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

• Published in: Neurochemistry international 2017-05, Vol.105, p.51-57
• Main Authors: Ota, Ami, Yamamoto, Akane, Kimura, Saeko, Mori, Yukiha, Mizushige, Takafumi, Nagashima, Yoshiki, Sato, Masaru, Suzuki, Hideyuki, Odagiri, Saori, Yamada, Daisuke, Sekiguchi, Masayuki, Wada, Keiji, Kanamoto, Ryuhei, Ohinata, Kousaku
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Anti-Anxiety Agents - administration & dosage; Antigens, Plant - administration & dosage; Anxiety - drug therapy; Anxiety - metabolism; Anxiety - psychology; Brain - drug effects; Brain - metabolism; Brain-gut interaction; Dose-Response Relationship, Drug; Enteric Nervous System - drug effects; Enteric Nervous System - metabolism; Gastrointestinal Tract - drug effects; Gastrointestinal Tract - metabolism; Globulins - administration & dosage; Glycine max; Male; Maze Learning - drug effects; Maze Learning - physiology; Mice; Middle-chain peptide; Orally active; Seed Storage Proteins - administration & dosage; Soybean; Soybean Proteins - administration & dosage; The vagus nerve; Vagus Nerve - drug effects; Vagus Nerve - metabolism
• ISSN: 0197-0186; 1872-9754
• DOI: 10.1016/j.neuint.2016.12.020

Here we found that the chymotryptic digest of soy β-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 β-conglycinin α subunit [βCGα(323–333)] emerged as a candidate. Oral administration of synthetic βCGα(323–333) exhibited anxiolytic-like effects in the elevated plus-maze and open-field test in male mice. Orally administered βCGα(323–333) exhibited anxiolytic-like effects in sham-operated control mice but not in vagotomized mice. In addition, oral administration of βCGα(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 βCGα(323–333) were also blocked by antagonists of the serotonin 5-HT1A, dopamine D1 and GABAA receptors. However βCGα(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, βCGα(323–333), may exhibit anxiolytic-like effects after oral administration via the vagus nerve and 5-HT1A, D1 and GABAA systems. •The chymotryptic digest of soy β-conglycinin exhibited anxiolytic-like effect in mice.•We found a novel anxiolytic soy undecapeptide based on a global analysis of the digest.•The soy undecapeptide exhibited potent anxiolytic-like effect after oral administration.•The anxiolytic-like effect was blocked by the 5-HT1A, D1and GABAA antagonists.•This is the first soy anxiolytic-like peptide coupled to the gut-brain communication.