Centre for Molecular and Medical Research, Deakin University, Geelong, VIC, Australia.
Laboratory of Molecular Psychiatry, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil.
J Psychopharmacol. 2020 Mar;34(3):370-379. doi: 10.1177/0269881119895534. Epub 2020 Jan 8.
The drugs commonly used to treat bipolar disorder have limited efficacy and drug discovery is hampered by the paucity of knowledge of the pathophysiology of this disease. This study aims to explore the role of microRNAs in bipolar disorder and understand the molecular mechanisms of action of commonly used bipolar disorder drugs.
The transcriptional effects of bipolar disorder drug combination (lithium, valproate, lamotrigine and quetiapine) in cultured human neuronal cells were studied using next generation sequencing. Differential expression of genes (=20) and microRNAs (=6) was assessed and the differentially expressed microRNAs were confirmed with TaqMan MicroRNA Assays. The expression of the differentially expressed microRNAs were inhibited to determine bipolar disorder drug effects on their target genes (=8). Independent samples -test was used for normally distributed data and Kruskal-Wallis/Mann-Whitney U test was used for data not distributed normally. Significance levels were set at <0.05.
We found that bipolar disorder drugs tended to increase the expression of miR-128 and miR-378 (<0.05). Putative target genes of these microRNAs targeted pathways including those identified as "neuron projection development" and "axonogenesis". Many of the target genes are inhibitors of neurite outgrowth and neurogenesis and were downregulated following bipolar disorder drug combination treatment (all <0.05). The bipolar disorder drug combination tended to decrease the expression of the target genes (, and ), however this effect could be reversed by the application of microRNA inhibitors.
We conclude that at a transcriptional level, bipolar disorder drugs affect several genes in concert that would increase neurite outgrowth and neurogenesis and hence neural plasticity, and that this effect is mediated (at least in part) by modulation of the expression of these two key microRNAs.
治疗双相情感障碍的常用药物疗效有限，而对这种疾病病理生理学的了解甚少，这也阻碍了药物研发。本研究旨在探讨 microRNAs 在双相情感障碍中的作用，并了解常用双相情感障碍药物的作用机制。
采用下一代测序技术研究双相情感障碍药物（锂、丙戊酸、拉莫三嗪和喹硫平）联合用药对培养的人神经元细胞的转录效应。评估差异表达基因（=20）和 microRNAs（=6），并用 TaqMan MicroRNA 检测试剂盒对差异表达 microRNAs 进行验证。抑制差异表达 microRNAs 的表达，以确定双相情感障碍药物对其靶基因（=8）的作用。正态分布数据采用独立样本 t 检验，非正态分布数据采用 Kruskal-Wallis/Mann-Whitney U 检验。显著性水平设为<0.05。
我们发现双相情感障碍药物倾向于增加 miR-128 和 miR-378 的表达（<0.05）。这些 microRNAs 的假定靶基因靶向包括“神经元投射发育”和“轴突发生”在内的途径。许多靶基因是神经突生长和神经发生的抑制剂，双相情感障碍药物联合治疗后这些基因下调（均<0.05）。双相情感障碍药物联合治疗倾向于降低靶基因（、和）的表达，但 microRNA 抑制剂的应用可以逆转这种作用。
我们得出结论，在转录水平上，双相情感障碍药物协同影响多个基因，这些基因可增加神经突生长和神经发生，从而增强神经可塑性，而这种作用至少部分是通过调节这两个关键 microRNAs 的表达来介导的。
