Departamento de Fisiologia y Farmacologia. IBBTEC. Facultad de Medicina. Herrera Oria s/n 39011 Santander. Cantabria. Spain.
Curr Pharm Des. 2014;20(23):3776-94. doi: 10.2174/13816128113196660736.
In the last years it has been proposed that the antidepressant action is mediated not only by changes in monoamine levels but also in association with modifications involving cell proliferation and plasticity in some brain limbic areas as hippocampus, and also frontal cortex and amygdala. This leads to the merging of the classic "monoaminergic hypothesis of depression", with the newer "neurotrophic hypothesis of depression". Here we review two important signaling pathways: the Wnt/β-catenin pathway -implicated in cellular proliferation and synaptic plasticity- that is downregulated in major depression and upregulated after antidepressant treatment; and the mTOR pathway -controling synaptic plasticity- recently related to present disrupted functioning in major depression, and as the target of some drugs with fast-acting potential antidepressant action. These pieces of evidences are confirmed in a variety of animal models of depression and are predictive of antidepressant actions. We also review the role of another two important neurotrophic factors: brain derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) that mediate the antidepressant effects. All of the above intracellular pathways interact by a crosstalk mediated by Akt, a key regulator molecule that may underlie the fine tuning between proliferative and neuroplasticity changes induced by antidepressant drugs.
在过去的几年中，有人提出抗抑郁作用不仅是通过改变单胺水平来介导的，而且还与某些脑边缘区域（如海马体、前额皮质和杏仁核）中的细胞增殖和可塑性的改变有关。这导致了经典的“单胺能抑郁假说”与更新的“抑郁神经发生假说”的融合。在这里，我们回顾了两个重要的信号通路：Wnt/β-catenin 通路——涉及细胞增殖和突触可塑性——在重度抑郁症中下调，而在抗抑郁治疗后上调；以及 mTOR 通路——控制突触可塑性——最近与重度抑郁症中目前的功能障碍有关，并且是一些具有快速抗抑郁作用的药物的靶点。这些证据在各种抑郁动物模型中得到了证实，并可预测抗抑郁作用。我们还回顾了另外两种重要的神经营养因子的作用：脑源性神经营养因子（BDNF）和血管内皮生长因子（VEGF），它们介导抗抑郁作用。所有上述细胞内途径通过 Akt 介导的串扰相互作用，Akt 是一种关键的调节分子，可能是抗抑郁药物诱导的增殖和神经可塑性变化之间精细调节的基础。
