4-hydroxy-2-nonenal and Memory-Disorders

While prolonged sleep deprivation (SD) could lead to profound negative health consequences, such as impairments in vital biological functions of immunity and cognition, melatonin possesses powerful ameliorating effects against those harmful insults. Melatonin has strong antioxidant and anti-inflammatory effects that help to restore body's immune and cognitive functions. In this study, we investigated the possible role of melatonin in reversing cognitive dysfunction induced by SD in rats. Our experimental results revealed that sleep-deprived animals exhibited spatial memory impairment in the Morris water maze tasks compared with the control groups. Furthermore, there was an increased glial activation most prominent in the hippocampal region of the SD group compared to the normal control (NC) group. Additionally, markers of oxidative stress such as 4-hydroxynonenal (4-HNE) and 7,8-dihydro-8-oxo-deoxyguanine (8-oxo-dG) were significantly increased, while fragile X-mental retardation protein (FMRP) expression was decreased in the SD group. Interestingly, melatonin treatment normalized these events to control levels following SD. Our data demonstrate that SD induces oxidative stress through glial activation and decreases FMRP expression in the neurons. Furthermore, our results suggest the efficacy of melatonin for the treatment of sleep-related neuronal dysfunction, which occurs in neurological disorders such as Alzheimer's disease and autism.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Aldehydes; Animals; Antioxidants; Brain; Cell Survival; Cells, Cultured; Cerebral Cortex; Deoxyguanosine; Disease Models, Animal; Embryo, Mammalian; Fragile X Mental Retardation Protein; Gene Expression Regulation; Male; Maze Learning; Melatonin; Memory Disorders; Neurons; Rats; Rats, Sprague-Dawley; Rats, Wistar; Reactive Oxygen Species; RNA, Small Interfering; Sleep Deprivation

GM-1 ganglioside (GM-1) has been proposed as a new therapeutic agent against Alzheimer's disease (AD). Therefore, in this study we aimed to investigate the effects of GM1 on memory deficits and oxidative stress in the hippocampus of rat model of AD. Wistar rats were randomly divided into three groups (n = 15): control group, model group, and treatment group, which were injected with vehicle, Aβ1-40, and Aβ1-40 together with GM-1, respectively. Morris water maze test was performed to evaluate spatial learning and memory of the rats. Brain malondialdehyde (MDA) content was detected by biochemical assay, and 4-hydroxynonenal (4-HNE) level in the hippocampus was examined by immunohistochemistry. The results showed that learning and memory deficits were improved in treatment group compared to model group. Brain MDA content and 4-HNE level in hippocampus CA1 were much lower in treatment group than in model group. In summary, we demonstrate that GM-1 could improve spatial learning and memory deficits in rat model of AD, and this may be mediated by the inhibition of oxidative stress and lipid peroxidation in the neurons. These data suggest that GM-1 is a potential agent for AD treatment.

Topics: Aldehydes; Alzheimer Disease; Animals; Disease Models, Animal; G(M1) Ganglioside; Hippocampus; Malondialdehyde; Maze Learning; Memory Disorders; Oxidative Stress; Rats; Rats, Wistar

The purpose of this study was to investigate the effect of antioxidant ingestion on stress-induced impairment of cognitive memory. Male C57BL/6 mice were divided into four groups as follows: (1) control mice (C mice) fed in a normal cage without immobilization; (2) restraint-stressed (RS mice) fed in a small cage; (3) vitamin E mice (VE mice), mice were fed in a small cage with a diet supplemented with vitamin E; (4) GliSODin mice (GS mice) fed in a small cage with a diet supplemented with GliSODin. RS, VE and GS mice were exposed to 12 h of immobilization daily. Five weeks later, spatial learning was measured using the Morris Water Maze (MWM) test. After water maze testing, we performed immunohistochemical analysis using 4-hydroxy-2-noneral (4-HNE) and an anti-Ki67 antibody. 4-HNE is a marker of lipid peroxidation. RS mice showed impaired spatial learning performance and an increased number of 4-HNE-positive cells in the granule cell layer (GCL) of the hippocampal dentate gyrus when compared to C mice. Moreover, RS mice showed a decreased number of Ki67-positive cells in the subgranular zone (SGZ). GS mice showed better spatial learning memory than RS mice. The number of 4-HNE-positive cells in the GCL of GS mice was significantly less than that of RS mice. The number of Ki67-positive cells in the SGZ of GS mice was significantly greater than that of RS mice. These finding suggests that GliSODin prevents stress-induced impairment of cognitive function and maintains neurogenesis in the hippocampus through antioxidant activity.

