Deficient PKR in RAX/PKR association ameliorates ethanol-induced neurotoxicity in the developing cerebellum

Hui Li, Jian Chen, Yuanlin Qi, Lu Dai, Mingfang Zhang, Jacqueline A. Frank, Jonathan W. Handshoe, Jiajun Cui, Wenhua Xu, Gang Chen

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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).

Original languageEnglish
Article numberA005
Pages (from-to)386-397
Number of pages12
JournalCerebellum
Volume14
Issue number4
DOIs
StatePublished - Aug 1 2015

Bibliographical note

Publisher Copyright:
© Springer Science+Business Media New York 2015.

Keywords

  • Alcohol
  • Apoptosis
  • Cerebellum
  • Fetal alcohol spectrum disorders
  • Neuron
  • PKR
  • Rax

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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