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-HT, dopamine D, or GABA receptors. We also clarified the order of receptor activation as 5-HT, D, and GABA, using selective agonists and antagonists. Taken together, soy-deprestatin may exhibit antidepressant-like effects after oral administration via a novel pathway mediated by 5-HT, followed by D and GABA 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.

It is ideal to ingest bioactive substances from daily foods to stay healthy. Rice is the staple food for almost half of the human population. We found that an orally administered enzymatic digest of rice endosperm protein exhibits antidepressant-like effects in the tail suspension test (TST) using mice. We performed a comprehensive peptide analysis of the digest using liquid chromatography-tandem mass spectrometry, and the tridecapeptide QQFLPEGQSQSQK emerged as a candidate of the antidepressant-like peptide. Oral administration of the chemosynthetic peptide exhibited antidepressant-like effects at a low dose comparable to known drugs in the TST. This also exhibited anti-depressant-like effect in the forced swim test. We named it rice endosperm-derived antidepressant-like peptide (REAP). Intriguingly, intraperitoneal administration had no effect. Orally administered REAP(8–13) but not REAP(1–7) exhibited antidepressant-like activity, suggesting that the C-terminal structure is important for the antidepressant-like effect. We confirmed the presence of REAP, corresponding to rice glutelin type B4(130–142) and B5(130–142), in the digest. The effects of REAP were blocked by either intraperitoneal or intracerebroventricular administration of a dopamine D1 antagonist; however, REAP had no affinity for the receptor. These results suggest that it exerts its antidepressant-like activity through promotion of endogenous dopamine release and activation of central D1 receptors. REAP-induced antidepressant-like effect was at least in part blocked by vagotomy, implying the gut-brain communication is associated with REAP’s effect. Taken together, oral administration of a novel tridecapeptide exhibited antidepressant-like effects via the dopamine D1 system. This is the first report of a rice-derived peptide that exhibits antidepressant-like effects.