THE LIVER-BRAIN AXIS: Brain acetaldehyde and alcohol addiction

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Israel Y1, Quintanilla ME1, Karahanian E2, Rivera-Meza M1, Morales P1, Berrios-Carcamo P1, Salinas-Luypaert C1, Herrera-Marschitz M1

1 Molec. Clin. Pharmacolgy, ICBM Faculty of Medicine, University of Chile,
2 Center for Biomedical Research, Universidad Autonoma de Chile

Studies in Canada, Spain, Italy and Chile have shown that in animals the oxidation of ethanol by brain catalase is needed to generate endogenous brain acetaldehyde, which initiates chronic ethanol intake. Studies show that inhibition of brain catalase synthesis or increasing brain acetaldehyde oxidation fully prevent the development of of chronic ethanol intake. Brain acetaldehyde spontaneously condenses with dopamine forming salsolinol, a strong oxidant which may add to the brain inflammation induced by LPS. Salsolinol administration (i.p. or intra-VTA) leads to marked daylight binge-drinking in ethanol-naïve animals (2 to 2.5 g ethanol/kg in 60 minutes).

After a steady chronic ethanol intake is achieved the perpetuation of ethanol intake is no longer dependent on acetaldehyde but on a brain system that recognizes mechanisms which are markedly inhibited (70-75%) by the administration of N-acetyl cysteine a strong anti-oxidant, which does not inhibit the initiation of chronic ethanol intake. Other anti-oxidant mechanisms directed to the brain may to reduce chronic ethanol and virtually abolish binge drinking.

Alcoholic hepatitis is accompanied by increased inflammatory cytokines and oxidative stress (known to potentiate each other). Noteworthy, a meta-analysis of 22 clinical trials of alcoholic hepatitis treatment showed that while corticosteroids – well known for their anti-inflammatory activity- reduced patient mortality by 45%, the addition to corticosteroids of N-acetyl cysteine resulted in an 85% reduction of mortality. Upon discontinuation of N-acetyl cysteine administration, mortality return to expected levels.

Overall, both liver and brain react positively to the administration of a clinically approved drug such as N-Acetyl cysteine, which may become a treatment of choice for alcohol use disorders.

Supported Fondecyt 1130012, 1130241, 1120079, Millennium P09015F