The hydrophobic dipeptide Leu-Ile inhibits immobility induced by repeated forced swimming via the induction of BDNF
The hydrophobic dipeptide Leu-Ile inhibits immobility induced by repeated forced swimming via the induction of BDNF
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DOI：
10.1016/j.bbr.2011.02.003
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发表时间：
2011-07-07
影响因子：
2.7
通讯作者：
Yamada, Kiyofumi
中科院分区：
文献类型：
--
作者：
Furukawa-Hibi, Yoko;Nitta, Atsumi;Yamada, Kiyofumi
抑郁症最近已经成为一个严重的问题。世界性的社会问题。然而，由于抑郁症的病因尚不清楚，我们缺乏适当的治疗工具。神经细胞的退化和神经发生的减少最近被认为是导致抑郁样行为的两个因素。此外，脑源性神经营养因子（BDNF）也被认为是从这种行为中恢复的重要因素。我们之前已经证明疏水二肽亮氨酸异亮氨酸（Leu-Ile）在培养的神经细胞中诱导BDNF。因此，我们使用重复强迫游泳试验（FST）在动物模型中研究了Leu-Ile可能的抗抑郁样作用。每天一次，小鼠在装有水的圆柱体中游泳6分钟。每次FST后立即用Leu-Ile sc或p.o.治疗小鼠。5天重复Leu-Ile治疗显著增加小鼠海马BDNF mRNA水平，激活BDNF/Akt/mTOR信号通路。虽然2周重复FST增加了固定时间，但2周的Leu-Ile治疗抵消了这一增加。在C57BL/6J-BDNF杂合敲除（BDNF(+/-)）小鼠中，Leu-Ile不能减少重复FST增加的不动时间。接下来，我们研究了海马细胞摄取5-溴-2'-脱氧尿苷（BrdU）时海马细胞增殖的程度。重复FST显著减少海马齿状回brdu阳性细胞的数量，而重复Leu-Ile治疗可防止这种缺陷。这些结果表明，Leu-Ile具有抗抑郁样作用，至少部分是通过BDNF信号通路支持细胞增殖。(C) 2011 Elsevier B.V.版权所有
Depression has recently become a serious. problem in society worldwide. However, we lack appropriate therapeutic tools, since the causes of depression remain unclear. Degeneration of neuronal cells and a decrease in neurogenesis have been suggested recently as two of the factors responsible for depression-like behavior. Furthermore, brain-derived neurotrophic factor (BDNF) is also suggested to be an important factor in recovering from such behavior. We have previously demonstrated that the hydrophobic dipeptide leucyl-isoleucine (Leu-Ile) induces BDNF in cultured neuronal cells. We therefore investigated possible antidepressant-like effects of Leu-Ile in an animal model using the repeated forced swim test (FST). Mice were forced to swim for 6 min once a day in a cylinder containing water. The mice were treated with Leu-Ile s.c. or p.o. immediately after each FST. Five-day repeated Leu-Ile treatment significantly increased BDNF mRNA levels and activated the BDNF/Akt/mTOR signaling pathway in the hippocampi of the mice. While 2-week repeated FST increased immobility time, Leu-Ile treatment for 2 weeks offset this increase. In C57BL/6J-BDNF heterozygous knockout (BDNF(+/-)) mice, Leu-Ile failed to reduce the immobility time increased by repeated FST. We next investigated the extent of cell proliferation in the hippocampus as 5-bromo-2'-deoxy-uridine (BrdU) uptake into hippocampal cells. Repeated FST significantly reduced the number of BrdU-positive cells in the hippocampal dentate gyrus, while this deficit was prevented by repeated Leu-Ile treatment. These results suggest that Leu-Ile has an antidepressant-like effect, at least in part by supporting cell proliferation through the BDNF signaling pathway. (C) 2011 Elsevier B.V. All rights reserved.