Electroconvulsive seizure, but not imipramine, rapidly up-regulates pro-BDNF and t-PA, leading to mature BDNF production, in the rat hippocampus.
Electroconvulsive seizure, but not imipramine, rapidly up-regulates pro-BDNF and t-PA, leading to mature BDNF production, in the rat hippocampus.
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DOI：
10.1017/s1461145712000053
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发表时间：
2013-03
期刊：
影响因子：
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通讯作者：
M. Segawa;S. Morinobu;Tomoya Matsumoto;Manabu Fuchikami;S. Yamawaki
中科院分区：
文献类型：
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作者：
M. Segawa;S. Morinobu;Tomoya Matsumoto;Manabu Fuchikami;S. Yamawaki
电休克治疗是抗抑郁药抵抗性抑郁症最有效的治疗方法，尽管其机制尚未完全阐明。以往的研究表明，电惊厥发作（ECS）诱导大鼠海马脑源性神经营养因子（BDNF）的表达。然而，与已知具有抗抑郁作用的成熟BDNF（mBDNF）相比，其前体（pro-BDNF）对神经元具有有害作用。因此，我们假设，有效的处理pro-BDNF是一个关键的要求，为抗抑郁作用的ECS。我们发现，ECS的单次给药不仅迅速增加了海马的BDNF原水平，而且还增加了激素原转化酶1（PC 1）和组织纤溶酶原激活物（t-PA）的水平，这两种蛋白酶分别参与了细胞内和细胞外的BDNF原加工。有趣的是，pro-BDNF和t-PA水平增加后，单ECS海马突触体，表明他们的运输到分泌网站。在接受10天重复ECS的大鼠中，观察到pro-BDNF的积累和由此产生的mBDNF水平增加。虽然t-PA水平增加和积累后，重复ECS，PC 1水平没有，这表明细胞内的处理能力是有限的。最后，丙咪嗪的长期管理显着增加mBDNF水平，但不pro-BDNF和蛋白酶水平，表明丙咪嗪的治疗机制不同于ECS。两者合计，这些结果表明，虽然内部和细胞外蛋白酶参与在单个ECS中的BDNF前体加工，t-PA在重复ECS后起主导作用。这种高效的前BDNF加工以及对BDNF表达的强烈诱导可能有助于ECS的抗抑郁作用。
Electroconvulsive therapy is the most effective treatment for antidepressant-resistant depression, although its mechanism has not been fully elucidated. Previous studies have demonstrated that electroconvulsive seizures (ECS) induce expression of brain-derived neurotrophic factor (BDNF) in the rat hippocampus. However, in contrast with mature BDNF (mBDNF) known to have antidepressant effects, its precursor (pro-BDNF) has harmful effects on neurons. We therefore hypothesized that efficient processing of pro-BDNF is a critical requirement for the antidepressant effects of ECS. We found that single administration of ECS rapidly increased not only hippocampal levels of pro-BDNF but also those of prohormone convertase 1 (PC1) and tissue-plasminogen activator (t-PA), which are proteases involved in intra- and extracellular pro-BDNF processing, respectively. Interestingly, pro-BDNF and t-PA levels were increased in hippocampal synaptosomes after single ECS, suggesting their transport to secretory sites. In rats receiving 10-d repeated ECS, accumulation of pro-BDNF and a resultant increase in mBDNF levels were observed. While t-PA levels increased and accumulated following repeated ECS, PC1 levels did not, suggesting that intracellular processing capacity is limited. Finally, chronic administration of imipramine significantly increased mBDNF levels, but not pro-BDNF and protease levels, indicating that the therapeutic mechanism of imipramine differs from that of ECS. Taken together, these results suggest that, while intra- and extracellular proteases are involved in pro-BDNF processing in single ECS, t-PA plays a dominant role following repeated ECS. Such efficient pro-BDNF processing as well as strong induction of BDNF expression may contribute to the antidepressant effects of ECS.