1. Academic Validation
  2. Dipeptide tyrosyl-leucine exhibits antidepressant-like activity in mice

Dipeptide tyrosyl-leucine exhibits antidepressant-like activity in mice

  • Sci Rep. 2020 Feb 10;10(1):2257. doi: 10.1038/s41598-020-59039-7.
Takafumi Mizushige 1 2 3 Tomoki Uchida 1 Kousaku Ohinata 4
Affiliations

Affiliations

  • 1 Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho Uji, Kyoto, 611-0011, Japan.
  • 2 Research Unit for Physiological Chemistry, C-PIER, Kyoto University, Kyoto, 606-8501, Japan.
  • 3 Department of Applied Biological Chemistry, Faculty of Agriculture, Utsunomiya University, 350 Minemachi, Utsunomiya, Tochigi, 321-8505, Japan.
  • 4 Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho Uji, Kyoto, 611-0011, Japan. ohinata@kais.kyoto-u.ac.jp.
Abstract

Depression is a worldwide health problem. In the present study, we found that a dipeptide, tyrosyl leucine (Tyr-Leu, YL), administered orally, intracerebroventricularly, or intraperitoneally exhibited a potent antidepressant-like activity in the forced swim and tail suspension tests in naïve mice. YL increased the amount of cells expressing c-Fos, a marker for neuronal activity, in the dentate gyrus of the hippocampus. YL increased bromo-2'-deoxyuridine-positive cells and doublecortin expression in the dentate gyrus of the hippocampus, suggesting that YL enhanced the proliferation of hippocampal progenitor cells in vivo and in vitro. YL did not affect hippocampal mRNA and protein expression of BDNF, which is a regulatory factor of both neurogenesis and depression-like behavior. Intriguingly, YL suppressed activation of the hypothalamo-pituitary-adrenal axis by forced swim stress. Moreover, other aromatic amino acid-leucines, Phe-Leu and Trp-Leu, also exhibited antidepressant-like activities, suggesting that the structure of aromatic amino acid-leucine may be important for antidepressant activity. In addition, bovine milk casein-derived peptide, Tyr-Leu-Gly (YLG), an anxiolytic peptide, exhibited an antidepressant-like activity. Our findings demonstrate that YL exhibits an antidepressant-like effect, moderates the stress response, and induces hippocampal neuronal proliferation through a signal pathway independent of BDNF.

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