Kugathasan Pirathiv, Waller Jessica, Westrich Ligia, Abdourahman Aicha, Tamm Joseph A, Pehrson Alan L, Dale Elena, Gulinello Maria, Sanchez Connie, Li Yan
1 Lundbeck Research, Paramus, NJ, USA.
2 Albert Einstein College of Medicine, Bronx, NY, USA.
J Psychopharmacol. 2017 Mar;31(3):365-376. doi: 10.1177/0269881116667710. Epub 2016 Sep 28.
Neuroplasticity is fundamental for brain functions, abnormal changes of which are associated with mood disorders and cognitive impairment. Neuroplasticity can be affected by neuroactive medications and by aging. Vortioxetine, a multimodal antidepressant, has shown positive effects on cognitive functions in both pre-clinical and clinical studies. In rodent studies, vortioxetine increases glutamate neurotransmission, promotes dendritic branching and spine maturation, and elevates hippocampal expression of the activity-regulated cytoskeleton-associated protein (Arc/Arg3.1) at the transcript level. The present study aims to assess the effects of vortioxetine on several neuroplasticity-related molecules in different experimental systems. Chronic (1 month) vortioxetine increased Arc/Arg3.1 protein levels in the cortical synaptosomes of young and middle-aged mice. In young mice, this was accompanied by an increase in actin-depolymerizing factor (ADF)/cofilin serine 3 phosphorylation without altering the total ADF/cofilin protein level, and an increase in the GluA1 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor phosphorylation at serine 845 (S845) without altering serine 831 (S831) GluA1 phosphorylation nor the total GluA1 protein level. Similar effects were detected in cultured rat hippocampal neurons: Acute vortioxetine increased S845 GluA1 phosphorylation without changing S831 GluA1 phosphorylation or the total GluA1 protein level. These changes were accompanied by an increase in α subunit of Ca/calmodulin-dependent kinase (CaMKIIα) phosphorylation (at threonine 286) without changing the total CaMKIIα protein level in cultured neurons. In addition, chronic (1 month) vortioxetine, but not fluoxetine, restored the age-associated reduction in Arc/Arg3.1 and c-Fos transcripts in the frontal cortex of middle-aged mice. Taken together, these results demonstrated that vortioxetine modulates molecular targets that are related to neuroplasticity.
神经可塑性是脑功能的基础，其异常变化与情绪障碍和认知障碍相关。神经可塑性会受到神经活性药物和衰老的影响。伏硫西汀是一种多模式抗抑郁药，在临床前和临床研究中均已显示出对认知功能的积极作用。在啮齿动物研究中，伏硫西汀可增加谷氨酸能神经传递，促进树突分支和棘突成熟，并在转录水平上提高海马中活性调节细胞骨架相关蛋白（Arc/Arg3.1）的表达。本研究旨在评估伏硫西汀在不同实验系统中对几种与神经可塑性相关分子的影响。慢性（1个月）给予伏硫西汀可增加年轻和中年小鼠皮质突触体中Arc/Arg3.1蛋白水平。在年轻小鼠中，这伴随着肌动蛋白解聚因子（ADF）/丝切蛋白丝氨酸3磷酸化增加，而总ADF/丝切蛋白蛋白水平未改变，以及α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体的GluA1亚基丝氨酸845（S845）磷酸化增加，而丝氨酸831（S831）GluA1磷酸化及总GluA1蛋白水平未改变。在培养的大鼠海马神经元中也检测到了类似的作用：急性给予伏硫西汀可增加S845 GluA1磷酸化，而不改变S831 GluA1磷酸化或总GluA1蛋白水平。这些变化伴随着钙/钙调蛋白依赖性激酶（CaMKIIα）α亚基（苏氨酸286）磷酸化增加，而培养神经元中的总CaMKIIα蛋白水平未改变。此外，慢性（1个月）给予伏硫西汀而非氟西汀可恢复中年小鼠额叶皮质中与年龄相关的Arc/Arg3.1和c-Fos转录本减少。综上所述，这些结果表明伏硫西汀可调节与神经可塑性相关的分子靶点。
