Modulation of neuroplastic molecules in selected brain regions after chronic administration of the novel antidepressant agomelatine
Modulation of neuroplastic molecules in selected brain regions after chronic administration of the novel antidepressant agomelatine
复制标题
DOI：
10.1007/s00213-010-2129-8
复制
发表时间：
2011-05-01
影响因子：
3.4
通讯作者：
Riva, Marco A.
中科院分区：
文献类型：
--
作者：
Calabrese, Francesca;Molteni, Raffaella;Riva, Marco A.
理论基础神经元的可塑性与抑郁症有关，可能是由于对细胞弹性重要的蛋白质表达改变的结果。因此，确定抗抑郁药物是否能够以及如何调节这些机制，以达到相关的临床效果是非常重要的。目的观察阿莫拉汀(一种MT(1)/MT(2)受体激动剂和5-羟色胺(2C)受体拮抗剂)慢性治疗对脑源性神经营养因子(BDNF)、成纤维细胞生长因子(FGF-2)和活性调节细胞骨架相关蛋白(Arc)的影响。或在最后一次注射后16小时(上午9点)结果Agomelatine可引起大鼠海马区转录水平的显著改变，而文拉法辛无此作用，BDNF和FGF2的表达明显上调。这两种药物都上调了Arc转录水平。在前额叶皮质没有观察到影响。相反，agomelatine提高了这两个区域的BDNF蛋白水平：药物对海马区和皮质中mRNA水平的影响不同，而对蛋白质的影响似乎具有相同的累积结果，提示这两个区域的调控机制不同。结论我们的数据为新的抗抑郁药agomelatine对脑功能的慢性影响的分子机制提供了新的信息。Agomelatine调节这些神经可塑性分子表达的能力遵循昼夜节律，这可能有助于其抗抑郁作用。
Rationale Neuronal plasticity is associated with depression, probably as a result of modified expression of proteins important for cellular resiliency. It is therefore important to establish if and how antidepressant drugs may be able to regulate these mechanisms in order to achieve relevant clinical effects.Objective We investigated the effects of chronic treatment with agomelatine (an MT(1)/MT(2) receptor agonist and 5-HT(2C) receptor antagonist) on the brain-derived neurotrophic factor (BDNF), fibroblast growth factor (FGF-2), and activity-regulated cytoskeleton-associated protein (Arc).Methods Animals were treated for 21 days with agomelatine, venlafaxine, or a vehicle and sacrificed 1 h (6 p.m.) or 16 h after the last injection (9 a.m.) to evaluate the messenger RNA (mRNA) and protein expression of these neuroplastic markers in the hippocampus and prefrontal cortex.Results Agomelatine, but not venlafaxine, produced major transcriptional changes in the hippocampus, where significant up-regulations of BDNF and FGF-2 were observed. Both drugs up-regulated the Arc transcription levels. No effects were observed in the prefrontal cortex. Instead, the levels of BDNF protein were elevated by agomelatine in both regions: the effects of the drug on mRNA levels in the hippocampus and cortex are different, while the effects on the protein seem to have the same cumulative result, suggesting different modulatory mechanisms in the two regions.Conclusions Our data provide new information regarding the molecular mechanisms that contribute to the chronic effects of the new antidepressant agomelatine on brain function. The ability of agomelatine to modulate the expression of these neuroplastic molecules, which follows a circadian rhythm, may contribute to its antidepressant action.