognitive Dysfunction; Dementia, Vascular; Disease Models, Animal; Hippocampus; Male; Microglia; Microvessels; NF-E2-Related Factor 2; Rats, Wistar; Signal Transduction; Up-Regulation

Mice deficient in the antioxidant enzyme Cu/Zn-superoxide dismutase (Sod1KO mice) have a significant reduction in lifespan, exhibit many phenotypes of accelerated aging, and have high levels of oxidative stress in various tissues. Age-associated cognitive decline is a hallmark of aging and the increase in oxidative stress/damage with age is one of the mechanisms proposed for cognitive decline with age. Therefore, the goal of this study was to determine if Sod1KO mice exhibit an accelerated loss in cognitive function similar to that observed in aged animals. Cognition was assessed in Sod1KO and wild type (WT) mice using an automated home-cage testing apparatus (Noldus PhenoTyper) that included an initial discrimination and reversal task. Comparison of the total distance moved by the mice during light and dark phases of the study demonstrated that the Sod1KO mice do not show a deficit in movement. Assessment of cognitive function showed no significant difference between Sod1KO and WT mice during the initial discrimination phase of learning. However, during the reversal task, Sod1KO mice showed a significantly greater number of incorrect entries compared to WT mice indicating a decline in cognition similar to that observed in aged animals. Markers of oxidative stress (4-Hydroxynonenal, 4-HNE) and neuroinflammation [proinflammatory cytokines (IL6 and IL-1β) and neuroinflammatory markers (CD68, TLR4, and MCP1)] were significantly elevated in the hippocampus of male and female Sod1KO compared to WT mice. This study provides important evidence that increases in oxidative stress alone are sufficient to induce neuroinflammation and cognitive dysfunction that parallels the memory deficits seen in advanced aging and neurodegenerative diseases.

Topics: Aging; Aldehydes; Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Biomarkers; Chemokine CCL2; Cognitive Dysfunction; Disease Models, Animal; Hippocampus; Interleukin-1beta; Interleukin-6; Mice, Knockout; Oxidative Stress; Superoxide Dismutase-1; Toll-Like Receptor 4

There is still a considerable debate concerning whether uric acid is neuroprotective or neurotoxic agent. To clarify this topic, we tested the effects of uric acid on neuronal cells biology by using differentiated SHSY5Y neuroblastoma cells incubated with amyloid β to reproduce an in vitro model of Alzheimer's disease. The incubation of cells with uric acid at the dose of 40 µM or higher significantly reduced cell viability and potentiated the proapoptotic effect of amyloid β. Finally, uric acid enhanced the generation of 4-hydroxynonenal and the expression of PPARβ/δ promoted by amyloid β, indicating a prooxidant effects. In conclusion, uric acid could exert a detrimental influence on neuronal biology being this influence further potentiated by the concomitant exposure to neurotoxic stimuli. This effect is evident for uric acid concentrations close to those achievable in cerebrospinal fluid in presence of mild hyperuricemia thus suggesting a potential role of uric acid in pathophysiology of cognitive dysfunction. These effects are influenced by the concentrations of uric acid and by the presence of favoring conditions that commonly occur in neurodegenerative disorders and well as in the aging brain, including increased oxidative stress and exposure to amyloid β. J. Cell. Physiol. 232: 1069-1078, 2017. © 2016 Wiley Periodicals, Inc.

Topics: Aldehydes; Amyloid; Amyloid beta-Peptides; Blotting, Western; Brain-Derived Neurotrophic Factor; Cell Line, Tumor; Cell Shape; Cell Survival; Cognitive Dysfunction; Cytoskeletal Proteins; Dementia; Humans; Intracellular Space; Models, Biological; Neurons; Oxidative Stress; PPAR-beta; Signal Transduction; Uric Acid

Biliverdin reductase-A (BVR-A) is a pleiotropic enzyme and plays pivotal role in the antioxidant defense against free radicals as well as in cell homeostasis. Together with heme oxygenase, BVR-A forms a powerful system involved in the cell stress response during neurodegenerative disorders including Alzheimer's disease (AD), whereas due to the serine/threonine/tyrosine kinase activity the enzyme regulates glucose metabolism and cell proliferation. In this paper, we report results that demonstrate BVR-A undergoes post-translational oxidative and nitrosative modifications in the hippocampus, but not cerebellum, of subjects with AD and amnestic mild cognitive impairment (MCI). A significant increase of nitrated BVR-A was demonstrated only in AD and MCI hippocampi, whereas no significant modifications were found in cerebellar tissue. In addition, a significant reduction in protein carbonyl-derivatives of BVR-A was found in both AD and MCI hippocampi (15% and 18%, respectively). Biliverdin reductase-bound 4-hydroxynonenals were not modified in hippocampi and cerebella from AD and MCI subjects. These results supported the hypothesis of a prevalence of nitrosative stress-induced modifications on BVR-A structure, and this evidence was confirmed by a significant upregulation of inducible nitric oxide synthase in hippocampal tissue of subjects with AD and MCI that was not present in cerebellum. In conclusion, nitrosative stress-induced modifications on hippocampal BVR-A are an early event in the pathogenesis of AD since they appear also in MCI subjects and could contribute to the antioxidant and metabolic derangement characteristic of these neurodegenerative disorders.

Topics: Aged; Aged, 80 and over; Aldehydes; Alzheimer Disease; Blotting, Western; Brain; Cerebellum; Cognitive Dysfunction; Female; Heme Oxygenase (Decyclizing); Hippocampus; Homeostasis; Humans; Immunoprecipitation; Male; Nitric Oxide Synthase Type II; Oxidative Stress; Oxidoreductases Acting on CH-CH Group Donors; Protein Carbonylation; Reactive Nitrogen Species; Tyrosine