title: The hydrophobic dipeptide Leu-Ile inhibits immobility induced by repeated forced swimming via the induction of BDNF.
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.
authors.affiliation: Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Furukawa-Hibi
authors.forename: Atsumi
authors.initials: A
authors.lastname: Nitta
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ikeda
authors.forename: Koji
authors.initials: K
authors.lastname: Morishita
authors.forename: Wenting
authors.initials: W
authors.lastname: Liu
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ibi
authors.forename: Tursun
authors.initials: T
authors.lastname: Alkam
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Nabeshima
authors.forename: Kiyofumi
authors.initials: K
authors.lastname: Yamada
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D000928:Antidepressive Agents / Q000008:administration & dosage*; D019208:Brain-Derived Neurotrophic Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D001973:Bromodeoxyuridine / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004151:Dipeptides / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D046352:Freezing Reaction, Cataleptic / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051058:Oncogene Protein v-akt / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013550:Swimming / Q000523:psychology*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D013997:Time Factors
chemical_list: D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D004151:Dipeptides; D012333:RNA, Messenger; C492946:leucyl-isoleucyl; D051058:Oncogene Protein v-akt; D058570:TOR Serine-Threonine Kinases; D001973:Bromodeoxyuridine