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Deficient PKR in RAX/PKR Association Ameliorates Ethanol-Induced Neurotoxicity in the Developing Cerebellum

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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).

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Acknowledgments

The authors would like to thank Dr. Ganes C. Sen at Cleveland Clinic Lerner Research Institute for providing the N-PKR−/− mice. This work was supported by NIH grant RO1AA020051 to GC.

Conflicts of Interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department Pharmacology & Nutritional Sciences, University of Kentucky College of Medicine, MN306, UKMC, 800 Rose street, Lexington, KY, 40536, USA

    Hui Li, Jacqueline A. Frank, Jiajun Cui & Gang Chen

  2. The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, 361001, China

    Jian Chen

  3. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian, 350004, China

    Yuanlin Qi

  4. Graduate Center for Toxicology, University of Kentucky College of Medicine, Lexington, KY, 40536, USA

    Lu Dai

  5. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian, 350004, China

    Mingfang Zhang

  6. University of Kentucky, Lexington, KY, 40536, USA

    Jonathan W. Handshoe

  7. Department of Neurology, Affiliated Provincial Hospital of Anhui Medical University, Hefei, 230001, China

    Wenhua Xu

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  1. Hui Li
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  2. Jian Chen
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  10. Gang Chen
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Correspondence to Gang Chen.

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Hui Li and Jian Chen contributed equally to this work.

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Li, H., Chen, J., Qi, Y. et al. Deficient PKR in RAX/PKR Association Ameliorates Ethanol-Induced Neurotoxicity in the Developing Cerebellum. Cerebellum 14, 386–397 (2015). https://doi.org/10.1007/s12311-015-0644-1

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