Alcohol alters IL-6 Signal Transduction in the CNS of Transgenic Mice with Increased Astrocyte Expression of IL-6

Gruol, Donna L.; Melkonian, Claudia; Huitrón‐Reséndiz, Salvador; Roberts, Amanda J.

doi:10.1007/s10571-020-00879-2

Cited by 12 publications

(18 citation statements)

References 112 publications

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“…The inflammatory profile induced by adolescent BD has been shown to be a core contributor to the long-term alcohol-induced brain damage underlying the behavioral alterations and increased risk for AUD in adulthood [ 37 , 105 , 106 ]. Rodent studies have reported increased astrocytes and microglia production of IL-6 protein in the CNS after ethanol exposure [ 62 , 107 , 108 ], even after one single acute ethanol challenge [ 109 ]. In agreement with previous results [ 27 , 35 , 66 ], binge-like EtOH treatment during adolescence increased IL-6 levels in the striatum and this effect persists during adulthood.…”

Section: Discussionmentioning

confidence: 99%

“…Considering that both HFD and ethanol induces neuroinflammatory processes in overlapping brain circuits, we measured two inflammatory markers in the striatum when their consumption was combined. The implication of cytokine IL-6 and chemokine fractalkine (CX3CL1) gene expression in the central alcohol-related immune response made these two inflammatory mediators our choice [ 61 , 62 , 63 ].…”

Section: Introductionmentioning

confidence: 99%

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Pairing Binge Drinking and a High-Fat Diet in Adolescence Modulates the Inflammatory Effects of Subsequent Alcohol Consumption in Mice

González-Portilla

Montagud‐Romero

Navarrete

et al. 2021

IJMS

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Alcohol binge drinking (BD) and poor nutritional habits are two frequent behaviors among many adolescents that alter gut microbiota in a pro-inflammatory direction. Dysbiotic changes in the gut microbiome are observed after alcohol and high-fat diet (HFD) consumption, even before obesity onset. In this study, we investigate the neuroinflammatory response of adolescent BD when combined with a continuous or intermittent HFD and its effects on adult ethanol consumption by using a self-administration (SA) paradigm in mice. The inflammatory biomarkers IL-6 and CX3CL1 were measured in the striatum 24 h after BD, 3 weeks later and after the ethanol (EtOH) SA. Adolescent BD increased alcohol consumption in the oral SA and caused a greater motivation to seek the substance. Likewise, mice with intermittent access to HFD exhibited higher EtOH consumption, while the opposite effect was found in mice with continuous HFD access. Biochemical analyses showed that after BD and three weeks later, striatal levels of IL-6 and CX3CL1 were increased. In addition, in saline-treated mice, CX3CL1 was increased after continuous access to HFD. After oral SA procedure, striatal IL-6 was increased only in animals exposed to BD and HFD. In addition, striatal CX3CL1 levels were increased in all BD- and HFD-exposed groups. Overall, our findings show that adolescent BD and intermittent HFD increase adult alcohol intake and point to neuroinflammation as an important mechanism modulating this interaction.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pairing Binge Drinking and a High-Fat Diet in Adolescence Modulates the Inflammatory Effects of Subsequent Alcohol Consumption in Mice

González-Portilla

Montagud‐Romero

Navarrete

et al. 2021

IJMS

View full text Add to dashboard Cite

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“…Another group found modest but statistically significant increases in pSTAT3 in the cerebellum and HPC of C57BL/6J mice during withdrawal from 3 cycles of 3 days each of chronic intermittent ethanol vapor exposure 25,26 and in the HPC after a single 4 g/kg injection of ethanol in mice 23 . Because of this, we expected to see increased pSTAT3 at least in the HPC after ethanol drinking.…”

Section: Discussionmentioning

confidence: 88%

“…The role of STAT3 in alcohol‐related disease has been well‐studied in the liver, 22 but its function in the brain in the context of AUD is less understood. STAT3 is activated in the hippocampus (HPC) 23 and Edinger‐Westphal nucleus 24 after an acute ethanol injection and in the cerebellum and HPC after chronic intermittent alcohol exposure 25,26 …”

Section: Introductionmentioning

confidence: 99%

Binge‐like ethanol drinking activates anaplastic lymphoma kinase signaling and increases the expression of STAT3 target genes in the mouse hippocampus and prefrontal cortex

