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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Clozapine and sulpiride but not haloperidol or olanzapine activate brain DNA demethylation
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Clozapine and sulpiride but not haloperidol or olanzapine activate brain DNA demethylation

机译：氯氮平和舒必利但不能使氟哌啶醇或奥氮平激活脑DNA脱甲基

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Cortical GABAergic dysfunction, a hallmark of both schizophrenia (SZ) and bipolar (BP) disorder pathophysiologies may relate to the hypermethylation of GABAergic gene promoters (i.e., reelin and GAD67). Benefits elicited by a combination of atypical antipsychot-ics with valproate (VPA) (a histone deacetylase inhibitor that may also activate brain DNA demethylation) in SZ or BP disorder treatment prompted us to investigate whether the beneficial action of this association depends on induction of a putative DNA demethylase activity. To monitor this activity, we measured the ratio of 5-methyl cytosine to unmethylated cytosine in reelin and GAD67 promoters in the mouse frontal cortex and striatum. We compared normal mice with mice pretreated with L-methionine (5.2 mmol/kg s.c. twice a day for 7 days) to hypermethylate promoters, including reelin and GAD67. Clinically relevant doses of clozapine (CLZ) (3.8 to 15 μmol/kg twice a day s.c. for 3 days) and sulpiride (SULP) (12.5 to 50 μmol/kg twice a day for 3 days) but not clinically relevant doses of haloperidol (HAL) (1.3 to 4 μmol/kg twice a day s.c. for 3 days) or olanzapine (OLZ) (4 to 15 μmol/kg twice a day for 3 days) exhibited dose-related increases in the cortical and striatal demethylation of hypermethylated reelin and GAD67 promoters. These effects of CLZ and SULP were dramatically potentiated by a clinically relevant VPA dose (0.5 mmol/kg twice a day for 3 days). By activating a DNA demethylase, the association of CLZ or SULP with VPA may facilitate a chromatin remodeling that normalizes the GABAergic gene expression down-regulation detected in the telencephalic regions of SZ and BP patients.
机译：精神分裂症（SZ）和双相情感障碍（BP）病理生理的标志性皮质GABA能功能障碍可能与GABA能基因启动子（即reelin和GAD67）的甲基化有关。非典型抗精神病药与丙戊酸盐（VPA）（一种组蛋白脱乙酰基酶抑制剂，也可能激活脑DNA脱甲基化）联合使用所引起的益处，促使我们研究这种关联的有益作用是否取决于诱导甲氧西林推定的DNA脱甲基酶活性。为了监测此活性，我们测量了小鼠额叶皮质和纹状体中reelin和GAD67启动子中5-甲基胞嘧啶与未甲基化胞嘧啶的比率。我们将正常小鼠与经L-甲硫氨酸（5.2 mmol / kg s.c.每天两次，共7天）预处理的小鼠进行高甲基化启动子的比较，其中包括reelin和GAD67。临床相关剂量的氯氮平（CLZ）（3.8至15μmol/ kg每天两次，连续3天）和舒必利（SULP）（12.5至50μmol/ kg，每天两次，连续3天），但无临床相关剂量的氟哌啶醇（ HAL）（每天1次，每天两次1.3至4μmol/ kg，连续3天）或olanzapine（OLZ）（每天两次，每天3次，每天4至15μmol/ kg，连续3天）在皮质和纹状体中的高甲基化瑞林的脱甲基化表现出剂量相关性和GAD67启动子。临床上相关的VPA剂量（每天两次，每次0.5 mmol / kg，连续3天）显着增强了CLZ和SULP的这些作用。通过激活DNA脱甲基酶，CLZ或SULP与VPA的结合可促进染色质重塑，从而使SZ和BP患者的脑脑区域中检测到的GABA能基因表达下调正常化。

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