Differential Contributions of Alcohol and the Nicotine-Derived Nitrosamine Ketone (NNK) to Insulin and Insulin-Like Growth Factor Resistance in the Adolescent Rat Brain
摘要:
AIMS: Since epidemiologic studies suggest that tobacco smoke toxins, e.g. the nicotine-derived nitrosamine ketone (NNK) tobacco-specific nitrosamine, can be a co-factor in alcohol-related brain disease (ARBD), we examined the independent and additive effects of alcohol and NNK exposures on spatial learning/memory, and brain insulin/IGF signaling, neuronal function and oxidative stress. METHODS: Adolescent Long Evans rats were fed liquid diets containing 0 or 26% caloric ethanol for 8 weeks. During weeks 3-8, rats were treated with i.p. NNK (2 mg/kg, 3/week) or saline. In weeks 7-8, ethanol groups were binge-administered ethanol (2 g/kg; 3/week). In week 8, at 12 weeks of age, rats were subjected to Morris Water Maze tests. Temporal lobes were used to assess molecular indices of insulin/IGF resistance, oxidative stress and neuronal function. RESULTS: Ethanol and NNK impaired spatial learning, and NNK ± ethanol impaired memory. Linear trend analysis demonstrated worsening performance from control to ethanol, to NNK, and then ethanol + NNK. Ethanol ± NNK, caused brain atrophy, inhibited insulin signaling through the insulin receptor and Akt, activated GSK-3, increased protein carbonyl and 3-nitrotyrosine, and reduced acetylcholinesterase. NNK increased NTyr. Ethanol + NNK had synergistic stimulatory effects on 8-iso-PGF-2±, inhibitory effects on p-p70S6K, tau and p-tau and trend effects on insulin-like growth factor type 1 (IGF-1) receptor expression and phosphorylation. CONCLUSIONS: Ethanol, NNK and combined ethanol + NNK exposures that begin in adolescence impair spatial learning and memory in young adults. The ethanol and/or NNK exposures differentially impair insulin/IGF signaling through neuronal growth, survival and plasticity pathways, increase cellular injury and oxidative stress and reduce expression of critical proteins needed for neuronal function. The Author 2015. Medical Council on Alcohol and Oxford University Press. All rights reserved.
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关键词:
Animals Humans Mice Lymph Nodes Receptors, Antigen Antibodies Antigens Cell Communication Immunologic Memory Antibody Formation
DOI:
10.1093/alcalc/agv102
被引量:
年份:
2015
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