title: Maternally Administered Cyclic Glycine-Proline Increases Insulin-Like Growth Factor-1 Bioavailability and Novelty Recognition in Developing Offspring.
abstract: Cyclic glycine-proline (cGP), a metabolite of IGF-1, is an endogenous neuropeptide that improves memory in adult rats. The presence and concentrations of endogenous cGP, and its association with IGF-1 and IGF binding protein-3 (IGFBP-3) in rat milk and plasma, were evaluated during postnatal development. Maternal-infantile transfer of cGP during lactation and its efficacy on the memory of developing offspring were also investigated. Dams were gavaged with either cGP (3 mg/kg) or saline daily from postnatal days 8-22. Concentrations of cGP were measured in dams' milk, and concentrations of cGP, IGF-1, and IGFBP-3 were measured in the plasma of dams, pups, and young adults. The recognition memory, locomotor function, and anxiety-like behavior of offspring were evaluated using behavioral tests. Endogenous cGP was detected in rat milk, and its concentration was higher during peak lactation compared with late lactation. Comparisons within control groups showed low endogenous IGF-1 and IGFBP-3 and high endogenous cGP concentrations in the plasma of male pups. The reduced IGFBP-3 and increased cGP may be a response to increase the bioavailability of IGF-1 during infancy. Exogenous cGP showed oral bioavailability and effective maternal-infantile transfer through milk. Maternally transferred cGP also led to improved recognition memory in the developing offspring, possibly through increased IGF-1 bioavailability, with no effect on locomotor activity and anxiety-like behavior. These results show that cGP is an essential endogenous peptide during early postnatal development as it improves the bioavailability of IGF-1 during infancy. Furthermore, maternal cGP supplementation offers an effective and natural route of administration for improving memory in the developing offspring.
authors.affiliation: Department of Pharmacology and Clinical Pharmacology (G.S.-M., J.G.), School of Medical Sciences, Faculty of Medical and Health Sciences, Gravida (G.S.-M., K.S., C.D.M., E.T., J.G.), National Centre for Growth and Development, Liggins Institute, Centre for Brain Research (G.S.-M., J.G.), Faculty of Medical and Health Sciences, Brain Research New Zealand (J.G.), Faculty of Medical and Health Sciences, and Department of Medicinal Chemistry (P.H., M.A.G.), School of Chemistry, University of Auckland, Grafton, 1142 Auckland, New Zealand; AgResearch Ltd (G.S.-M., K.S., C.D.M.), Ruakura Research Centre, Hamilton 3240, New Zealand.
authors.forename: Gagandeep
authors.initials: G
authors.lastname: Singh-Mallah
authors.affiliation: Department of Pharmacology and Clinical Pharmacology (G.S.-M., J.G.), School of Medical Sciences, Faculty of Medical and Health Sciences, Gravida (G.S.-M., K.S., C.D.M., E.T., J.G.), National Centre for Growth and Development, Liggins Institute, Centre for Brain Research (G.S.-M., J.G.), Faculty of Medical and Health Sciences, Brain Research New Zealand (J.G.), Faculty of Medical and Health Sciences, and Department of Medicinal Chemistry (P.H., M.A.G.), School of Chemistry, University of Auckland, Grafton, 1142 Auckland, New Zealand; AgResearch Ltd (G.S.-M., K.S., C.D.M.), Ruakura Research Centre, Hamilton 3240, New Zealand.
