The Activation of Aldehyde Dehydrogenase 2 (ALDH2) by Alda-1 and Flurbiprofen as a Common Mechanism to Reduce Alcohol Intake in Rats

Excessive alcohol consumption causes millions of deaths annually, yet current pharmacological treatments for alcohol use disorders show limited efficacy and poor adherence, creating an urgent need for new therapeutic alternatives. Aldehyde dehydrogenase 2 (ALDH2) metabolizes acetaldehyde, a key mediator of the rewarding effects of alcohol in the brain, making ALDH2 activation a promising therapeutic target. This study investigated whether flurbiprofen, an FDA-approved nonsteroidal anti-inflammatory drug that activates ALDH2, reduces alcohol intake compared to the experimental ALDH2 activator Alda-1 and the structurally similar NSAID ibuprofen. Male alcohol-preferring UChB rats received oral flurbiprofen (2.5–10 mg/kg), Alda-1 (5 mg/kg), or ibuprofen (5 mg/kg) during acquisition and chronic phases of voluntary alcohol consumption under a two-bottle free-choice paradigm. Both flurbiprofen and Alda-1 reduced alcohol intake by approximately 60% and similarly increased ALDH2 activity 3–4-fold in brain and liver tissues. Ibuprofen showed modest effects (25% alcohol intake reduction). In vitro assays confirmed that flurbiprofen and Alda-1, but not ibuprofen, activated ALDH2 in PC-12 cells. Enzymatic assays and molecular docking revealed that Alda-1 lacks cyclooxygenase-inhibitory activity, unlike flurbiprofen, suggesting that ALDH2 activation is the primary mechanism underlying reduced alcohol consumption. These findings identify flurbiprofen as a clinically available ALDH2 activator with significant translational potential for treating alcohol use disorders.