Ethanol Impairs Activation of Retinoic Acid Receptors in Cerebellar Granule Cells in a Rodent Model of Fetal Alcohol Spectrum Disorders
Ethanol Impairs Activation of Retinoic Acid Receptors in Cerebellar Granule Cells in a Rodent Model of Fetal Alcohol Spectrum Disorders
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DOI：
10.1111/j.1530-0277.2010.01166.x
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发表时间：
2010-05-01
影响因子：
3.2
通讯作者：
Singh, Ugra S.
中科院分区：
文献类型：
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作者：
Kumar, Ambrish;Singh, Chandra K.;Singh, Ugra S.
背景：乙醇是酒精的主要成瘾性和神经毒性成分。胚胎发育过程中的乙醇暴露会导致中枢神经系统（CNS）功能障碍，并导致胎儿酒精谱系障碍。小脑是中枢神经系统中特别容易受到乙醇毒性影响的区域之一。视黄酸（RA）是维生素A的生理活性代谢产物，在小脑局部合成。研究表明，RA是神经元发育所必需的，但乙醇是否会损害RA信号传导，从而诱导神经元畸形仍不清楚。在这项研究中，我们测试的假设，即乙醇损害的表达和激活的RA受体在小脑和小脑颗粒cells.Methods：小脑的乙醇未暴露和暴露的小狗被用来研究维甲酸受体（RARs或RXRs）的表达免疫组化和Western印迹分析。我们还研究了乙醇对小脑颗粒细胞RA受体表达的影响。激活RA受体（DNA结合活性）在响应高剂量乙醇的电泳迁移率变化和supershift assays.Results：这些研究的结果表明，乙醇暴露减少了RAR α/γ的表达，而它增加了RXR α/γ在小脑和小脑颗粒神经元的表达。免疫组织学研究进一步加强了响应于乙醇的RA受体的表达模式。RARs的DNA结合活性降低，而RXRs的DNA结合活性增加，在响应乙醇exposed.Conclusion：为第一次，我们的研究表明，高剂量乙醇影响RA受体的表达和激活，这可能会损害信号转导事件，并诱导有害的影响小脑颗粒细胞的生存和分化。总的来说，这些发现可以为过量乙醇暴露引起的大脑缺陷（如胎儿酒精谱系障碍）的治疗方案提供见解。
Background:Ethanol is the main addictive and neurotoxic constituent of alcohol. Ethanol exposure during embryonic development causes dysfunction of the central nervous system (CNS) and leads to fetal alcohol spectrum disorders. The cerebellum is one of the CNS regions that are particularly vulnerable to ethanol toxic effects. Retinoic acid (RA) is a physiologically active metabolite of vitamin A that is locally synthesized in the cerebellum. Studies have shown that RA is required for neuronal development, but it remains unknown if ethanol impairs RA signaling and thus induces neuronal malformations. In this study, we tested the hypothesis that ethanol impairs the expression and activation of RA receptors in cerebellum and in cerebellar granule cells.Methods:The cerebellum of ethanol unexposed and exposed pups was used to study the expression of retinoic acid receptors (RARs or RXRs) by immunohistochemistry and by Western blot analysis. We also studied the effect of ethanol on expression of RA receptors in the cerebellar granule cells. Activation of RA receptors (DNA-binding activities) in response to high-dose ethanol was determined by electrophoretic mobility shift and supershift assays.Results:Findings from these studies demonstrated that ethanol exposure reduced the expression of RAR alpha/gamma while it increased the expression of RXR alpha/gamma in the cerebellum and in cerebellar granule neurons. Immuno-histological studies further strengthened the expression pattern of RA receptors in response to ethanol. The DNA-binding activity of RARs was reduced, while DNA-binding activity of RXRs was increased in response to ethanol exposure.Conclusion:For the first time, our studies have demonstrated that high-dose ethanol affects the expression and activation of RA receptors, which could impair the signaling events and induce harmful effects on the survival and differentiation of cerebellar granule cells. Taken together, these findings could provide insight into the treatment options for brain defects caused by excessive ethanol exposure, such as in Fetal Alcohol Spectrum Disorders.