authors.forename: Kuljeet
authors.initials: K
authors.lastname: Singh
authors.affiliation: Department of Pharmacology and Clinical Pharmacology (G.S.-M., J.G.), School of Medical Sciences, Faculty of Medical and Health Sciences, Gravida (G.S.-M., K.S., C.D.M., E.T., J.G.), National Centre for Growth and Development, Liggins Institute, Centre for Brain Research (G.S.-M., J.G.), Faculty of Medical and Health Sciences, Brain Research New Zealand (J.G.), Faculty of Medical and Health Sciences, and Department of Medicinal Chemistry (P.H., M.A.G.), School of Chemistry, University of Auckland, Grafton, 1142 Auckland, New Zealand; AgResearch Ltd (G.S.-M., K.S., C.D.M.), Ruakura Research Centre, Hamilton 3240, New Zealand.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: McMahon
authors.affiliation: Department of Pharmacology and Clinical Pharmacology (G.S.-M., J.G.), School of Medical Sciences, Faculty of Medical and Health Sciences, Gravida (G.S.-M., K.S., C.D.M., E.T., J.G.), National Centre for Growth and Development, Liggins Institute, Centre for Brain Research (G.S.-M., J.G.), Faculty of Medical and Health Sciences, Brain Research New Zealand (J.G.), Faculty of Medical and Health Sciences, and Department of Medicinal Chemistry (P.H., M.A.G.), School of Chemistry, University of Auckland, Grafton, 1142 Auckland, New Zealand; AgResearch Ltd (G.S.-M., K.S., C.D.M.), Ruakura Research Centre, Hamilton 3240, New Zealand.
authors.forename: Paul
authors.initials: P
authors.lastname: Harris
authors.affiliation: Department of Pharmacology and Clinical Pharmacology (G.S.-M., J.G.), School of Medical Sciences, Faculty of Medical and Health Sciences, Gravida (G.S.-M., K.S., C.D.M., E.T., J.G.), National Centre for Growth and Development, Liggins Institute, Centre for Brain Research (G.S.-M., J.G.), Faculty of Medical and Health Sciences, Brain Research New Zealand (J.G.), Faculty of Medical and Health Sciences, and Department of Medicinal Chemistry (P.H., M.A.G.), School of Chemistry, University of Auckland, Grafton, 1142 Auckland, New Zealand; AgResearch Ltd (G.S.-M., K.S., C.D.M.), Ruakura Research Centre, Hamilton 3240, New Zealand.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Brimble
authors.affiliation: Department of Pharmacology and Clinical Pharmacology (G.S.-M., J.G.), School of Medical Sciences, Faculty of Medical and Health Sciences, Gravida (G.S.-M., K.S., C.D.M., E.T., J.G.), National Centre for Growth and Development, Liggins Institute, Centre for Brain Research (G.S.-M., J.G.), Faculty of Medical and Health Sciences, Brain Research New Zealand (J.G.), Faculty of Medical and Health Sciences, and Department of Medicinal Chemistry (P.H., M.A.G.), School of Chemistry, University of Auckland, Grafton, 1142 Auckland, New Zealand; AgResearch Ltd (G.S.-M., K.S., C.D.M.), Ruakura Research Centre, Hamilton 3240, New Zealand.
authors.forename: Eric
authors.initials: E
authors.lastname: Thorstensen
authors.affiliation: Department of Pharmacology and Clinical Pharmacology (G.S.-M., J.G.), School of Medical Sciences, Faculty of Medical and Health Sciences, Gravida (G.S.-M., K.S., C.D.M., E.T., J.G.), National Centre for Growth and Development, Liggins Institute, Centre for Brain Research (G.S.-M., J.G.), Faculty of Medical and Health Sciences, Brain Research New Zealand (J.G.), Faculty of Medical and Health Sciences, and Department of Medicinal Chemistry (P.H., M.A.G.), School of Chemistry, University of Auckland, Grafton, 1142 Auckland, New Zealand; AgResearch Ltd (G.S.-M., K.S., C.D.M.), Ruakura Research Centre, Hamilton 3240, New Zealand.
authors.forename: Jian
authors.initials: J
authors.lastname: Guan
mesh_terms: D000818:Animals; D001682:Biological Availability; D005106:Exploratory Behavior / Q000187:drug effects*; D005260:Female; D005998:Glycine / Q000008:administration & dosage / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000493:pharmacokinetics*; D008297:Male; D039382:Maternal Nutritional Physiological Phenomena; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000494:pharmacology*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism / Q000523:psychology; D011392:Proline / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D021641:Recognition, Psychology / Q000187:drug effects*
chemical_list: D010456:Peptides, Cyclic; D007334:Insulin-Like Growth Factor I; D011392:Proline; D005998:Glycine