Preclinical evaluation of avermectins as novel therapeutic agents for alcohol use disorders

Abstract

The deleterious effects of alcohol use disorders (AUDs) on human health have been documented worldwide. The enormous socioeconomic burden coupled with lack of efficacious pharmacotherapies underlies the need for improved treatment strategies. At present, there is a growing body of preclinical evidence that demonstrates the potential of avermectins [ivermectin (IVM), selamectin (SEL), abamectin (ABM), and moxidectin (MOX)] in treatment of AUDs. Avermectins are derived by fermentation of soil micro-organism, Streptomyces avermitilis, and have been extensively used for treatment of parasitic infections. From the mechanistic standpoint, avermectins are positive modulators of purinergic P2X4 receptors (P2X4Rs). P2X4Rs belong to P2X superfamily of cation-permeable ion channels gated by adenosine 5'-triphosphate (ATP). Building evidence has implicated a role for P2X4Rs in regulation of ethanol intake and that ethanol can inhibit ATP-gated currents in P2X4Rs. Investigations using recombinant cell models and animal models of alcohol drinking have reported that IVM, ABM, and MOX, but not SEL, were able to antagonize the inhibitory effects of ethanol on P2X4Rs in vitro and reduce ethanol intake in vivo. Furthermore, IVM was shown to reduce ethanol consumption via P2X4R potentiation in vivo, supporting the involvement of P2X4Rs in IVM's anti-alcohol effects and that P2X4Rs can be used as a platform for developing novel anti-alcohol compounds. Taken together, these findings support the utility of avermectins as a novel class of drug candidates for treatment of AUDs.

Avermectin Derivatives, Pharmacokinetics, Therapeutic and Toxic Dosages, Mechanism of Action, and Their Biological Effects

“…Four different types of AVM were tested for their potential as anti-alcohol therapy, namely selamectin (SEL), abamectin (ABM), ivermectin (IVM) and moxidectin (MOX). IVM modulates the action of ethanol on P2X4Rs in an in vivo study, which may be associated with a decrease in alcohol intake [124]. Also in both male and female mice of the C57BL/6J strain.…”

Candidate drugs against SARS-CoV-2 and COVID-19

“…The triple combination of cepharanthine (an anti-inflammatory alkaloid from Stephania cepharantha Hayata), (CAS number: 48,104,902), selamectin (an avermectin isolated from Streptomyces avermitilis and used as an anti-helminthic and parasiticide drug in veterinary medicine), (CAS number. 220119−17-5), and mefloquine hydrochloride (Lariam™, used for the prophylaxis and treatment of malaria) [57][58][59] has recently been shown to inhibit infection of simian Vero E6 cells with pangolin coronavirus GX_P2V/2017/Guangxi (GX_P2V), whose S protein shares 92.2 % amino acid identity with that of SARS-CoV-2 [60]. Further, it was demonstrated that GX_P2V also uses ACE2 as the receptor for viral cell entry [60].…”

Resolving the Ionotropic P2X4 Receptor Mystery Points towards a New Therapeutic Target for Cardiovascular Diseases

“…Rather than deleterious, the P2X4R expression and function in the brain reward system have been associated with salutary effects in alcohol abuse. Ethanol is a preferential inhibitor of the P2X4R, a situation that can be overcome by positive allosteric modulators, like ivermectin or derivates, which have been shown to reduce ethanol drinking behavior (reviewed in [200,201]).…”