Insulin-like growth factor 1 supplementation supports motor coordination and affects myelination in preterm pigs

Authors: CHRISTIANSEN, LINE - University Of Copenhagen; VENTURA, GEMMA - University Of Copenhagen; HOLMQVIST, BO - Imagene-It; AASMUL-OLSEN, KAROLINE - University Of Copenhagen; LINDHOLM, SANDY E - University Of Copenhagen; LYCAS, MATTHEW - University Of Copenhagen; MORI, YUKI - University Of Copenhagen; BOJSEN-MØLLER SECHER, JAN - University Of Copenhagen; Burrin, Douglas - Doug; THYMANN, THOMAS - University Of Copenhagen; SANGILD, PER TORP - University Of Copenhagen; PANKRATOVA, STANISLAVA - University Of Copenhagen

Submitted to: Frontiers in Neuroscience
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/23/2023
Publication Date: 6/19/2023
Citation: Christiansen, L.I., Ventura, G.C., Holmqvist, B., Aasmul-Olsen, K., Lindholm, S.H., Lycas, M.D., Mori, Y., Bojsen-Møller Secher, J., Burrin, D.G., Thymann, T., Sangild, P., Pankratova, S. 2023. Insulin-like growth factor 1 supplementation supports motor coordination and affects myelination in preterm pigs. Frontiers in Neuroscience. 17. Article 1205819. https://doi.org/10.3389/fnins.2023.1205819.
DOI: https://doi.org/10.3389/fnins.2023.1205819

Interpretive Summary: Preterm infants have increased risk of impaired neurodevelopment and reduced systemic levels of insulin-like growth factor (IGF-1) in the weeks after birth may play a role. Researchers investigated if postnatal IGF-1 supplementation improved brain development in preterm pigs, used as a model for preterm infants. Our data supports the idea that supplementary IGF-1 in the postnatal period of preterm neonates enhances maturation of a range of body systems, including neurodevelopment, and thereby critical capacities, such as motor function. More studies in both pigs and infants are required to define the optimal time, length and dose for the various groups of (extremely, very, moderate) preterm infants suffering various clinical complications.

Technical Abstract: Preterm infants have increased risk of impaired neurodevelopment and reduced systemic levels of insulin-like growth factor (IGF-1) in the weeks after birth may play a role. Hence, we investigated if postnatal IGF-1 supplementation improved brain development in preterm pigs, used as a model for preterm infants. Caesarean-delivered preterm pigs received recombinant human IGF-1/IGF binding protein-3 complex (rhIGF-1/rhIGFBP-3, 2.25 mg/kg/day) or vehicle from birth to postnatal day 19. Motor function and cognition were assessed by monitoring of in-cage activity, open field, balance beam test, gait parameters, novel object recognition and operant conditioning tests. Collected brains were subject to magnetic resonance imaging (MRI), immunohistochemistry, gene expression analyses and protein synthesis measurements. The IGF-1 treatment increased cerebellar protein synthesis rates (both in vivo and ex vivo). Performance in the balance beam test was improved by IGF-1 but not in other neurofunctional tests. The treatment decreased total and relative caudate nucleus weights, without any effects to total brain weight or grey/white matter volumes. Supplementation with IGF-1 reduced myelination in caudate nucleus, cerebellum, and white matter regions and decreased hilar synapse formation, without effects to oligodendrocyte maturation or neuron differentiation. Gene expression analyses indicated enhanced maturation of the GABAergic system in the caudate nucleus (decreased NKCC1:KCC2 ratio) with limited effects in cerebellum or hippocampus. Supplemental IGF-1 during the first three weeks after preterm birth may support motor function by enhancing GABAergic maturation in the caudate nucleus, despite reduced myelination. Supplemental IGF-1 may support postnatal brain development in preterm infants, but more studies are required to identify optimal treatment regimens for subgroups of very or extremely preterm infants.