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Safety aspects of longitudinal administration of IGF-I/IGFBP-3 complex in neonatal mice
Gunnel Hellgren1, Wei Han, Xiaoyang Wang
1Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden. gunnel.hellgren@vgregion.se
Insights
Prolonged administration of recombinant human insulin-like growth factor-I/insulin-like growth factor-binding protein-3 (rhIGF-I/rhIGFBP-3) in newborn mice did not negatively affect blood glucose. This treatment promoted beneficial total body growth and increased oligodendrocyte precursor cells in the white matter.
Area of Science:
- Neonatal Research
- Endocrinology
- Developmental Biology
Background:
- Very preterm birth is linked to significant morbidity and low serum insulin-like growth factor I (IGF-I) levels, crucial for brain development.
- Low IGF-I levels are associated with retinopathy of prematurity, highlighting the need for therapeutic interventions.
Purpose of the Study:
- To investigate the effects of prolonged, low-dose recombinant human IGF-I/IGFBP-3 (rhIGF-I/rhIGFBP-3) administration in newborn mice.
- To assess impacts on glucose levels, body weight, organ weights (liver, spleen, brain), and gray and white matter development.
Main Methods:
- Three experimental trials involving C57BL/6N mice treated with rhIGF-I/rhIGFBP-3 complex or saline.
- Assessment of blood glucose, serum IGF-I levels, body and organ weights, and white matter markers (Olig2, MBP, CNPase, neurofilament) via immunoreactivity.
Main Results:
- rhIGF-I/rhIGFBP-3 treatment did not alter blood glucose levels compared to baseline, though transient decreases were observed 3 hours post-injection.
- Total body weight was significantly increased in treated mice by postnatal day 18, without affecting brain, liver, or spleen weights.
- White matter analysis revealed a significant increase in Olig2-positive cells (oligodendrocyte precursors) in rhIGF-I/rhIGFBP-3 treated mice, with no changes in gray matter or other white matter markers.
Conclusions:
- Prolonged administration of rhIGF-I/rhIGFBP-3 is safe concerning blood glucose levels in newborn mice.
- This therapeutic approach shows promise for enhancing overall body growth and promoting oligodendrocyte development in the central nervous system.
Objective:
Very preterm birth is associated with a high risk of morbidity. Infants born very preterm have low serum levels of insulin-like growth factor I (IGF-I), that further decrease after birth. IGF-I is essential for brain development and low serum levels have been associated with retinopathy of prematurity. The present study aimed to investigate the effects of prolonged administration of a low dose of rhIGF-I/rhIGFBP-3 on glucose levels and total body weight, as well as liver, spleen and brain weights, and gray and subcortical white matter in newborn mice.
Design:
The study was performed as three different trials. In all experiments C57BL/6N mice were injected with a rhIGF-I/rhIGFBP-3 complex or saline. In the first experimental trial, blood glucose levels were assessed 30 min, 1 h, 1.5 h, 3 h, 6 h, 24 h and 48 h after the rhIGF-I/rhIGFBP-3 or saline injection on postnatal day (PND) 6. In the second trial, mice were injected daily from PND 3 to 11 and sacrificed on PND 12 for analysis of IGF-I serum levels. In the third trial, body and organ weights and effects on gray and white matter were assessed on PND 18 after PND 3-11 treatments as above. Effects on gray and white matter were measured using immunoreactivity for microtubule-associated protein-2 (MAP-2), myelin basic protein (MBP), 2',3'-cyclic nucleotide 3' phosphodiesterase (CNPase), neurofilament and oligodendrocyte lineage transcription factor 2 (Olig2).
Results:
Blood glucose levels were unchanged in the rhIGF-I/rhIGFBP-3-treated group compared to baseline. In the control group glucose levels increased 30 min after the second saline injection; levels were not elevated at the subsequent time point. Three hours after the rhIGF-I/rhIGFBP-3 or saline, glucose levels were lower in rhIGF-I/rhIGFBP-3-treated animals than in saline treated (p=0.026). At PND 18, total body weight was higher in rhIGF-I/rhIGFBP-3-treated mice compared with controls (p<0.05), but there were no differences between groups in brain, liver or spleen weights. No differences in gray matter area were found between groups. Analyses of white matter markers showed an increased number of Olig2-positive cells in rhIGF-I/rhIGFBP-3-treated mice compared with controls (p<0.001). There were no differences between groups in terms of MBP, CNPase or neurofilament immunoreactivity.
Conclusions:
Prolonged administration of rhIGF-I/rhIGFBP-3 did not have a negative impact on blood glucose levels and was beneficial for total body growth.
