Journal article
4-Phenylbutyric Acid Protects Against Ethanol-Induced Damage in the Developing Mouse Brain
Alcoholism, clinical and experimental research, Vol.43(1), pp.69-78
01/2019
DOI: 10.1111/acer.13918
PMCID: PMC6318008
PMID: 30403409
Abstract
Background
Ethanol (EtOH) exposure during pregnancy may result in fetal alcohol spectrum disorders (FASD). 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 (PD4) mice but not PD12 mice. This differential susceptibility may result from an insufficient cellular stress response system such as unfolded protein response (also known as endoplasmic reticulum [ER] stress) in PD4 mice. In this study, we compared the effect of EtOH on ER stress in PD4 and PD12 mice and determined whether the inhibition of ER stress could protect the developing brain against EtOH damage.
Methods
We used a third-trimester equivalent mouse model of FASD. PD4 and PD12 C57BL/6 mice were subcutaneously injected with saline (control), EtOH, EtOH plus 4-phenylbutyric acid (4-PBA), a chemical chaperone known as ER stress inhibitor, and 4-PBA alone. The expression of apoptosis marker, ER stress markers, and markers for glial cell activation was examined in the cerebral cortex.
Results
EtOH induced neuroapoptosis and increased the expression of ER stress markers, such as activating transcription factor 6, 78-kDa glucose-regulated protein, inositol-requiring enzyme 1α, mesencephalic astrocyte-derived neurotrophic factor, and caspase-12 in PD4 but not PD12 mice. EtOH exposure also activated microglia and astrocytes. Interestingly, treatment with 4-PBA attenuated EtOH-induced neuroapoptosis. Moreover, 4-PBA inhibited the expression of the aforementioned ER stress markers and EtOH-induced glial activation in PD4 mice.
Conclusions
ER stress plays an important role in EtOH-induced damage to the developing brain. Inhibition of ER stress is neuroprotective and may provide a new therapeutic strategy for treating FASD.
Details
- Title: Subtitle
- 4-Phenylbutyric Acid Protects Against Ethanol-Induced Damage in the Developing Mouse Brain
- Creators
- Hui Li - University of KentuckyWen Wen - University of KentuckyHong Xu - University of KentuckyHuaxun Wu - Anhui Medical UniversityMei Xu - University of KentuckyJacqueline A Frank - University of KentuckyJia Luo - University of Kentucky
- Resource Type
- Journal article
- Publication Details
- Alcoholism, clinical and experimental research, Vol.43(1), pp.69-78
- DOI
- 10.1111/acer.13918
- PMID
- 30403409
- PMCID
- PMC6318008
- NLM abbreviation
- Alcohol Clin Exp Res
- ISSN
- 0145-6008
- eISSN
- 1530-0277
- Publisher
- Wiley
- Grant note
- BX001721 / Office of Research and Development [Biomedical Laboratory Research and Development: Merit Review] I01 BX001721 / BLRD VA R01 AA015407 / NIAAA NIH HHS R01 AA017226 / NIAAA NIH HHS Department of Veterans Affairs, Veterans Health Administration
- Language
- English
- Date published
- 01/2019
- Academic Unit
- Pathology
- Record Identifier
- 9984186537502771
Metrics
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