Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8258857 | Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease | 2017 | 63 Pages |
Abstract
Ethanol exposure during development causes fetal alcohol spectrum disorders (FASD). A large body of evidence shows that ethanol produces multiple abnormalities in the developing central nervous system (CNS), such as smaller brain size, reduced volume of cerebral white matter, permanent loss of neurons, and alterations in synaptogenesis and myelinogenesis. The effects of ethanol on the developing spinal cord, however, receive little attention and remain unclear. We used a third trimester equivalent mouse model to investigate the effect of ethanol on the developing spinal cord. Ethanol caused apoptosis and neurodegeneration in the dorsal horn neurons of mice of early postnatal days, which was accompanied by glial activation, macrophage infiltration, and increased expression of CCR2, a receptor for monocyte chemoattractant protein 1 (MCP-1). Ethanol-induced neuronal death during development resulted in permanent loss of spinal cord neurons in adult mice. Ethanol stimulated endoplasmic reticulum (ER) stress and oxidative stress, and activated glycogen synthase kinase 3β (GSK3β) and c-Jun N-terminal kinase (JNK) pathways. Knocking out MCP-1 or CCR2 made mice resistant to ethanol-induced apoptosis, ER stress, glial activation, and activation of GSK3β and JNK. CCR2 knock out offered much better protection against ethanol-induced damage to the spinal cord. Thus, developmental ethanol exposure caused permanent loss of spinal cord neurons and CCR2 signaling played an important role in ethanol neurotoxicity.
Keywords
UPRprotein kinase R-like endoplasmic reticulum kinaseMCPIP1FASDsCCR2PARPHNEGSK3βATF6eIF2αXBP1DNPMCP-1Jnk4-hydroxynonenalGFAPC/EBP homologous proteinMAPKFetal alcohol spectrum disordersinflammationAlcoholNeurodegenerationCHOPX-box binding protein-1ApoptosisCNSdinitrophenolDevelopmentpostnatal daycentral nervous systemendoplasmic reticulumeukaryotic initiation factor 2αactivating transcription factor 6MANFUnfolded protein responseGlial fibrillary acidic proteinmitogen-activated protein kinasePERKpoly (ADP-ribose) polymeraseGlycogen synthase kinase 3β
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Authors
Zhenhua Ren, Xin Wang, Fanmuyi Yang, Mei Xu, Jacqueline A. Frank, Haiping Wang, Siying Wang, Zun-ji Ke, Jia Luo,