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

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.

Identification of Dihydromyricetin and Metabolites in Serum and Brain Associated with Acute Anti-Ethanol Intoxicating Effects in Mice

“…Additionally, Huang et al demonstrated that absorption of DHM was increased by the addition of verapamil, an inhibitor of P-glycoprotein (Pgp) efflux transporters [ 35 ]. This suggests that activity of Pgp transporters in the intestinal tract decreases DHM bioavailability and correlates with reports of DHM to act as a Pgp substate and inhibitor [ 36 , 37 ]. Interestingly, we found sex to have a significant influence on DHM serum exposure following PO, but not IP administration.…”

Strategic developments in the drug delivery of natural product dihydromyricetin: applications, prospects, and challenges

“…In addition, DHM can inhibit ROS accumulation through pGC-1α/SIRT3 signal pathway and protect cells from apoptotic cell death, thus preventing hearing loss caused by oxidative damage of auditory hair cells (Han et al., 2020 ). DHM can also reverse the reduced bioavailability of ivermectin (IVA) due to the presence of P-glycoprotein, which is an innovative therapy for alcohol use disorder and secondary alcoholic liver disease (Silva et al., 2021 ). Moreover, the use of DHM as an adjunct to BACE1 inhibitors in the treatment of Alzheimer’s disease (AD) can reduce the cross-inhibitory toxicity of BACE1 inhibitors, and can delay or reverse the AD progression (Das et al., 2020 ).…”

Action Mechanisms and Pharmacokinetics of Dihydromyricetin against Obesity

“…It also has effects on nonalcoholic fatty liver disease, aging-related tissue fibrosis, metabolic syndrome, diabetes and diabetic complications, inflammation-induced muscle atrophy, Alzheimer’s disease, etc. It is known that DHM inhibits dihydropyrimidinase (with an IC 50 of 48 μM, antibacterial activity), − p-glycoprotein ATPase, SIRT1, and GRP78 in vitro studies. Those targets have not been verified in vivo .…”