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.
Keywords: GABAA; dopamine D1; serotonin 5-HT1A; vagus nerve.