Increased neuroinflammatory signaling and memory deficits caused by early-life ethanol exposure and the potential benefits of anti-inflammatory treatment

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The Ohio State University

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Alcohol consumption during pregnancy can lead to physical irregularities and deficits in cognition collectively known as fetal alcohol spectrum disorders (FASD). Impairments in cognition, particularly hippocampus-dependent memory, may be due to ethanol-induced neuroinflammation resulting from third trimester alcohol consumption, a period of development in which the brain undergoes rapid growth and synaptogenesis. This study utilized a third trimester binge-drinking rodent model of FASD, in which rats were intubated and given ethanol (5g/kg/day; 5E) or sham intubated (SI) over postnatal days (PD)4-9. The ability of two anti-inflammatory drugs, ibuprofen and glycyrrhizin, to normalize neuroinflammation and cognition were investigated. Animals in the ibuprofen group received subcutaneous injections 2h following ethanol treatment (100mg/kg on PD4, 50mg/kg/day following, IBU) or an equivalent volume of PBS (vehicle; VEH). Glycyrrhizin animals received the drug (20mg/kg/day; GLY) or an equivalent volume of VEH via intraperitoneal injections 20-30min prior to ethanol administration. On PD10 the rats were euthanized and hippocampi removed for quantification of inflammation-related gene expression. In the IBU experiment, but not the GLY experiment, the 5E-VEH rats showed significant increases in hippocampal IL-1β and TNF-α, but not CD11B or GFAP, expression compared to SI-VEH and 5E-IBU. Next, we assessed in juvenile 5E rats whether ibuprofen or glycyrrhizin could rescue previously documented deficits in Trace Fear Conditioning (TFC), a challenging hippocampus-dependent associative memory task. Results indicate IBU but not GLY rescued TFC test performance in 5E rats. Taken together, postnatal ethanol upregulated pro-inflammatory cytokine expression on PD10 and impaired TFC over PD31-33. Ibuprofen, but not glycyrrhizin, ameliorated both effects, suggesting the potential benefits of anti-inflammatory drug treatment in improving cognition in FASD individuals.



Neuroinflammation, Fetal Alcohol Spectrum Disorder, Fear conditioning, Anti-inflammatory