Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.
Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil; Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, Brazil.
Behav Brain Res. 2020 Jun 18;388:112627. doi: 10.1016/j.bbr.2020.112627. Epub 2020 Apr 26.
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.
大麻二酚（CBD）是大麻植物的一种非致幻成分，在包括抑郁症在内的精神疾病中显示出治疗潜力。CBD 产生抗抑郁样作用的分子机制尚不清楚。先前在分化皮肤细胞中的研究表明，CBD 可调节 DNA 甲基化，这是一种整体抑制性表观遗传机制。应激暴露和抗抑郁治疗都可以调节大脑中的 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暴露于强迫游泳试验（FST）的小鼠前额叶皮层（PFC）和海马（HPC）中的 DNA 甲基化变化有关。因此，我们评估了：i）CBD 和 DNA 甲基化抑制剂（DNMTi：5-AzaD 和 RG108）单独或联合使用时引起的行为效应；ii）CBD 和 DNMTi 对 PFC 和 HPC 中整体 DNA 甲基化和 DNMT 活性的影响。结果表明，CBD（10mg/kg）、5-AzaD 和 RG108（0.2mg/kg）的治疗可在 FST 中诱导抗抑郁样作用。在使用亚有效剂量的 CBD（7mg/kg）与 5-AzaD 或 CBD（7mg/kg）与 RG108（0.1mg/kg）联合使用时也观察到了类似的效果。此外，应激降低了 HPC 中的 DNA 甲基化和 DNMT 活性，并增加了 PFC 中的 DNA 甲基化和 DNMT 活性。CBD 和 DNMTi 治疗可防止这两种脑结构中的这些变化。总之，我们的结果表明，CBD 可调节与抑郁症神经生物学相关的大脑区域中的 DNA 甲基化，表明该机制可能与 CBD 诱导的抗抑郁作用有关。
