| 1. |
- Ekström, Claes, et al.
(författare)
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Evaluation of recombinant human IGF-1/IGFBP-3 on intraventricular hemorrhage prevention and survival in the preterm rabbit pup model
- 2023
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Ingår i: Scientific Reports. - 2045-2322. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Insulin-like growth factor-1 (IGF-1) is essential for normal brain development and regulates processes of vascular maturation. The pathogenesis of intraventricular hemorrhage (IVH) relates to the fragility of the immature capillaries in the germinal matrix, and its inability to resist fluctuations in cerebral blood flow. In this work, using different experimental setups, we aimed to (i) establish an optimal time-point for glycerol-induction of IVH in relation to time-point of recombinant human (rh) IGF-1/rhIGFBP-3 administration, and (ii) to evaluate the effects of a physiologic replacement dose of rhIGF-1/rhIGFBP-3 on prevention of IVH and survival in the preterm rabbit pup. The presence of IVH was evaluated using high-frequency ultrasound and post-mortem examinations. In the first part of the study, the highest incidence of IVH (> 60%), occurred when glycerol was administered at the earliest timepoint, e.g., 6h after birth. At later time-points (18 and 24h) the incidence decreased substantially. In the second part of the study, the incidence of IVH and mortality rate following rhIGF-1/rhIGFBP-3 administration was not statistically different compared to vehicle treated animals. To evaluate the importance of maintaining intrauterine serum levels of IGF-1 following preterm birth, as reported in human interventional studies, additional studies are needed to further characterize and establish the potential of rhIGF-1/rhIGFBP-3 in reducing the prevalence of IVH and improving survival in the preterm rabbit pup.
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| 2. |
- Ekström, Claes, et al.
(författare)
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THE INSULIN-LIKE GROWTH FACTOR 1 (IGF-1) SYSTEM IN THE PRETERM RABBIT PUP : A CHARACTERIZATION OF THE IGF-1 MRNA EXPRESSION IN LIVER, IGF-1 PROTEIN LEVELS IN SERUM AND BRAIN DISTRIBUTION OF IGF-1 RECEPTORS
- 2019
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Konferensbidrag (refereegranskat)abstract
- IGF-1 is an essential regulator of fetal growth and brain development. Preterm birth in the human is followed by a rapid decrease in serum levels of IGF-1 and decreased levels of IGF-1 have been associated with development of severemorbidity. A recent clinical trial indicated that supplementation with IGF-1 prevented development of severe intraventricular hemorrhage (IVH) in extremely preterm infants. In order to better understand possible mechanisms involved in IGF-1-induced IVH prevention, we evaluated important aspects of the endogenous IGF-1 system; IGF-I mRNA expression in the liver and associated serum protein levels and brain IGF-1 receptor (IGFR) distribution in the preterm rabbit.Rabbit pups were delivered by cesarean section at E29 (preterm) or by vaginal delivery (term = E32), housed in a controlled environment and fed twice daily with bovine colostrum via a gastric tube. Serum concentrations of IGF-1protein and liver expression of IGF-1 mRNA were determined at 0, 2, 6, 12, 24, 48 and 72 h of age in preterm pups. Paraffin brain sections from perfusion fixed untreated animals (preterm pups at 20 h and term pups at 5-7 h and 96 h) were prepared for immunohistochemistry against IGF1R, by labeling with primary antibodies against IGF1R, and processed for chromogen visualization and density/quantitation analysis with confocal microscopy. Mean (SD) serum concentrations of IGF-1 decreased from 166 (33) ng/ml at birth (E29) to 28 (9) ng/ml at day 3 (P0). Hepatic expression of IGF-1 mRNA did not vary over time. The IGF1R was widely distributed in multiple brain regions in both preterm and term pups (Fig). The most abundant density of IGF1R was observed in the choroid plexus, the subfornical organ, the meninges, major fiber tracts, the cortex and sub-ependymal germinal zones. The IGF1R, was mainly localized on outer cell membranes, on cell bodies and along nerve fibers. Quantitative analysis of IGF1R immunoreactivity showed similar IGF1R densities in preterm and term pups of corresponding ages. IGF1R density decreased with increasing postnatal age in term pups.In line with what is observed in the preterm human infant, serum protein levels of IGF-1 in the preterm rabbit pup decrease rapidly following birth. The IGF1R is widely expressed in the brain following birth, with high expressions in regions and structures relevant for vessel rupture in IVH. The preterm rabbit thus presents a well-suited model for characterization and evaluation of mechanisms involved in IGF-1 induced prevention of IVH.
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| 3. |
- Ortenlöf, Niklas, et al.
(författare)
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Characterization of choroid plexus in the preterm rabbit pup following subcutaneous administration of recombinant human IGF-1/IGFBP-3
- 2023
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Ingår i: Fluids and Barriers of the CNS. - 2045-8118. ; 20:1
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Tidskriftsartikel (refereegranskat)abstract
- Insulin-like growth factor-1 (IGF-1) is essential for normal brain development and regulates essential processes of vascular maturation and stabilization. Importantly, preterm birth is associated with reduced serum levels of IGF-1 as compared to in utero levels. Using a preterm rabbit pup model, we investigated the uptake of systemic recombinant human (rh) IGF-1 in complex with its main binding protein IGF-binding protein 3 (BP-3) to the brain parenchyma via the choroid plexus. Five hours after subcutaneous administration, labeled rhIGF-1/rhIGFBP-3 displayed a widespread presence in the choroid plexus of the lateral and third ventricle, however, to a less degree in the fourth, as well as in the perivascular and subarachnoid space. We found a time-dependent uptake of IGF-1 in cerebrospinal fluid, decreasing with postnatal age, and a translocation of IGF-1 through the choroid plexus. The impact of systemic rhIGF-1/rhIGFBP-3 on IGF-1 receptor activation in the choroid plexus decreased with postnatal age, correlating with IGF-1 uptake in cerebrospinal fluid. In addition, choroid plexus gene expression was observed to increase with postnatal age. Moreover, using choroid plexus in vitro cell cultures, gene expression and protein synthesis were further investigated upon rhIGF-1/rhIGFBP-3 stimulation as compared to rhIGF-1 alone, and found not to be differently altered. Here, we characterize the uptake of systemic rhIGF-1/rhIGFBP-3 to the preterm brain, and show that the interaction between systemic rhIGF-1/rhIGFBP-3 and choroid plexus varies over time.
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