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10.3390/molecules26061791
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Article

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

by
Joshua Silva
1,
Eileen Carry
2,
Chen Xue
1,
Jifeng Zhang
1,
Jing Liang
1,
Jacques Y. Roberge
2 and
Daryl L. Davies
1,*
1
Titus Family Department of Clinical Pharmacy, University of Southern California School of Pharmacy, Los Angeles, CA 90089, USA
2
Molecular Design and Synthesis Group, Rutgers University Biomedical Research Innovation Core, Piscataway, NJ 08854, USA
*
Author to whom correspondence should be addressed.
Molecules 2021, 26(6), 1791; https://doi.org/10.3390/molecules26061791
Submission received: 28 January 2021 / Revised: 18 March 2021 / Accepted: 19 March 2021 / Published: 22 March 2021
(This article belongs to the Special Issue Natural Products: Therapeutic Properties and Beyond)
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Abstract

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.
Keywords: dihydromyricetin; flavonoids; alcohol; alcohol use disorder; ivermectin dihydromyricetin; flavonoids; alcohol; alcohol use disorder; ivermectin

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MDPI and ACS Style

Silva, J.; Carry, E.; Xue, C.; Zhang, J.; Liang, J.; Roberge, J.Y.; Davies, D.L. A Novel Dual Drug Approach That Combines Ivermectin and Dihydromyricetin (DHM) to Reduce Alcohol Drinking and Preference in Mice. Molecules 2021, 26, 1791. https://doi.org/10.3390/molecules26061791

AMA Style

Silva J, Carry E, Xue C, Zhang J, Liang J, Roberge JY, Davies DL. A Novel Dual Drug Approach That Combines Ivermectin and Dihydromyricetin (DHM) to Reduce Alcohol Drinking and Preference in Mice. Molecules. 2021; 26(6):1791. https://doi.org/10.3390/molecules26061791

Chicago/Turabian Style

Silva, Joshua, Eileen Carry, Chen Xue, Jifeng Zhang, Jing Liang, Jacques Y. Roberge, and Daryl L. Davies. 2021. "A Novel Dual Drug Approach That Combines Ivermectin and Dihydromyricetin (DHM) to Reduce Alcohol Drinking and Preference in Mice" Molecules 26, no. 6: 1791. https://doi.org/10.3390/molecules26061791

APA Style

Silva, J., Carry, E., Xue, C., Zhang, J., Liang, J., Roberge, J. Y., & Davies, D. L. (2021). A Novel Dual Drug Approach That Combines Ivermectin and Dihydromyricetin (DHM) to Reduce Alcohol Drinking and Preference in Mice. Molecules, 26(6), 1791. https://doi.org/10.3390/molecules26061791

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