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One of the most deleterious consequences of EtOH exposure is neuronal loss in the developing brain. Previously, we showed that EtOH exposure induced neuroapoptosis in the brain of postnatal day 4 (<jats:styled-content style=\"fixed-case\">PD<\/jats:styled-content>4) mice but not <jats:styled-content style=\"fixed-case\">PD<\/jats:styled-content>12 mice. This differential susceptibility may result from an insufficient cellular stress response system such as unfolded protein response (also known as endoplasmic reticulum [<jats:styled-content style=\"fixed-case\">ER<\/jats:styled-content>] stress) in <jats:styled-content style=\"fixed-case\">PD<\/jats:styled-content>4 mice. In this study, we compared the effect of EtOH on <jats:styled-content style=\"fixed-case\">ER<\/jats:styled-content> stress in <jats:styled-content style=\"fixed-case\">PD<\/jats:styled-content>4 and <jats:styled-content style=\"fixed-case\">PD<\/jats:styled-content>12 mice and determined whether the inhibition of <jats:styled-content style=\"fixed-case\">ER<\/jats:styled-content> stress could protect the developing brain against EtOH damage.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We used a third\u2010trimester equivalent mouse model of <jats:styled-content style=\"fixed-case\">FASD<\/jats:styled-content>. <jats:styled-content style=\"fixed-case\">PD<\/jats:styled-content>4 and <jats:styled-content style=\"fixed-case\">PD<\/jats:styled-content>12 C57<jats:styled-content style=\"fixed-case\">BL<\/jats:styled-content>\/6 mice were subcutaneously injected with saline (control), EtOH, EtOH plus 4\u2010phenylbutyric acid (4\u2010<jats:styled-content style=\"fixed-case\">PBA<\/jats:styled-content>), a chemical chaperone known as <jats:styled-content style=\"fixed-case\">ER<\/jats:styled-content> stress inhibitor, and 4\u2010<jats:styled-content style=\"fixed-case\">PBA<\/jats:styled-content> alone. The expression of apoptosis marker, <jats:styled-content style=\"fixed-case\">ER<\/jats:styled-content> stress markers, and markers for glial cell activation was examined in the cerebral cortex.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>EtOH induced neuroapoptosis and increased the expression of <jats:styled-content style=\"fixed-case\">ER<\/jats:styled-content> stress markers, such as activating transcription factor 6, 78\u2010<jats:styled-content style=\"fixed-case\">kD<\/jats:styled-content>a glucose\u2010regulated protein, inositol\u2010requiring enzyme 1\u03b1, mesencephalic astrocyte\u2010derived neurotrophic factor, and caspase\u201012 in <jats:styled-content style=\"fixed-case\">PD<\/jats:styled-content>4 but not <jats:styled-content style=\"fixed-case\">PD<\/jats:styled-content>12 mice. EtOH exposure also activated microglia and astrocytes. Interestingly, treatment with 4\u2010<jats:styled-content style=\"fixed-case\">PBA<\/jats:styled-content> attenuated EtOH\u2010induced neuroapoptosis. Moreover, 4\u2010<jats:styled-content style=\"fixed-case\">PBA<\/jats:styled-content> inhibited the expression of the aforementioned <jats:styled-content style=\"fixed-case\">ER<\/jats:styled-content> stress markers and EtOH\u2010induced glial activation in <jats:styled-content style=\"fixed-case\">PD<\/jats:styled-content>4 mice.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p><jats:styled-content style=\"fixed-case\">ER<\/jats:styled-content> stress plays an important role in EtOH\u2010induced damage to the developing brain. Inhibition of <jats:styled-content style=\"fixed-case\">ER<\/jats:styled-content> stress is neuroprotective and may provide a new therapeutic strategy for treating <jats:styled-content style=\"fixed-case\">FASD<\/jats:styled-content>.<\/jats:p><\/jats:sec>","DOI":"10.1111\/acer.13918","type":"journal-article","created":{"date-parts":[[2018,11,7]],"date-time":"2018-11-07T16:58:35Z","timestamp":1541609915000},"page":"69-78","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["4\u2010Phenylbutyric Acid Protects Against Ethanol\u2010Induced Damage in the Developing Mouse Brain"],"prefix":"10.1111","volume":"43","author":[{"given":"Hui","family":"Li","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Nutritional Sciences University of Kentucky College of Medicine Lexington Kentucky"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wen","family":"Wen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Nutritional Sciences University of Kentucky College of Medicine Lexington Kentucky"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hong","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Nutritional Sciences University of Kentucky College of Medicine Lexington Kentucky"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huaxun","family":"Wu","sequence":"additional","affiliation":[{"name":"Institute of Clinical Pharmacology Key Laboratory of Anti\u2010Inflammatory and Immune Medicine Anhui Medical University Hefei China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mei","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Nutritional Sciences University of Kentucky College of Medicine 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