Department of Psychiatry & Behavioural Neurosciences, McMaster University, 1200 Main Street, Hamilton, Ontario, Canada L8N 3Z5.
Eur Neuropsychopharmacol. 2017 Aug;27(8):828-832. doi: 10.1016/j.euroneuro.2017.06.002. Epub 2017 Jun 22.
We have reported that the anticonvulsant/mood stabilizer and histone deacetylase (HDAC) inhibitor valproate (VPA) induces expression of melatonin receptors both in vitro and in vivo, but the mechanisms involved were not known. Here we show that pharmacological inhibition of CREB, PKC, PI3K, or GSK3β signaling pathways, which are known targets for VPA, do not prevent its upregulation of melatonin MT receptors in rat C6 glioma cells. M344, an HDAC inhibitor unrelated to VPA, mimics the effects of VPA on MT expression, whereas valpromide, a VPA derivative lacking HDAC inhibitory activity, does not. Furthermore, VPA, at a concentration which upregulates the MT receptor, induces histone H3 hyperacetylation along the length of the MT receptor promoter. These results show that an epigenetic mechanism involving histone acetylation underlies induction of MT receptor expression by VPA. Given the neuropsychiatric effects of melatonin coupled with evidence that VPA upregulates melatonin receptors in the rat brain, these findings suggest that the melatonergic system contributes to the psychotropic effects of VPA.
我们曾报道过抗惊厥/心境稳定剂和组蛋白去乙酰化酶（HDAC）抑制剂丙戊酸（VPA）可在体外和体内诱导褪黑素受体的表达，但具体的机制尚不清楚。在这里，我们发现 CREB、PKC、PI3K 或 GSK3β 信号通路的药理学抑制（这些通路是 VPA 的已知靶点）并不能阻止 VPA 上调大鼠 C6 神经胶质瘤细胞中褪黑素 MT 受体的表达。M344 是一种与 VPA 无关的 HDAC 抑制剂，可模拟 VPA 对 MT 表达的作用，而缺乏 HDAC 抑制活性的 VPA 衍生物 valpromide 则没有这种作用。此外，VPA 在上调 MT 受体的浓度下，可诱导 MT 受体启动子全长的组蛋白 H3 乙酰化。这些结果表明，一种涉及组蛋白乙酰化的表观遗传机制是 VPA 诱导 MT 受体表达的基础。鉴于褪黑素的神经精神作用，以及 VPA 可上调大鼠大脑中的褪黑素受体的证据，这些发现表明，褪黑素能系统有助于 VPA 的精神治疗作用。