Hamada

Ferguson

Mayfield

et al. 2021

Genes Brain and Behavior

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Alcohol use disorder (AUD) has a complex pathogenesis, making it a difficult disorder to treat. Identifying relevant signaling pathways in the brain may be useful for finding new pharmacological targets to treat AUD. The receptor tyrosine kinase anaplastic lymphoma kinase (ALK) activates the transcription factor STAT3 in response to ethanol in cell lines. Here, we show ALK activation and upregulation of known STAT3 target genes (Socs3, Gfap and Tnfrsf1a) in the prefrontal cortex (PFC) and ventral hippocampus (HPC) of mice after 4 days of binge‐like ethanol drinking. Mice treated with the STAT3 inhibitor stattic drank less ethanol than vehicle‐treated mice, demonstrating the behavioral importance of STAT3. To identify novel ethanol‐induced target genes downstream of the ALK and STAT3 pathway, we analyzed the NIH LINCS L1000 database for gene signature overlap between ALK inhibitor (alectinib and NVP‐TAE684) and STAT3 inhibitor (niclosamide) treatments on cell lines. These genes were then compared with differentially expressed genes in the PFC of mice after binge‐like drinking. We found 95 unique gene candidates, out of which 57 had STAT3 binding motifs in their promoters. We further showed by qPCR that expression of the putative STAT3 genes Nr1h2, Smarcc1, Smarca4 and Gpnmb were increased in either the PFC or HPC after binge‐like drinking. Together, these results indicate activation of the ALK‐STAT3 signaling pathway in the brain after binge‐like ethanol consumption, identify putative novel ethanol‐responsive STAT3 target genes, and suggest that STAT3 inhibition may be a potential method to reduce binge drinking in humans.

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“…To test the effects of apremilast in a more chronic model of dependence-induced escalations in alcohol drinking, female and male C57BL/6J mice underwent a standard CIE protocol 18,[32][33][34][35] . Following 4 cycles of ethanol vapor exposure, mice showed an increase in alcohol intake relative to control mice (Fig.…”

Section: Apremilast Reduces Dependence-induced Escalations In Alcohol Intake In C57bl/6j Micementioning

confidence: 99%

The FDA-approved drug apremilast suppresses alcohol intake: clinical and pre-clinical validation

Grigsby

et al. 2021

Preprint

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Treatment options for Alcohol Use Disorders (AUD) have minimally advanced since 2004, while the annual deaths and economic toll have become alarmingly high. Bringing potential therapeutics beyond the bench and into the clinic for AUD requires rigorous pharmacological screening across molecular, behavioral, pre-clinical, and clinical studies in neuroscience. The repurposing of FDA approved compounds is an effective and expedited means of screening pharmacotherapies for AUD. Here, we demonstrate that apremilast, a phosphodiesterase type 4 inhibitor that is FDA approved for psoriasis and psoriatic arthritis, reduces binge-like alcohol intake and behavioral measures of motivation in unique, preclinical genetic risk models for drinking to intoxication and reduces excessive alcohol drinking in models of stress facilitated drinking and alcohol dependence. In a double blind, placebo-controlled human laboratory study in non-treatment seeking individuals with AUD, apremilast significantly reduced the number of drinks per day. Lastly, using site-directed drug infusions and electrophysiology we determined that apremilast may act by increasing neural activity in the nucleus accumbens, an important alcohol-related brain region, to reduce alcohol intake in mice. These results demonstrate that apremilast reduces excessive alcohol drinking across a spectrum of AUD severity and support its importance as a potential therapeutic for AUD.

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Alcohol alters IL-6 Signal Transduction in the CNS of Transgenic Mice with Increased Astrocyte Expression of IL-6

Cited by 12 publications

References 112 publications

Pairing Binge Drinking and a High-Fat Diet in Adolescence Modulates the Inflammatory Effects of Subsequent Alcohol Consumption in Mice

Pairing Binge Drinking and a High-Fat Diet in Adolescence Modulates the Inflammatory Effects of Subsequent Alcohol Consumption in Mice

Binge‐like ethanol drinking activates anaplastic lymphoma kinase signaling and increases the expression of STAT3 target genes in the mouse hippocampus and prefrontal cortex

The FDA-approved drug apremilast suppresses alcohol intake: clinical and pre-clinical validation

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