The hydrophobic dipeptide Leu-Ile inhibits immobility induced by repeated forced swimming via the induction of BDNF

Yoko Furukawa-Hibi, Atsumi Nitta, Takeshi Ikeda, Koji Morishita, Wenting Liu, Daisuke Ibi, Tursun Alkam, Toshitaka Nabeshima, Kiyofumi Yamada

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)271-280
Number of pages10
JournalBehavioural Brain Research
Volume220
Issue number2
DOIs
Publication statusPublished - 07-07-2011
Externally publishedYes

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Isoleucine
Dipeptides
Brain-Derived Neurotrophic Factor
Bromodeoxyuridine
Depression
Antidepressive Agents
Hippocampus
Cell Proliferation
Parahippocampal Gyrus
Neurogenesis
Dentate Gyrus
Cultured Cells
Animal Models
Messenger RNA
Water

All Science Journal Classification (ASJC) codes

  • Behavioral Neuroscience

Cite this

Furukawa-Hibi, Yoko ; Nitta, Atsumi ; Ikeda, Takeshi ; Morishita, Koji ; Liu, Wenting ; Ibi, Daisuke ; Alkam, Tursun ; Nabeshima, Toshitaka ; Yamada, Kiyofumi. / The hydrophobic dipeptide Leu-Ile inhibits immobility induced by repeated forced swimming via the induction of BDNF. In: Behavioural Brain Research. 2011 ; Vol. 220, No. 2. pp. 271-280.
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abstract = "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.",
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Furukawa-Hibi, Y, Nitta, A, Ikeda, T, Morishita, K, Liu, W, Ibi, D, Alkam, T, Nabeshima, T & Yamada, K 2011, 'The hydrophobic dipeptide Leu-Ile inhibits immobility induced by repeated forced swimming via the induction of BDNF', Behavioural Brain Research, vol. 220, no. 2, pp. 271-280. https://doi.org/10.1016/j.bbr.2011.02.003

The hydrophobic dipeptide Leu-Ile inhibits immobility induced by repeated forced swimming via the induction of BDNF. / Furukawa-Hibi, Yoko; Nitta, Atsumi; Ikeda, Takeshi; Morishita, Koji; Liu, Wenting; Ibi, Daisuke; Alkam, Tursun; Nabeshima, Toshitaka; Yamada, Kiyofumi.

In: Behavioural Brain Research, Vol. 220, No. 2, 07.07.2011, p. 271-280.

Research output: Contribution to journalArticle

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T1 - The hydrophobic dipeptide Leu-Ile inhibits immobility induced by repeated forced swimming via the induction of BDNF

AU - Furukawa-Hibi, Yoko

AU - Nitta, Atsumi

AU - Ikeda, Takeshi

AU - Morishita, Koji

AU - Liu, Wenting

AU - Ibi, Daisuke

AU - Alkam, Tursun

AU - Nabeshima, Toshitaka

AU - Yamada, Kiyofumi

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