Bioinformatics Analyses Reveal Age-Specific Neuroimmune Modulation as a Target for Treatment of High Ethanol Drinking

Abstract

Background Use of in silico bioinformatics analyses has led to important leads in the complex nature of alcoholism at the genomic, epigenomic, and proteomic level, but has not previously been successfully translated to the development of effective pharmacotherapies. In this study, a bioinformatics approach led to the discovery of neuroimmune pathways as an age-specific druggable target. Minocycline, a neuroimmune modulator, reduced high ethanol drinking in adult, but not adolescent, mice as predicted a priori. Methods Age and sex-divergent effects in alcohol consumption were quantified in FVB/NJ × C57BL/6J F1 mice given access to 20% alcohol using a 4 hr/day, 4-day Drinking-In-Dark (DID) paradigm. In silico bioinformatics pathway over-representation analysis for age-specific effects of alcohol in brain was performed using gene expression data collected in control and DID-treated, adolescent and adult, male mice. Minocycline (50 mg/kg i.p., once daily) or saline alone was tested for an effect on ethanol intake in the F1 and C57BL/6J (B6) mice across both age and gender groups. Effects of minocycline on the pharmacokinetic properties of alcohol were evaluated by comparing the rates of ethanol elimination between the saline and minocycline treated F1 and B6 mice. Results Age and gender differences in DID consumption were identified. Only males showed a clear developmental increase difference in drinking over time. In silico analyses revealed neuroimmune-related pathways as significantly over-represented in adult, but not adolescent, male mice. As predicted, minocycline treatment reduced drinking in adult, but not adolescent, mice. The age effect was present for both genders, and in both the F1 and B6 mice. Minocycline had no effect on the pharmacokinetic elimination of ethanol. Conclusions Our results are a proof of concept that bioinformatics analysis of brain gene expression can lead to the generation of new hypotheses and a positive translational outcome for individualized pharmacotherapeutic treatment of high alcohol consumption.

Fetal Alcohol Spectrum Disorders and Neuroimmune Changes

“…Further, in our investigations, we discovered that ethanol increases neuroinflammation in adult, but not adolescent mice (Kane et al, 2014). This is interesting in light of the observation that minocycline decreases alcohol consumption in adult but not adolescent mice supporting the concept that minocycline suppresses alcohol consumption by suppressing neuroinflammation (Agrawal et al, 2014). …”

Inhibition of IKKβ Reduces Ethanol Consumption in C57BL/6J Mice

“…Decreased levels of proinflammatory cytokines in blood, for example, could translate to decreased cytokine release and signaling across the BBB, ultimately decreasing levels of inflammatory mediators in brain. We also note that other anti-inflammatory agents, such as minocycline, were proposed to reduce drinking in mice through direct central actions (Agrawal et al, 2014). It has been hypothesized that alcohol-induced inflammatory responses signal via peripheral-central positive-feedback cycles (Robinson et al, 2014).…”

Neuroimmune Pathways in Alcohol Consumption: Evidence from Behavioral and Genetic Studies in Rodents and Humans

“…Both adult and adolescent mice showed increased GFAP (glial fibrillary acidic protein) immunostaining, suggesting that astrocytes may play a role in the inflammatory response to ethanol (Kane et al, 2014). A bioinformatics analysis of adult mouse brains showed differential expression of TLR, JAK/STAT (Janus kinase/signal transducers and activators of transcription), MAPK (mitogen-activated protein kinase), T-cell, and chemokine signaling following a drinking in the dark paradigm, while these pathways were not overexpressed in adolescent mice (Agrawal et al, 2014). Also, minocycline, which has antiinflammatory properties, reduced drinking in adult but not in adolescent mice (Agrawal et al, 2014).…”

“…A bioinformatics analysis of adult mouse brains showed differential expression of TLR, JAK/STAT (Janus kinase/signal transducers and activators of transcription), MAPK (mitogen-activated protein kinase), T-cell, and chemokine signaling following a drinking in the dark paradigm, while these pathways were not overexpressed in adolescent mice (Agrawal et al, 2014). Also, minocycline, which has antiinflammatory properties, reduced drinking in adult but not in adolescent mice (Agrawal et al, 2014). However, other studies have reported opposite results.…”