S-adenosyl-L-methionine modulates hippocampal DNA methylation, exerting fast and long-lasting anti-stress effects independent of alterations in TrkB-mTOR expression

Amanda J. Sales, Izaque S. Maciel, Francisco S. Guimarães
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Abstract

Emerging evidence suggests that targeting DNA methylation, a key epigenetic mechanism, may represent a promising therapeutic approach for the treatment of stress-related disorders, including depression. Preclinical studies indicate that the inhibition of DNA methylation induces rapid and sustained antidepressant-like effects through the increased BDNF-TrkB-mTOR signaling in the prefrontal cortex, a brain region associated to the neurobiology of depression and neuroplasticity. S-adenosyl-l-methionine (SAMe), a methyl donor, has been shown to reverse depressive-like behaviors by modulating DNA methylation. However, the molecular mechanisms underlying the SAMe antidepressant effects are not yet fully understood. Therefore, this study evaluated whether SAMe induces rapid and long-lasting behavioral effects by modulating DNA methylation and mTOR-TrkB expression in mice. For this purpose, male Swiss mice received intraperitoneal (i.p.) injections of SAMe (25, 50, and 100 mg/kg) or vehicle (10 mL/kg), 30 minutes, 7 days, or 14 days prior to the forced swimming test (FST) or tail suspension test (TST), two predictive tests of antidepressant action. Global DNA methylation and mTOR-TrkB levels were measured in the hippocampus and prefrontal cortex. SAMe (50 mg/kg) induced a rapid and sustained decrease in immobility time in both the FST and TST, and prevented the stress-induced effects in hippocampal DNA methylation without changing the analyzed protein expression. These findings suggest that the rapid and sustained anti-stress effects observed in mice, resulting from the modulation of hippocampal DNA methylation due to acute SAMe treatment, are not related with TrkB-mTOR signaling.
s -腺苷-l -蛋氨酸调节海马DNA甲基化,发挥快速和持久的抗应激作用,不依赖于TrkB-mTOR表达的改变
新出现的证据表明,靶向DNA甲基化(一种关键的表观遗传机制)可能是治疗压力相关疾病(包括抑郁症)的一种有希望的治疗方法。临床前研究表明,DNA甲基化的抑制通过前额叶皮层中BDNF-TrkB-mTOR信号的增加而诱导快速和持续的抗抑郁样作用,前额叶皮层是与抑郁和神经可塑性的神经生物学相关的大脑区域。s -腺苷-l-蛋氨酸(SAMe),一种甲基供体,已被证明通过调节DNA甲基化来逆转抑郁样行为。然而,同样的抗抑郁作用的分子机制尚不完全清楚。因此,本研究评估了SAMe是否通过调节小鼠DNA甲基化和mTOR-TrkB表达来诱导快速和持久的行为效应。为此,雄性瑞士小鼠在强迫游泳试验(FST)或悬尾试验(TST)前30 分钟、7天或14天,分别腹腔注射SAMe(25、50和100 mg/kg)或对照物(10 mL/kg),这是两项抗抑郁作用的预测试验。在海马和前额皮质中测量整体DNA甲基化和mTOR-TrkB水平。SAMe(50 mg/kg)诱导FST和TST的静止时间快速持续减少,并在不改变分析蛋白表达的情况下阻止应激诱导的海马DNA甲基化效应。这些发现表明,在小鼠中观察到的快速和持续的抗应激作用是由急性SAMe治疗引起的海马DNA甲基化调节引起的,与TrkB-mTOR信号传导无关。
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