Insulin-Like Growth Factor 1 in the Preterm Rabbit Pup: Characterization of Cerebrovascular Maturation following Administration of Recombinant Human Insulin-Like Growth Factor 1/Insulin-Like Growth Factor 1-Binding Protein 3

Abstract

Following preterm birth, serum levels of insulin-like growth factor 1 (IGF-1) decrease compared to corresponding in utero levels. A recent clinical trial indicated that supplementation with recombinant human (rh) IGF-1/rhIGF-binding protein 3 (rhIGF-1/rhIGFBP-3) prevents severe intraventricular hemorrhage (IVH) in extremely preterm infants. In a preterm rabbit pup model, we characterized endogenous serum and hepatic IGF-1, along with brain distribution of IGF-1 and IGF-1 receptor (IGF1R). We then evaluated the effects of rhIGF-1/rhIGFBP-3 on gene expression of regulators of cerebrovascular maturation and structure. Similar to preterm infants, serum IGF-1 concentrations decreased rapidly after preterm birth in the rabbit pup. Administration of rhIGF-1/rhIGFBP-3 restored in utero serum levels but was rapidly eliminated. Immunolabeled IGF1R was widely distributed in multiple brain regions, displaying an abundant density in the choroid plexus and sub-ependymal germinal zones. Increased IGF-1 immunoreactivity, distributed as IGF1R, was detected 4 h after rhIGF-1/rhIGFBP-3 administration. The rhIGF-1/rhIGFBP-3 treatment led to upregulation of choroid plexus genes involved in vascular maturation and structure, with corresponding protein translation for most of these genes. The preterm rabbit pup model is well suited for evaluation of IGF-1-based prevention of IVH. Administration of rhIGF-1/rhIGFBP-3 affects cerebrovascular maturation, suggesting a role for it in preventing preterm IVH.

Insulin-Like Growth Factor-1 Supplementation Promotes Brain Maturation in Preterm Pigs

“…On the other hand, it cannot be excluded that the transient downregulation of TTR mRNA, encoding protein transthyretin, might negatively affect hippocampal IGF1R expression ( Vieira et al, 2015 ), as it is known to act synergistically with IGF-1 on IGF1R activation ( Vieira et al, 2016 ). Alternatively, the transient alterations in the expression of IGF-1 and related genes might arise before P5, as it was recently shown for IGF-1 expression in the choroid plexus of preterm rabbit pups treated with IGF-1/IGFBP3 complex ( Gram et al, 2021 ). In this study, the greatest changes in gene expression were observed at 24 h and limited changes at 72 h after treatment start, suggesting an acute and transient effects of systemic IGF-1 on brain gene expression ( Gram et al, 2021 ).…”

“…Alternatively, the transient alterations in the expression of IGF-1 and related genes might arise before P5, as it was recently shown for IGF-1 expression in the choroid plexus of preterm rabbit pups treated with IGF-1/IGFBP3 complex ( Gram et al, 2021 ). In this study, the greatest changes in gene expression were observed at 24 h and limited changes at 72 h after treatment start, suggesting an acute and transient effects of systemic IGF-1 on brain gene expression ( Gram et al, 2021 ). Our RNA-seq data of the entire hippocampal structure at P5 showed marginal changes in gene expression, while IHC results at the same time point indicated clear region-dependent differences between groups.…”

Characterization of choroid plexus in the preterm rabbit pup following subcutaneous administration of recombinant human IGF-1/IGFBP-3

“…The mitogenic peptide insulin-like growth factor 1 (IGF) is involved in the regulation of cell metabolism and angiogenesis, and is an essential element in fetal brain development [ 1 , 2 ]. Serum levels of IGF-1 are considerably lower following preterm birth compared to the fetus of corresponding gestational age remaining in utero [ 3 – 5 ]. Reduced postnatal serum levels of IGF-1 are associated with elevated risk for neurodevelopment impairment, along with poor weight gain and lower brain volumes [ 5 ].…”

“…The selective transcytosis of systemic IGF-1 through the ChP is believed to involve the IGF-1 receptor (IGF-1R) which is abundantly expressed in the ChP [ 9 ]. However, in the immature brain of the preterm rabbit pup, the IGF-1R has been shown to be mainly located at the epithelial border of the ChP, thereby facing the CSF, and to a lesser extent at the endothelial side [ 3 ]. Therefore, it is reasonable to consider other putative mechanism of IGF-1 transcytosis through the ChP besides the involvement of the IGF-1R, such as in extracellular vesicles encapsulation.…”

“…In addition, the IGF-1R is abundantly distributed throughout the preterm rabbit brain, 4 h after postnatal birth. However, expect for ChP, the presence of the IGF-1R was significantly reduced at 96 h postnatal age [ 3 ]. Therefore, we aimed to investigate if the uptake of IGF-1 from the circulation to the CSF follows the same temporal pattern as the IGF-1R distribution in the preterm rabbit brain.…”