The rapid antidepressant and anxiolytic-like effects of YY-21 involve enhancement of excitatory synaptic transmission via activation of mTOR signaling in the mPFC
The rapid antidepressant and anxiolytic-like effects of YY-21 involve enhancement of excitatory synaptic transmission via activation of mTOR signaling in the mPFC
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YY-21 的快速抗抑郁和抗焦虑样作用涉及通过激活 mPFC 中的 mTOR 信号来增强兴奋性突触传递
DOI：
10.1016/j.euroneuro.2016.05.006
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发表时间：
2016-07-01
影响因子：
5.6
通讯作者：
Li, Yang
中科院分区：
文献类型：
--
作者：
Guo, Fei;Zhang, Bing;Li, Yang
尽管抗抑郁药已被广泛用于治疗重度抑郁症（MDD）患者，但人们对改进抗抑郁药治疗的必要性几乎没有异议，因为典型的治疗方法起效缓慢且疗效中等。本研究从知母皂苷B-III中分离得到一个新化合物YY-21。从初步的结果中，我们发现，YY-21明显增加突触前谷氨酸释放和增强长时程突触活动在10分钟内分别测定兴奋性突触后电流（EPSC）和场兴奋性突触后电位（fEPSP）在内侧前额叶皮层（mPFC）切片。YY-21在未处理动物中急性给药后表现出抗焦虑样作用，并逆转了慢性不可预测的轻度应激（CMS）诱导的抑郁样和焦虑表型，治疗起效相对较快。此外，对细胞内信号通路的分析表明，YY-21使CMS诱导的GluN 2B、p-mTOR、突触相关蛋白如BDNF、PSD-95和GluA 1的低蛋白水平正常化。预先应用mTOR选择性抑制剂雷帕霉素阻断YY-21诱导的长时程突触增强。这些发现表明，激活BDNF依赖的mTOR信号，导致突触后蛋白PSD-95和GluA 1的快速增加，并进一步触发突触神经传递的长期增强，可能是YY-21诱导的快速抗抑郁和抗焦虑作用的机制。(C)2016 Elsevier B.V.和ECNP。All rights reserved.
Although antidepressants have been widely prescribed to treat patients with major depressive disease (MDD), there is little disagreement over the need for improved antidepressant therapeutics as the typical treatments have a slow therapeutic onset and moderate efficacy. In the present study, we assessed a novel compound, YY-21, from timosaponin B-III derived from sarsasapogenin of Anemarrhenae Rhizoma. From the initial results, we found that YY-21 obviously increased presynaptic glutamate release and enhanced long-term synaptic activity within 10 min as determined by excitatory postsynaptic current (EPSC) and field excitatory postsynaptic potential (fEPSP) in medial prefrontal cortex (mPFC) slices, respectively. YY-21 demonstrated anxiolytic-like effects following acute administration in naive animals and reversed the depressive-like and anxiety phenotypes induced by chronic unpredictable mild stress (CMS) with a relatively fast therapeutic onset. Furthermore, analysis of intracellular signaling pathways showed that YY-21 normalized the CMS-induced low protein levels of GluN2B, p-mTOR, synaptic-related proteins, such as BDNF, PSD-95 and GluA1. Pre-application of the mTOR-selective inhibitor rapamycin blocked YY-21-induced long-term synaptic enhancement. These findings suggest that the activation of BDNF-dependent mTOR signaling, which produces a rapid increase in the postsynaptic protein PSD-95 and GluA1 and further triggers the long-term enhancement of synaptic neurotransmission, may be the mechanism underlying the rapid antidepressant and anxiolytic effects induced by YY-21. (C) 2016 Elsevier B.V. and ECNP. All rights reserved.