Histone deacetylase inhibitors up-regulate astrocyte GDNF and BDNF gene transcription and protect dopaminergic neurons.
Histone deacetylase inhibitors up-regulate astrocyte GDNF and BDNF gene transcription and protect dopaminergic neurons.
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DOI：
10.1017/s1461145708009024
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发表时间：
2008-12
期刊：
影响因子：
--
通讯作者：
Hong JS
中科院分区：
文献类型：
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作者：
Wu X;Chen PS;Dallas S;Wilson B;Block ML;Wang CC;Kinyamu H;Lu N;Gao X;Leng Y;Chuang DM;Zhang W;Lu RB;Hong JS
帕金森病（PD）的特征是中脑黑质多巴胺能神经元的选择性和进行性丢失。目前，可用的治疗无法改变PD进展。以前，我们证明，丙戊酸（VPA），情绪稳定剂，抗惊厥和组蛋白去乙酰化酶（HDAC）抑制剂，增加胶质细胞源性神经营养因子（GDNF）和脑源性神经营养因子（BDNF）在星形胶质细胞中的表达，以保护DA神经元在中脑神经胶质细胞培养。本研究调查这些影响是否是由于HDAC抑制和组蛋白乙酰化。在这里，我们表明，两个额外的HDAC抑制剂，丁酸钠（SB）和阿司他丁A（TSA），模仿VPA对DA神经元的神经胶质细胞培养的生存促进和保护作用。与VPA相似，SB和TSA均以时间依赖性方式增加星形胶质细胞中GDNF和BDNF的转录。此外，在用所有三种化合物处理的星形胶质细胞中，GDNF启动子活性和启动子相关组蛋白H3乙酰化显着增加，其中乙酰化的时间过程与基因转录的时间过程相似。总之，我们的研究结果表明，HDAC抑制剂上调GDNF和BDNF在星形胶质细胞中的表达，并保护DA神经元，至少部分，通过HDAC抑制。这项研究表明星形胶质细胞可能是HDAC抑制剂的一个关键神经保护机制，揭示了治疗精神病和神经退行性疾病的新靶点。
Parkinson’s disease (PD) is characterized by the selective and progressive loss of dopaminergic (DA) neurons in the midbrain substantia nigra. Currently, available treatment is unable to alter PD progression. Previously, we demonstrated that valproic acid (VPA), a mood stabilizer, anticonvulsant and histone deacetylase (HDAC) inhibitor, increases the expression of glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) in astrocytes to protect DA neurons in midbrain neuron-glia cultures. The present study investigated whether these effects are due to HDAC inhibition and histone acetylation. Here, we show that two additional HDAC inhibitors, sodium butyrate (SB) and trichostatin A (TSA), mimic the survival-promoting and protective effects of VPA on DA neurons in neuron-glia cultures. Similar to VPA, both SB and TSA increased GDNF and BDNF transcripts in astrocytes in a time-dependent manner. Furthermore, marked increases in GDNF promoter activity and promoter-associated histone H3 acetylation were noted in astrocytes treated with all three compounds, where the time-course for acetylation was similar to that for gene transcription. Taken together, our results indicate that HDAC inhibitors up-regulate GDNF and BDNF expression in astrocytes and protect DA neurons, at least in part, through HDAC inhibition. This study indicates that astrocytes may be a critical neuroprotective mechanism of HDAC inhibitors, revealing a novel target for the treatment of psychiatric and neurodegenerative diseases.