title: Antidepressant-like effect of food-derived pyroglutamyl peptides in mice.
abstract: 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.
authors.affiliation: Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho Uji, Kyoto 611-0011, Japan.
authors.forename: Yukako
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho Uji, Kyoto 611-0011, Japan; Research Unit for Physiological Chemistry, C-PIER, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Mizushige
authors.affiliation: Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho Uji, Kyoto 611-0011, Japan.
authors.forename: Yukiha
authors.initials: Y
authors.lastname: Mori
authors.affiliation: Health Care Research Center, R&D Division, Nisshin Pharma Inc., 5-3-1 Tsurugaoka, Fujimino City, Saitama 356-8511, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Shimmura
authors.affiliation: Health Care Research Center, R&D Division, Nisshin Pharma Inc., 5-3-1 Tsurugaoka, Fujimino City, Saitama 356-8511, Japan.
authors.forename: Ruuta
authors.initials: R
authors.lastname: Fukutomi
authors.affiliation: Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho Uji, Kyoto 611-0011, Japan.
authors.forename: Ryuhei
authors.initials: R
authors.lastname: Kanamoto
authors.affiliation: Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasho Uji, Kyoto 611-0011, Japan. Electronic address: ohinata@kais.kyoto-u.ac.jp.
authors.forename: Kousaku
authors.initials: K
authors.lastname: Ohinata
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects*; D019208:Brain-Derived Neurotrophic Factor; D049109:Cell Proliferation / Q000187:drug effects; D003863:Depression / Q000188:drug therapy; D004151:Dipeptides / Q000494:pharmacology* / Q000627:therapeutic use; D019417:Hindlimb Suspension; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D055495:Neurogenesis / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D013550:Swimming
chemical_list: D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D004151:Dipeptides; C041765:pyroglutamylleucine; D011761:Pyrrolidonecarboxylic Acid
keywords: Antidepressant-like effect; Emotional regulation; Gluten; Neurogenesis; Pyroglutamyl peptide