Dipeptide tyrosyl-leucine exhibits antidepressant-like activity in mice

• Published in: Scientific reports Vol. 10; no. 1; p. 2257
• Main Authors: Mizushige, Takafumi, Uchida, Tomoki, Ohinata, Kousaku
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.02.2020; Nature Publishing Group
• Subjects: 13/51; 38/35; 38/77; 631/378/1831; 631/45/611; 64/60; Amino acids; Animals; Antidepressants; Antidepressive Agents - pharmacology; Antidepressive Agents - therapeutic use; Brain-derived neurotrophic factor; Brain-Derived Neurotrophic Factor - metabolism; c-Fos protein; Casein; Cell proliferation; Cow's milk; Dentate gyrus; Depression - drug therapy; Dipeptides - pharmacology; Dipeptides - therapeutic use; Doublecortin protein; Drug Discovery; Gene expression; Hippocampus; Humanities and Social Sciences; Hypothalamic-pituitary-adrenal axis; Hypothalamo-Hypophyseal System - drug effects; Leucine; Male; Mental depression; Mice; mRNA; multidisciplinary; Neural stem cells; Neurogenesis; Oligopeptides - therapeutic use; Oral administration; Peptides; Pituitary; Progenitor cells; Science; Science (multidisciplinary); Stress response
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-59039-7

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.