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.
Highlights
We previously revealed that a novel signaling pathway with serotonin 5-HT1A receptor activation followed by the activation of dopamine D1 and GABAA receptors mediate antidepressant-like and anxiolytic-like activities[1,6]
We found that a dipeptide, YL, exhibits a potent antidepressant-like effect after peripheral administration in behavioral tests, comparable to that of antidepressants, imipramine and fluvoxamine
It cannot be ruled out that YL reaches the brain in dipeptide-form and act on the central nervous system (CNS)
Summary
We reported that bioactive peptides derived from food proteins exhibit anxiolytic-like effects[1,2,3,4,5,6,7], suggesting interactions between food components and the nervous system. We examined the hippocampal c-Fos protein-positive cells, known as a general neural activity marker[13,14,15], and the effects of the proliferation of progenitor cells in vivo and in vitro. Brain-derived neurotrophic factor (BDNF) is known to induce the proliferation of hippocampal progenitor cells and has an antidepressant-like effect[16,17,18].
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