Characterization of soy-deprestatin, a novel orally active decapeptide that exerts antidepressant-like effects via gut-brain communication.

We found that the orally administered thermolysin digest of ß-conglycinin exhibits antidepressant-like effects in tail suspension and forced swim tests in mice. A comprehensive peptide analysis of the digest using liquid chromatography/mass spectrometry was performed, and LSSTQAQQSY emerged as a candidate antidepressant-like peptide. Orally administered synthetic LSSTQAQQSY exhibited antidepressant-like effects at a dose of 0.3 mg/kg; therefore, we named the decapeptide soy-deprestatin. In contrast, intraperitoneally administered soy-deprestatin was ineffective. We then hypothesized that it acted on the gut, and its signal was transferred to the brain. Indeed, orally administered soy-deprestatin exhibited antidepressant-like activity in sham-treated, but not vagotomized, mice. Oral administration of soy-deprestatin also increased the c-Fos expression in the nucleus of the solitary tract, which receives inputs from the vagus nerve. These results suggested that the antidepressant-like effects were mediated by the vagus nerve. Thermolysin digest- and soy-deprestatin-induced antidepressant-like effects were also blocked by antagonists of serotonin 5-HT1A, dopamine D1, or GABAA receptors. We also clarified the order of receptor activation as 5-HT1A, D1, and GABAA, using selective agonists and antagonists. Taken together, soy-deprestatin may exhibit antidepressant-like effects after oral administration via a novel pathway mediated by 5-HT1A, followed by D1 and GABAA systems. This is the first orally active peptide demonstrating antidepressant-like effects via gut-brain communication.-Mori, Y., Asakura, S., Yamamoto, A., Odagiri, S., Yamada, D., Sekiguchi, M., Wada, K., Sato, M., Kurabayashi, A., Suzuki, H., Kanamoto, R., Ohinata, K. Characterization of soy-deprestatin, a novel orally active decapeptide that exerts antidepressant-like effects via gut-brain communication.

Rational identification of a novel soy-derived anxiolytic-like undecapeptide acting via gut-brain axis after oral administration.

Here we found that the chymotryptic digest of soy ß-conglycinin, a major storage protein, exhibited anxiolytic-like effects in mice. We then searched for anxiolytic-like peptides in the digest. Based on a comprehensive peptide analysis of the chymotryptic digest by high performance liquid chromatograph connected to an LTQ Orbitrap mass spectrometer and the structure-activity relationship of known peptides, we explored anxiolytic-like peptides present in the digest. FLSSTEAQQSY, which corresponds to 323-333 of the ß-conglycinin α subunit [ßCGα(323-333)] emerged as a candidate. Oral administration of synthetic ßCGα(323-333) exhibited anxiolytic-like effects in the elevated plus-maze and open-field test in male mice. Orally administered ßCGα(323-333) exhibited anxiolytic-like effects in sham-operated control mice but not in vagotomized mice. In addition, oral administration of ßCGα(323-333) increased the expression of c-Fos, a marker of neuronal activity, in the nucleus of the solitary tract, which receives inputs from the vagus nerve. These results suggest that the anxiolytic-like effects were mediated by the vagus nerve. The anxiolytic-like effects of ßCGα(323-333) were also blocked by antagonists of the serotonin 5-HT1A, dopamine D1 and GABAA receptors. However ßCGα(323-333) had no affinity for these receptors, suggesting it stimulates the release of endogenous neurotransmitters to activate the receptors. Taken together, a soy-derived undecapeptide, ßCGα(323-333), may exhibit anxiolytic-like effects after oral administration via the vagus nerve and 5-HT1A, D1 and GABAA systems.

Antidepressant-like effect of food-derived pyroglutamyl peptides in mice.

The N-terminal glutamine residue, exposed by enzymatic cleavage of precursor proteins, is known to be modified to a pyroglutamyl residue with a cyclic structure in not only endogenous but also food-derived peptides. We investigated the effects of wheat-derived pyroglutamyl peptides on emotional behaviors. Pyroglutamyl leucine (pyroGlu-Leu, pEL) and pyroglutamyl glutaminyl leucine (pyroGlu-Gln-Leu, pEQL) exhibited antidepressant-like activity in the tail suspension and forced swim tests in mice. pEQL exhibited more potent antidepressant-like activity than pEL after i.p. and i.c.v. administration. pEQL exhibited antidepressant-like activity at a lower dose than Gln-Gln-Leu, suggesting that pyroglutamyl peptide had more potent activity. To examine whether pyroglutamyl peptides increased hippocampus neurogenesis, associated with the effects of antidepressants, we measured 5-bromo-2'-deoxyuridine (BrdU) incorporation. pEL and pEQL increased BrdU-positive cells in the dentate gyrus of the hippocampus. Intriguingly, pEL did not increase hippocampal mRNA and protein expression of brain-derived neurotrophic factor (BDNF), which is a factor associated with both neuropoietic and antidepressive effects. Thus, pyroglutamyl peptides may enhance hippocampal neurogenesis via a pathway independent of BDNF. We also confirmed that pEL and pEQL were produced in the subtilisin digest of major wheat proteins, glutenin and gliadin, after heat treatment. pEL and pEQL are the first peptides derived from wheat proteins to be shown to exhibit an antidepressant-like activity.