Histone Deacetylase Inhibitors Promote Neurosteroid-Mediated Cell Differentiation and Enhance Serotonin-Stimulated Brain-Derived Neurotrophic Factor Gene Expression in Rat C6 Glioma Cells
Histone Deacetylase Inhibitors Promote Neurosteroid-Mediated Cell Differentiation and Enhance Serotonin-Stimulated Brain-Derived Neurotrophic Factor Gene Expression in Rat C6 Glioma Cells
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DOI：
10.1002/jnr.22072
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发表时间：
2009-08-15
影响因子：
4.2
通讯作者：
Her, Song
中科院分区：
文献类型：
--
作者：
Morita, Kyoji;Gotohda, Takako;Her, Song
此前有报道称，黄体酮治疗可能通过产生5 α -减少的神经类固醇来促进神经胶质细胞的分化，导致血清素刺激的脑源性神经营养因子（BDNF）基因表达增强，这被认为有助于大脑神经元细胞的存活、再生和可塑性，因此被认为可以改善抑郁症患者的情绪障碍和其他症状。基于这些先前的观察结果，以大鼠C6胶质瘤细胞为模型，研究了组蛋白去乙酰化酶（HIDAC）抑制剂对胶质细胞的影响，这种抑制剂被称为促进细胞分化的药物。因此，曲古抑素A （TSA）、丁酸钠（NaB）和丙戊酸（VPA）刺激神经胶质纤维酸性蛋白（GFAP）基因表达，而非那雄胺（一种产生5 α -还原性神经类固醇的酶抑制剂）处理这些细胞可以抑制它们对GFAP基因表达的刺激作用。此外，HDAC抑制剂增强了5 -羟色胺刺激的BDNF基因表达，这种增强可以通过抑制胶质瘤细胞中5 - α减少的神经类固醇的产生而消除。这些结果表明，HDAC抑制剂可能能够通过产生5 α -减少的神经类固醇来促进大鼠C6胶质瘤细胞的分化，从而增强血清素刺激的BDNF基因表达，从而促进其分化，这表明分化的胶质细胞可能与保持神经网络的完整性以及改善大脑神经元细胞的功能有关。(C) 2009 wiley-Liss, Inc。
Progesterone treatment has previously been reported to promote the differentiation of glial cells probably through the production of 5 alpha-reduced neurosteroids, resulting in the enhancement of serotonin-stimulated brain-derived neurotrophic factor (BDNF) gene expression, which is considered to contribute to the survival, regeneration, and plasticity of neuronal cells in the brain and hence has been suggested to improve mood disorders and other symptoms in depressive patients. Based on these previous observations, the effects on glial cells of histone deacetylase (HIDAC) inhibitors, which are known as agents promoting cell differentiation, were examined using rat C6 glioma cells as a model for in vitro studies. Consequently, trichostatin A (TSA), sodium butyrate (NaB), and valproic acid (VPA) stimulated glial fibrillary acidic protein (GFAP) gene expression, and their stimulatory effects on GFAP gene expression were inhibited by treatment of these cells with finasteride, an inhibitor of the enzyme producing 5 alpha-reduced neurosteroids. In addition, HDAC inhibitors enhanced serotonin-stimulated BDNF gene expression, the enhancement of which could be abolished by the inhibition of 5 alpha-reduced neurosteroid production in the glioma cells. These results suggest that HDAC inhibitors may be able to promote the differentiation of rat C6 glioma cells through the production of 5 alpha-reduced neurosteroids, resulting in the enhancement of serotonin-stimulated BDNF gene expression as a consequence of promoting their differentiation, indicating the possibility that differentiated glial cells may be implicated in preserving the integrity of neural networks as well as improving the function of neuronal cells in the brain. (C) 2009 wiley-Liss, Inc.