Role of cyclic-glycine-proline in neurodevelopmental programming: New insights into the physiological regulation of IGF-1 function

Abstract

Insulin-like growth factor-1 (IGF-1) is critical for postnatal brain development and adult cognition. As a metabolite of IGF-1, cyclic-glycine-proline (cGP) regulates the bioavailability of IGF-1, and thus normalizes IGF-1 function under pathophysiological conditions. The presence and changes in concentrations of endogenous cGP in rat milk and plasma were evaluated during lactation and postnatal development, respectively. The efficacy of maternal administration of cGP during lactation on normal brain development and function of offspring, and the lactational capacity of dams was also investigated. Sprague-Dawley dams were gavaged with either cGP (3mg/kg) or saline daily from postnatal d8-22. Concentrations of cGP, IGF-1 and IGF binding protein-3 (IGFBP-3) were measured in dams’ milk, and in the plasma of dams and offspring. Neuroplasticity and memory of offspring were evaluated. The effect of cGP on milk production, and various morphological, cellular and molecular markers of post-lactational involution were investigated. Concentrations of endogenous cGP were higher in milk during peak, than during late lactation. Concentrations of endogenous IGF-1 and IGFBP-3 were low, whereas concentrations of endogenous cGP were high in the plasma of pups. The reduced IGFBP-3 and increased cGP were a response to increase the bioavailability of IGF-1 during infancy. Exogenous cGP showed oral bioavailability in dams and effective maternal-infantile transfer through milk, which resulted in an increase in the bioavailability of IGF-1 in both dams and pups. Maternally transferred cGP improved learning and memory of offspring at adolescence and adulthood, which was associated with increased glutamatergic neuroplasticity. Milk production and composition of dams was not affected. However, cGP promoted the apoptosis of mammary cells, the loss of intact alveoli and the upregulation of cell survival factors during early-involution, and the reduction in phosphorylation of IGF-1 receptor during late-involution. This is the first study to show the role of cGP in autocrine regulation of IGF-1 in vivo, and the efficacy of maternally-administered cGP in optimizing normal brain development and function of offspring. The role of cGP in promoting mammary gland involution, and the physiological decline in IGF-1 function are also novel findings. The positive modulation of neurodevelopmental programming supports clinical translation of cGP as maternal supplementation.