Pharmacological activators of ALDH2: A new strategy for the treatment of alcohol use disorders

In mammals, ethanol is metabolized to acetaldehyde mainly by the liver alcohol dehydrogenase (ADH), and acetaldehyde is subsequently oxidized to acetate by mitochondrial aldehyde dehydrogenase (ALDH2). The presence of an inactive variant of ALDH2 or the use of inhibitors of this enzyme leads to an accumulation of acetaldehyde after ethanol consumption, generating an aversive reaction that inhibits subsequent alcohol intake. However, experimental evidence shows that acetaldehyde has potent rewarding effects at the central level, suggesting that acetaldehyde would be responsible for the addictive effect of alcohol. Alda-1 is an organic molecule that acts as a pharmacological activator of ALDH2. Studies in animal models of alcohol use disorders (AUD; i.e. alcoholism) have shown that Alda-1 can inhibit the acquisition, the chronic intake, and the relapse of alcohol consumption. These effects are reversible without any effects on water consumption or other natural reinforcer such as saccharin. It has also been reported that Alda-1 can act as a protective agent from the toxic effects on various tissues and organs mediated by ethanol-derived acetaldehyde, including liver damage, cancer, and central nervous system (CNS) alterations. Using in silico tools such as molecular docking the identification of important molecular interactions between Alda-1 and ALDH2 has been demonstrated, identifying new molecules with higher pharmacological features. Thus, there is now preclinical evidence supporting the use of activators of ALDH2 as a pharmacological strategy for the treatment of AUD.