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CBD modulates DNA methylation in the prefrontal cortex and hippocampus of mice exposed to forced swim.

CBD 调节暴露于强迫游泳的小鼠前额叶皮层和海马的 DNA 甲基化。

  • 影响因子:3.16
  • DOI:10.1016/j.bbr.2020.112627
  • 作者列表:"Sales AJ","Guimarães FS","Joca SRL
  • 发表时间:2020-06-18
Abstract

:Cannabidiol (CBD), a non-psychotomimetic component of Cannabis sativa plant, shows therapeutic potential in psychiatric disorders, including depression. The molecular mechanisms underlying the antidepressant-like effects of CBD are not yet understood. Previous studies in differentiated skin cells demonstrated that CBD regulates DNA methylation, an overall repressive epigenetic mechanism. Both stress exposure and antidepressant treatment can modulate DNA methylation in the brain, and lead to gene expression changes associated with depression neurobiology. We investigated herein if the antidepressant effect of CBD could be associated with changes in DNA methylation in the prefrontal cortex (PFC) and hippocampus (HPC) of mice submitted to the forced swimming test (FST). Therefore, we assessed: i) the behavioral effects induced by CBD and DNA methylation inhibitors (DNMTi: 5-AzaD and RG108), alone or in association; ii) the effects induced by CBD and DNMTi in global DNA methylation and DNMT activity, in PFC and HPC. Results showed that treatment with CBD (10 mg/kg), 5-AzaD and RG108 (0.2 mg/kg) induced an antidepressant-like effect in the FST. Similar effects were observed after the combination of sub-effective doses of CBD (7 mg/kg) and 5-AzaD or CBD (7 mg/kg) and RG108 (0.1 mg/kg). Also, stress reduced DNA methylation and DNMT activity in the HPC and increased it in the PFC. CBD and DNMTi treatment prevented these changes in both brain structures. Altogether, our results indicate that CBD regulates DNA methylation in brain regions relevant for depression neurobiology, suggesting that this mechanism could be related to CBD-induced antidepressant effects.

摘要

: 大麻二酚 (CBD) 是大麻植物的非精神模拟成分,在包括抑郁症在内的精神疾病中显示出治疗潜力。CBD 抗抑郁样作用的分子机制尚不清楚。以前在分化的皮肤细胞中的研究表明,CBD 调节 DNA 甲基化,这是一种整体的抑制性表观遗传机制。压力暴露和抗抑郁治疗均可调节大脑中的 DNA 甲基化,并导致与抑郁症神经生物学相关的基因表达变化。我们在此研究了 CBD 的抗抑郁作用是否与前额叶皮质 (PFC) 和海马 (HPC) 中 DNA 甲基化的变化有关提交强制游泳试验 (FST) 的小鼠。因此,我们评估了: i) CBD 和 DNA 甲基化抑制剂 (DNMTi: 5-AzaD 和 RG108) 单独或联合诱导的行为效应; ii) CBD 和 DNMTi 在全局 DNA 甲基化和 DNMT 活性、 PFC 和 HPC 中诱导的效应。结果表明,CBD (10 mg/kg) 、 5-AzaD 和 RG108 (0.2 mg/kg) 治疗可诱导 FST 中的抗抑郁样作用。在组合亚有效剂量的 CBD (7 mg/kg) 和 5-AzaD 或 CBD (7 mg/kg) 和 RG108 (0.1 mg/kg) 后观察到类似的效果。同样,压力降低了 HPC 中的 DNA 甲基化和 DNMT 活性,增加了 PFC 中的 DNA 甲基化和 DNMT 活性。CBD 和 DNMTi 治疗阻止了这两种脑结构的这些变化。总之,我们的研究结果表明,CBD 调节与抑郁症神经生物学相关的脑区 DNA 甲基化,提示该机制可能与 CBD 诱导的抗抑郁作用有关。

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DOI:10.1038/s41380-020-0649-0
作者列表:["Li C","Meng F","Garza JC","Liu J","Lei Y","Kirov SA","Guo M","Lu XY"]

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影响因子:5.83
发表时间:2020-01-22
DOI:10.1523/JNEUROSCI.0786-19.2019
作者列表:["Torretta S","Rampino A","Basso M","Pergola G","Di Carlo P","Shin JH","Kleinman JE","Hyde TM","Weinberger DR","Masellis R","Blasi G","Pennuto M","Bertolino A"]

METHODS::Multiple schizophrenia (SCZ) risk loci may be involved in gene co-regulation mechanisms, and analysis of coexpressed gene networks may help to clarify SCZ molecular basis. We have previously identified a dopamine D2 receptor (DRD2) coexpression module enriched for SCZ risk genes and associated with cognitive and neuroimaging phenotypes of SCZ, as well as with response to treatment with antipsychotics. Here we aimed to identify regulatory factors modulating this coexpression module and their relevance to SCZ. We performed motif enrichment analysis to identify transcription factor (TF) binding sites in human promoters of genes coexpressed with DRD2. Then, we measured transcript levels of a group of these genes in primary mouse cortical neurons in basal conditions and upon overexpression and knockdown of predicted TFs. Finally, we analyzed expression levels of these TFs in dorsolateral prefrontal cortex (DLPFC) of SCZ patients. Our in silico analysis revealed enrichment for NURR1 and ERR1 binding sites. In neuronal cultures, the expression of genes either relevant to SCZ risk (Drd2, Gatad2a, Slc28a1, Cnr1) or indexing coexpression in our module (Btg4, Chit1, Osr1, Gpld1) was significantly modified by gain and loss of Nurr1 and Err1. Postmortem DLPFC expression data analysis showed decreased expression levels of NURR1 and ERR1 in patients with SCZ. For NURR1 such decreased expression is associated with treatment with antipsychotics. Our results show that NURR1 and ERR1 modulate the transcription of DRD2 coexpression partners and support the hypothesis that NURR1 is involved in the response to SCZ treatment.SIGNIFICANCE STATEMENT In the present study, we provide in silico and experimental evidence for a role of the TFs NURR1 and ERR1 in modulating the expression pattern of genes coexpressed with DRD2 in human DLPFC. Notably, genetic variations in these genes is associated with SCZ risk and behavioral and neuroimaging phenotypes of the disease, as well as with response to treatment. Furthermore, this study presents novel findings on a possible interplay between D2 receptor-mediated dopamine signaling involved in treatment with antipsychotics and the transcriptional regulation mechanisms exerted by NURR1. Our results suggest that coexpression and co-regulation mechanisms may help to explain some of the complex biology of genetic associations with SCZ.

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影响因子:6.22
发表时间:2020-01-17
DOI:10.1038/s41386-020-0614-2
作者列表:["Chadha R","Meador-Woodruff JH"]

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