A Novel Dual Drug Approach that Combines Ivermectin and Dihydromyricetin (DHM) to Reduce Alcohol Drinking and Preference in Mice

Molecules

JacquesY. Roberge¹  Eileen Carry¹  DarylL. Davies²  Joshua Silva²  Chen Xue²  Jing Liang²  Jifeng Zhang² 

[1] Molecular Design and Synthesis Group, Rutgers University Biomedical Research Innovation Core, Piscataway, NJ 08854, USA;Titus Family Department of Clinical Pharmacy, University of Southern California School of Pharmacy, Los Angeles, CA 90089, USA;

关键词: dihydromyricetin;    flavonoids;    alcohol;    alcohol use disorder;    ivermectin;   

DOI  :  10.3390/molecules26061791

来源: DOAJ

【 摘 要 】

Alcohol use disorder (AUD) affects over 18 million people in the US. Unfortunately, pharmacotherapies available for AUD have limited clinical success and are under prescribed. Previously, we established that avermectin compounds (ivermectin [IVM] and moxidectin) reduce alcohol (ethanol/EtOH) consumption in mice, but these effects are limited by P-glycoprotein (Pgp/ABCB1) efflux. The current study tested the hypothesis that dihydromyricetin (DHM), a natural product suggested to inhibit Pgp, will enhance IVM potency as measured by changes in EtOH consumption. Using a within-subjects study design and two-bottle choice study, we tested the combination of DHM (10 mg/kg; i.p.) and IVM (0.5–2.5 mg/kg; i.p.) on EtOH intake and preference in male and female C57BL/6J mice. We also conducted molecular modeling studies of DHM with the nucleotide-binding domain of human Pgp that identified key binding residues associated with Pgp inhibition. We found that DHM increased the potency of IVM in reducing EtOH consumption, resulting in significant effects at the 1.0 mg/kg dose. This combination supports our hypothesis that inhibiting Pgp improves the potency of IVM in reducing EtOH consumption. Collectively, we demonstrate the feasibility of this novel combinatorial approach in reducing EtOH consumption and illustrate the utility of DHM in a novel combinatorial approach.

【 授权许可】

Unknown