Waller Jessica A, Nygaard Sara Holm, Li Yan, du Jardin Kristian Gaarn, Tamm Joseph A, Abdourahman Aicha, Elfving Betina, Pehrson Alan L, Sánchez Connie, Wernersson Rasmus
External Sourcing and Scientific Excellence, Lundbeck Research U.S.A., Paramus, NJ, 07652, USA.
Intomics A/S, Diplomvej 377, 2800, Lyngby, Denmark.
BMC Neurosci. 2017 Aug 4;18(1):56. doi: 10.1186/s12868-017-0376-x.
The identification of biomarkers that predict susceptibility to major depressive disorder and treatment response to antidepressants is a major challenge. Vortioxetine is a novel multimodal antidepressant that possesses pro-cognitive properties and differentiates from other conventional antidepressants on various cognitive and plasticity measures. The aim of the present study was to identify biological systems rather than single biomarkers that may underlie vortioxetine's treatment effects.
We show that the biological systems regulated by vortioxetine are overlapping between mouse and rat in response to distinct treatment regimens and in different brain regions. Furthermore, analysis of complexes of physically-interacting proteins reveal that biomarkers involved in transcriptional regulation, neurodevelopment, neuroplasticity, and endocytosis are modulated by vortioxetine. A subsequent qPCR study examining the expression of targets in the protein-protein interactome space in response to chronic vortioxetine treatment over a range of doses provides further biological validation that vortioxetine engages neuroplasticity networks. Thus, the same biology is regulated in different species and sexes, different brain regions, and in response to distinct routes of administration and regimens.
A recurring theme, based on the present study as well as previous findings, is that networks related to synaptic plasticity, synaptic transmission, signal transduction, and neurodevelopment are modulated in response to vortioxetine treatment. Regulation of these signaling pathways by vortioxetine may underlie vortioxetine's cognitive-enhancing properties.
识别可预测重度抑郁症易感性及对抗抑郁药治疗反应的生物标志物是一项重大挑战。伏硫西汀是一种新型多模式抗抑郁药，具有促认知特性，在各种认知和可塑性指标上与其他传统抗抑郁药不同。本研究的目的是识别可能是伏硫西汀治疗效果基础的生物系统而非单一生物标志物。
我们表明，伏硫西汀调节的生物系统在小鼠和大鼠中，在不同的治疗方案和不同脑区中存在重叠。此外，对物理相互作用蛋白复合物的分析表明，参与转录调控、神经发育、神经可塑性和内吞作用的生物标志物受伏硫西汀调节。随后一项qPCR研究检测了在一系列剂量下慢性伏硫西汀治疗后蛋白质-蛋白质相互作用组空间中靶点的表达，进一步从生物学角度验证了伏硫西汀参与神经可塑性网络。因此，相同的生物学过程在不同物种和性别、不同脑区以及对不同给药途径和方案的反应中受到调节。
基于本研究以及先前的发现，一个反复出现的主题是，与突触可塑性、突触传递、信号转导和神经发育相关的网络在伏硫西汀治疗后受到调节。伏硫西汀对这些信号通路的调节可能是其认知增强特性的基础。
