Mario Rivera-Meza1, María Elena Quintanilla, Lutske Tampier. 1. Faculty of Medicine, Institute of Biomedical Sciences, Program of Molecular and Clinical Pharmacology, Laboratory of Pharmacogenetics of Alcoholism, University of Chile, Av. Independencia 1027, Independencia, Santiago, Chile. mariorivera@med.uchile.cl
Abstract
AIMS: To mimic, in an animal model of alcoholism, the protective phenotype against alcohol consumption observed in humans carrying a fast alcohol dehydrogenase (ADH1B*2) and an inactive aldehyde dehydrogenase (ALDH2*2). METHODS: We developed a multiple expression cassette adenoviral vector (AdV-ADH/asALDH2) encoding both a fast rat ADH and an antisense RNA against rat ALDH2. A control adenoviral vector (AdV-C) containing intronic non-coding DNA was also developed. These adenoviral vectors were administered intravenously to rats bred as high alcohol-drinkers (University of Chile bibulous) that were previously rendered alcohol dependent by a 75-day period of voluntary 10% ethanol intake. RESULTS: Animals administered AdV-ADH/asALDH2 showed a 176% increase in liver ADH activity, whereas liver ALDH2 activity was reduced by 24%, and upon the administration of a dose of ethanol (1 g/kg, i.p.), these showed arterial acetaldehyde levels that were 400% higher than those of animals administered AdV-C. Rats that received the AdV-ADH/asALDH2 vector reduced by 60% their voluntary ethanol intake versus controls. CONCLUSION: This study provides evidence that the simultaneous increase of liver ADH and a reduction of ALDH activity by gene transfer could constitute a potential therapeutic strategy for the treatment of alcoholism.
AIMS: To mimic, in an animal model of alcoholism, the protective phenotype against alcohol consumption observed in humans carrying a fast alcohol dehydrogenase (ADH1B*2) and an inactive aldehyde dehydrogenase (ALDH2*2). METHODS: We developed a multiple expression cassette adenoviral vector (AdV-ADH/asALDH2) encoding both a fast ratADH and an antisense RNA against ratALDH2. A control adenoviral vector (AdV-C) containing intronic non-coding DNA was also developed. These adenoviral vectors were administered intravenously to rats bred as high alcohol-drinkers (University of Chile bibulous) that were previously rendered alcohol dependent by a 75-day period of voluntary 10% ethanol intake. RESULTS: Animals administered AdV-ADH/asALDH2 showed a 176% increase in liver ADH activity, whereas liver ALDH2 activity was reduced by 24%, and upon the administration of a dose of ethanol (1 g/kg, i.p.), these showed arterial acetaldehyde levels that were 400% higher than those of animals administered AdV-C. Rats that received the AdV-ADH/asALDH2 vector reduced by 60% their voluntary ethanol intake versus controls. CONCLUSION: This study provides evidence that the simultaneous increase of liver ADH and a reduction of ALDH activity by gene transfer could constitute a potential therapeutic strategy for the treatment of alcoholism.
Authors: Gabriele Toietta; Viraj P Mane; Wilma S Norona; Milton J Finegold; Philip Ng; Antony F McDonagh; Arthur L Beaudet; Brendan Lee Journal: Proc Natl Acad Sci U S A Date: 2005-03-07 Impact factor: 11.205
Authors: Gerald A Deehan; Sheketha R Hauser; Jessica A Wilden; William A Truitt; Zachary A Rodd Journal: Front Behav Neurosci Date: 2013-08-23 Impact factor: 3.558
Authors: Mario Rivera-Meza; Daniel Muñoz; Erik Jerez; María E Quintanilla; Catalina Salinas-Luypaert; Katia Fernandez; Eduardo Karahanian Journal: Front Behav Neurosci Date: 2017-07-14 Impact factor: 3.558