Topics: Administration, Oral; Aldehydes; Animals; Antioxidants; Cucurbitaceae; Hippocampus; Ki-67 Antigen; Male; Maze Learning; Memory Disorders; Mice; Mice, Inbred C57BL; Neurogenesis; Neurons; Nutritional Support; Reaction Time; Restraint, Physical; Stress, Psychological; Superoxide Dismutase; Tocopherols

Oxidative stress may underlie age-dependent memory loss and cognitive decline. Toxic aldehydes, including 4-hydroxy-2-nonenal (HNE), an end product of lipid peroxides, are known to accumulate in the brain in neurodegenerative disease. We have previously shown that mitochondrial aldehyde dehydrogenase 2 (ALDH2) detoxifies HNE by oxidizing its aldehyde group. To investigate the role of such toxic aldehydes, we produced transgenic mice, which expressed a dominant-negative form of ALDH2 in the brain. The mice had decreased ability to detoxify HNE in their cortical neurons and accelerated accumulation of HNE in the brain. Consequently, their lifespan was shortened and age-dependent neurodegeneration and hyperphosphorylation of tau were observed. Object recognition and Morris water maze tests revealed that the onset of cognitive impairment correlated with the degeneration, which was further accelerated by APOE (apolipoprotein E) knock-out; therefore, the accumulation of toxic aldehydes is by itself critical in the progression of neurodegenerative disease, which could be suppressed by ALDH2.

Topics: Aging; Aldehyde Dehydrogenase; Aldehyde Dehydrogenase, Mitochondrial; Aldehydes; Analysis of Variance; Animals; Behavior, Animal; Cells, Cultured; Cerebral Cortex; Embryo, Mammalian; Exploratory Behavior; Gene Expression Regulation, Developmental; Humans; In Situ Nick-End Labeling; Maze Learning; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nerve Tissue Proteins; Neurodegenerative Diseases; Neurons; Pattern Recognition, Visual; Peptide Elongation Factor 1; Psychomotor Performance

Amyloid beta-peptide (Abeta) is known to induce free radical-mediated oxidative stress in the brain. Free radical-mediated damage to the neuronal membrane components has been implicated in the etiology of Alzheimer's disease (AD). Abeta is produced by proteolytic processing of the amyloid precursor protein (APP). The senescence accelerated mouse prone 8 (SAMP8) strain was developed by phenotypic selection from a common genetic pool. The SAMP8 strain exhibits age-related deterioration in memory and learning as well as Abeta accumulation, and it is considered an effective model for studying brain aging in accelerated senescence. Previous research has shown that a phosphorothiolated antisense oligonucleotide directed against the Abeta region of APP decreases the expression of APP and reverses deficits in learning and memory in aged SAMP8 mice. Consistent with other reports, our previous study showed that 12-month-old SAMP8 mice have increased levels of oxidative stress markers in the brain compared with that in brains from 4-month-old SAMP8 mice. In the current study, 12-month-old SAMP8 mice were treated with antisense oligonucleotide directed against the Abeta region of APP, and the oxidative markers in brain were decreased significantly. Therefore, we conclude that Abeta may contribute to the oxidative stress found in aged SAMP8 mice that have learning and memory impairments. These results are discussed in reference to AD.

Topics: Aging; Aldehydes; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Biomarkers; Brain; Cells, Cultured; Disease Models, Animal; Down-Regulation; Glutamate-Ammonia Ligase; Lipid Peroxidation; Memory Disorders; Mice; Mice, Inbred Strains; Neurons; Oligonucleotides, Antisense; Oxidative Stress; Rats; Rats, Sprague-Dawley; Thiobarbituric Acid Reactive Substances; Tyrosine