title: Deficient PKR in RAX/PKR Association Ameliorates Ethanol-Induced Neurotoxicity in the Developing Cerebellum.
abstract: Ethanol-induced neuronal loss is closely related to the pathogenesis of fetal alcohol spectrum disorders. The cerebellum is one of the brain areas that are most sensitive to ethanol. The mechanism underlying ethanol neurotoxicity remains unclear. Our previous in vitro studies have shown that the double-stranded RNA (dsRNA)-activated protein kinase (PKR) regulates neuronal apoptosis upon ethanol exposure and ethanol activates PKR through association with its intracellular activator RAX. However, the role of PKR and its interaction with RAX in vivo have not been investigated. In the current study, by utilizing N-PKR-/- mice, C57BL/6J mice with a deficient RAX-binding domain in PKR, we determined the critical role of RAX/PKR association in PKR-regulated ethanol neurotoxicity in the developing cerebellum. Our data indicate that while N-PKR-/- mice have a similar BAC profile as wild-type mice, ethanol induces less brain/body mass reduction as well as cerebellar neuronal loss. In addition, ethanol promotes interleukin-1β (IL-1β) secretion, and IL-1β is a master cytokine regulating inflammatory response. Importantly, ethanol-promoted IL-1β secretion is inhibited in the developing cerebellum of N-PKR-/- mice. Thus, RAX/PKR interaction and PKR activation regulate ethanol neurotoxicity in the developing cerebellum, which may involve ethanol-induced neuroinflammation. Further, PKR could be a possible target for pharmacological intervention to prevent or treat fetal alcohol spectrum disorder (FASD).
authors.affiliation: Department Pharmacology & Nutritional Sciences, University of Kentucky College of Medicine, MN306, UKMC, 800 Rose street, Lexington, KY, 40536, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Jian
authors.initials: J
authors.lastname: Chen
authors.forename: Yuanlin
authors.initials: Y
authors.lastname: Qi
authors.forename: Lu
authors.initials: L
authors.lastname: Dai
authors.forename: Mingfang
authors.initials: M
authors.lastname: Zhang
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Frank
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Handshoe
authors.forename: Jiajun
authors.initials: J
authors.lastname: Cui
authors.forename: Wenhua
authors.initials: W
authors.lastname: Xu
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
mesh_terms: D000367:Age Factors; D000818:Animals; D030801:Animals, Genetically Modified; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D002492:Central Nervous System Depressants / Q000633:toxicity*; D002531:Cerebellum / Q000187:drug effects / Q000254:growth & development / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D000431:Ethanol / Q000633:toxicity*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000209:etiology* / Q000473:pathology; D009929:Organ Size / Q000187:drug effects / Q000235:genetics; D012844:Sincalide / Q000494:pharmacology; D013997:Time Factors; D019892:eIF-2 Kinase / Q000172:deficiency* / Q000235:genetics
chemical_list: D002492:Central Nervous System Depressants; D016207:Cytokines; D000431:Ethanol; D019892:eIF-2 Kinase; D012844:Sincalide