TY - JOUR
T1 - Deficient PKR in RAX/PKR association ameliorates ethanol-induced neurotoxicity in the developing cerebellum
AU - Li, Hui
AU - Chen, Jian
AU - Qi, Yuanlin
AU - Dai, Lu
AU - Zhang, Mingfang
AU - Frank, Jacqueline A.
AU - Handshoe, Jonathan W.
AU - Cui, Jiajun
AU - Xu, Wenhua
AU - Chen, Gang
N1 - Publisher Copyright:
© Springer Science+Business Media New York 2015.
PY - 2015/8/1
Y1 - 2015/8/1
N2 - 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).
AB - 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).
KW - Alcohol
KW - Apoptosis
KW - Cerebellum
KW - Fetal alcohol spectrum disorders
KW - Neuron
KW - PKR
KW - Rax
UR - http://www.scopus.com/inward/record.url?scp=84943197353&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84943197353&partnerID=8YFLogxK
U2 - 10.1007/s12311-015-0644-1
DO - 10.1007/s12311-015-0644-1
M3 - Article
C2 - 25592072
AN - SCOPUS:84943197353
SN - 1473-4222
VL - 14
SP - 386
EP - 397
JO - Cerebellum
JF - Cerebellum
IS - 4
M1 - A005
ER -