Ming Tong1, Rosa Yu2, Chetram Deochand3, Suzanne M de la Monte4. 1. Department of Medicine, Division of Gastroenterology, and the Liver Research Center, Rhode Island Hospital, Providence, RI, USA Warren Alpert Medical School of Brown University, Providence, RI, USA. 2. Departments of Pathology and Neurology, and the Division of Neuropathology, Rhode Island Hospital, Providence, RI, USA. 3. Biotechnology Graduate Program, Brown University, Providence, RI, USA. 4. Department of Medicine, Division of Gastroenterology, and the Liver Research Center, Rhode Island Hospital, Providence, RI, USA Warren Alpert Medical School of Brown University, Providence, RI, USA Departments of Pathology and Neurology, and the Division of Neuropathology, Rhode Island Hospital, Providence, RI, USA suzanne_delamonte_md@brown.edu.
Abstract
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-3β, increased protein carbonyl and 3-nitrotyrosine, and reduced acetylcholinesterase. NNK increased NTyr. Ethanol + NNK had synergistic stimulatory effects on 8-iso-PGF-2α, 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.
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 ± ethanolimpaired 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-3β, increased protein carbonyl and 3-nitrotyrosine, and reduced acetylcholinesterase. NNK increased NTyr. Ethanol + NNK had synergistic stimulatory effects on 8-iso-PGF-2α, 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.
Authors: Ming Tong; Alexander Neusner; Lisa Longato; Margot Lawton; Jack R Wands; Suzanne M de la Monte Journal: J Alzheimers Dis Date: 2009 Impact factor: 4.472
Authors: J D Morrow; T A Minton; C R Mukundan; M D Campbell; W E Zackert; V C Daniel; K F Badr; I A Blair; L J Roberts Journal: J Biol Chem Date: 1994-02-11 Impact factor: 5.157
Authors: Suzanne M de la Monte; Jong-Eun Yeon; Ming Tong; Lisa Longato; Rajeev Chaudhry; Mao-Yin Pang; Kevin Duan; Jack R Wands Journal: J Gastroenterol Hepatol Date: 2008-05-26 Impact factor: 4.029
Authors: Ming Tong; Rosa Yu; Elizabeth Silbermann; Valerie Zabala; Chetram Deochand; Suzanne M de la Monte Journal: Alcohol Alcohol Date: 2015-09-15 Impact factor: 2.826
Authors: Rosa Yu; Chetram Deochand; Alexander Krotow; Raiane Leão; Ming Tong; Amit R Agarwal; Enrique Cadenas; Suzanne M de la Monte Journal: J Alzheimers Dis Date: 2016 Impact factor: 4.472
Authors: Kavin Nunez; Jared Kay; Alexander Krotow; Ming Tong; Amit R Agarwal; Enrique Cadenas; Suzanne M de la Monte Journal: J Alzheimers Dis Date: 2016 Impact factor: 4.472
Authors: Ming Tong; Howard Gonzalez-Navarrete; Tyler Kirchberg; Billy Gotama; Emine B Yalcin; Jared Kay; Suzanne M de la Monte Journal: J Drug Alcohol Res Date: 2017-08-23
Authors: Valerie Zabala; Elizabeth Silbermann; Edward Re; Tomas Andreani; Ming Tong; Teresa Ramirez; Fusun Gundogan; Suzanne M de la Monte Journal: Gynecol Obstet Res Date: 2016-03-15