Deficient PKR in RAX/PKR Association Ameliorates Ethanol-Induced Neurotoxicity in the Developing Cerebellum
Deficient PKR in RAX/PKR Association Ameliorates Ethanol-Induced Neurotoxicity in the Developing Cerebellum
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DOI：
10.1007/s12311-015-0644-1
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发表时间：
2015-08-01
期刊：
影响因子：
3.5
通讯作者：
Chen, Gang
中科院分区：
文献类型：
--
作者：
Li, Hui;Chen, Jian;Chen, Gang
乙醇引起的神经元损失与胎儿酒精谱系障碍的发病机制密切相关。小脑是对乙醇最敏感的大脑区域之一。乙醇神经毒性的机制仍不清楚。我们之前的体外研究表明，双链RNA（dsRNA）激活蛋白激酶（PKR）在乙醇暴露后调节神经元凋亡，并且乙醇通过与其细胞内激活剂RAX结合来激活PKR。然而，PKR 的作用及其与 RAX 在体内的相互作用尚未得到研究。在当前的研究中，通过利用 PKR 中 RAX 结合域缺陷的 N-PKR-/- 小鼠、C57BL/6J 小鼠，我们确定了 RAX/PKR 关联在发育中小脑中 PKR 调节的乙醇神经毒性中的关键作用。我们的数据表明，虽然 N-PKR-/- 小鼠具有与野生型小鼠相似的 BAC 特征，但乙醇引起的大脑/体重减少以及小脑神经元损失较少。此外，乙醇还能促进白细胞介素1β（IL-1β）的分泌，而IL-1β是调节炎症反应的主要细胞因子。重要的是，在 N-PKR-/- 小鼠发育中的小脑中，乙醇促进的 IL-1 β 分泌受到抑制。因此，RAX/PKR 相互作用和 PKR 激活调节发育中小脑中的乙醇神经毒性，这可能涉及乙醇诱导的神经炎症。此外，PKR 可能是预防或治疗胎儿酒精谱系障碍 (FASD) 的药物干预的可能目标。
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-1 beta (IL-1 beta) secretion, and IL-1 beta is a master cytokine regulating inflammatory response. Importantly, ethanol-promoted IL-1 beta 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).