Identification of Molecular Targets Associated with Ethanol Toxicity and Implications in Drug Development

Abstract

Alcohol dependence is a major disease burden of adults in modern society worldwide. There is no cure for alcohol dependence. In this study, we have examined the molecular targets of ethanol-induced toxicity in humans based on a systematic review of literature data and then discussed current and potential therapeutic targets for alcohol abuse and dependence. Using human samples with ethanol exposure, microarray analyses of gene expression have shown that numerous genes are up- and/or down-regulated by alcohol exposure. The ethanol-responsive genes mainly encode functional proteins such as proteins involved in nucleic acid binding, transcription factors, selected regulatory molecules, and receptors. These genes are also correlated with important biological pathways, such as angiogenesis, integrin signalling pathway, inflammation, wnt signaling pathway, platelet-derived growth factor signaling pathway, p53 pathway, epidermal growth factor receptor signaling pathway and apoptosis signaling pathway. Currently, only three medications were approved by the U.S. Food and Drug Administration (FDA) for the treatment of alcohol abuse and alcohol dependence, including the aldehyde dehydrogenase inhibitor disulfiram, the micro-opioid receptor antagonist naltrexone, and the N-methyl-D-aspartate (NMDA) receptor inhibitor acamprosate (oral and injectable extended-release formulations). In addition, a number of agents are being investigated as novel treatments for alcohol abuse and dependence. These include selective 5-HT reuptake inhibitors (e.g. fluoxetine), 5-HT(1) receptor agonists (e.g. buspirone), 5-HT(2) receptor antagonists (e.g. ritanserin), 5-HT(3) receptor antagonists (e.g. ondansetron), dopamine receptor antagonists (e.g. aripiprazole and quetiapine), dopamine receptor agonists (e.g. bromocriptine), GABA(B) receptor agonists (e.g. baclofen), and cannabinoid-1 (CB(1)) receptor antagonists. Some of these agents have shown promising efficacy in initial clinical studies. However, further randomized studies with larger samples are warranted to establish their efficacy and safety profiles in the treatment of alcohol dependence.

Understanding the addiction cycle: A complex biology with distinct contributions of genotype vs. sex at each stage

“…Furthermore, supporting the importance of the developmental biology reactome in this model, bioinformatics analysis in human populations representing the low LR to alcohol phenotype identified Nervous System Development/Function as a top enriched function (Joslyn et al, 2010). Consistent with changes in atherosclerosis signaling during abstinence, alcohol abuse is associated with a 2- to 3-fold increase in mortality risk for cardiovascular disease at least in some genotypes (Roerecke and Rehm, 2014) and previous analysis has identified angiogenesis and the platelet-derived growth factor signaling pathways as molecular targets associated with overall ethanol toxicity (Wang et al, 2007, Wang et al, 2010). It is possible that expression differences determined by heritable factors as reflected in the selected phenotype, combined with plastic neuroadapative changes that persist after chronic intoxication and withdrawal, increase the risk of relapse (see Petronis, 2010).…”

Ethanol induced impairment of glucose metabolism involves alterations of GABAergic signaling in pancreatic β-cells

“…Ethanol toxicity is associated with multiple molecular targets that are expressed in various cell types (Wang et al, 2010). On the other hand, both type-A and type-B GABA receptors are expressed in various non neuronal cells outside the CNS (Erdo and Wolff, 1990).…”

Treating alcohol withdrawal with oral baclofen: A randomized, double‐blind, placebo‐controlled trial

“…9 Much of alcohol's acute effects on the central nervous system are mediated by its stimulation of the gamma-aminobutyric acid (GABA) system, which is neuroinhibitory. 10 Chronic alcohol use leads to habituation partly by inducing configuration changes of GABA-A receptor subunits. This renders the GABA-A receptor less sensitive to alcohol, barbiturates, and benzodiazepines.…”