Larsen Marianne H, Rosenbrock Holger, Sams-Dodd Frank, Mikkelsen Jens D
Department of Translational Neurobiology, NeuroSearch A/S, Pederstrupvej 93, 2750 Ballerup, Denmark.
Eur J Pharmacol. 2007 Jan 26;555(2-3):115-21. doi: 10.1016/j.ejphar.2006.10.029. Epub 2006 Oct 19.
The changes of gene expression resulting from long-term exposure to monoamine antidepressant drugs in experimental animals are key to understanding the mechanisms of action of this class of drugs in man. Many of these genes and their products are either relevant biomarkers or directly involved in structural changes that are perhaps necessary for the antidepressant effect. Tesofensine is a novel triple monoamine reuptake inhibitor that acts to increase noradrenaline, serotonin, and dopamine neurotransmission. This study was undertaken to examine the effect of sub-chronic (5 days) and chronic (14 days) administration of Tesofensine on the expression of brain derived neurotrophic factor (BDNF) and activity-regulated cytoskeleton protein (Arc) in the rat hippocampus. Furthermore, hippocampi from the same animals were used to investigate the effect on cell proliferation by means of Ki-67- and NeuroD-immunoreactivity. We find that chronic, but not sub-chronic treatment with Tesofensine increases BDNF mRNA in the CA3 region of the hippocampus (35%), and Arc mRNA in the CA1 of the hippocampus (65%). Furthermore, the number of Ki-67- and neuroD-positive cells increased after chronic, but not sub-chronic treatment. This study shows that Tesofensine enhances hippocampal gene expression and new cell formation indicative for an antidepressant potential of this novel drug substance.
实验动物长期暴露于单胺类抗抑郁药物所导致的基因表达变化，是理解这类药物在人体中作用机制的关键。这些基因及其产物中的许多要么是相关生物标志物，要么直接参与了可能对抗抑郁作用至关重要的结构变化。替索芬辛是一种新型的三重单胺再摄取抑制剂，其作用是增强去甲肾上腺素、5-羟色胺和多巴胺的神经传递。本研究旨在考察亚慢性（5天）和慢性（14天）给予替索芬辛对大鼠海马体中脑源性神经营养因子（BDNF）表达及活性调节细胞骨架蛋白（Arc）的影响。此外，利用同一批动物的海马体，通过Ki-67和NeuroD免疫反应性来研究对细胞增殖的影响。我们发现，替索芬辛的慢性给药而非亚慢性给药可使海马体CA3区的BDNF mRNA增加（35%），海马体CA1区的Arc mRNA增加（65%）。此外，慢性给药而非亚慢性给药后，Ki-67和NeuroD阳性细胞数量增加。本研究表明，替索芬辛可增强海马体基因表达和新细胞形成，这表明这种新型药物具有抗抑郁潜力。
