Insulin-like growth factor-1 supplementation promotes brain maturation in preterm pigs

Authors: CHRISTIANSEN, LINE - University Of Copenhagen; HOLMQVIST, BO - Lund University; PAN, XIAOYU - University Of Copenhagen; HOLGERSEN, KRISTINE - University Of Copenhagen; LINDHOLM, SANDY - University Of Copenhagen; HENRIKSEN, NICOLE - University Of Copenhagen; Burrin, Douglas - Doug; LEY, DAVID - Lund University; THYMANN, THOMAS - University Of Copenhagen; SANGILD, PER TORP - University Of Copenhagen; PANKRATOVA, STANISLAVA - University Of Copenhagen

Submitted to: eNeuro
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/21/2023
Publication Date: 3/27/2023
Citation: Christiansen, L.I., Holmqvist, B., Pan, X., Holgersen, K., Lindholm, S.E., Henriksen, N.L., Burrin, D.G., Ley, D., Thymann, T., Sangild, P., Pankratova, S. 2023. Insulin-like growth factor-1 supplementation promotes brain maturation in preterm pigs. eNeuro. 10(4):1-15. https://doi.org/10.1523/ENEURO.0430-22.2023.
DOI: https://doi.org/10.1523/ENEURO.0430-22.2023

Interpretive Summary: The survival rates of very premature infants are increasing but many of these infants experience poor growth in the months after birth. Insulin-like growth factor-1 (IGF-1) is a key hormone involved in the regulation of infant growth and organ development. Premature infants has sustained period of low plasma IGF-1 levels after birth and these low levels correlate directly with poor growth. Premature infants also experience delayed or poor brain development, and this may be related to low IGF-1 in the blood since this growth factor can promote brain growth. We showed in this study that premature neonatal piglets also have low plasma IGF-1 after birth and we tested whether intravenous administration of IGF-1 fused with a binding protein (IGFBP-3) would restore normal IGF-1 blood levels and promote motor function and brain growth in these piglets. Our results showed that treatment with IGF-1 for 9 days after birth resulted in increase brain development and protein synthesis in association with genes involved in neuron development and maturation. IGF-1 did not improve motor function in treated piglets. These results provide support for therapeutic treatment with IGF-1 in the early postnatal period in preterm infants.

Technical Abstract: Very preterm infants show low levels of insulin-like growth factor-1 (IGF-1), which is associated with postnatal growth restriction, morbidities, and poor neurological outcomes. It remains unknown whether supplemental IGF-1 may stimulate neurodevelopment in preterm neonates. Using cesarean-delivered preterm pigs as a model of preterm infants, we investigated the effects of supplemental IGF-1 on motor function and regional and cellular brain development. Pigs were treated with 2.25 mg/kg/day of recombinant human IGF-1/IGF binding protein 3 complex (IGF-1) from birth until Day 5 or 9 before collection of brain samples for quantitative immunohistochemistry (IHC), RNA-seq and qPCR analyses. Brain protein synthesis was measured using in vivo labeling with [2H5] phenylalanine. We showed that the IGF-1 receptor (IGF1R) was widely distributed in the brain and largely coexisted with immature neurons. Region specific quantification of IHC labeling showed that treatment with IGF-1 promoted neuronal differentiation, increased subcortical myelination and attenuated synaptogenesis in a region- and time-dependent manner. The expression levels of genes involved in neuronal and oligodendrocyte maturation, angiogenic and transport functions were altered, reflecting enhanced brain maturation in response to IGF-1 treatment. Cerebellar protein synthesis was increased by 19% at Day 5 and 14% at Day 9 after IGF-1 treatment. Treatment had no effect on Iba1-positive microglia or regional brain weights and did not affect motor development or the expression of genes related to IGF-1 signaling. In conclusion, the data show that supplemental IGF-1 promotes brain maturation in newborn preterm pigs. The results provide further support for IGF-1 supplementation therapy in the early postnatal period in preterm infants.