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 β‐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. FASEB J. 32, 568–575 (2018). www.fasebj.org