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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.

SUBMITTER: Gram M

PROVIDER: S-EPMC8623584 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Cerebellar growth is impeded following very preterm birth in human infants and the observed reduction in cerebellar volume is associated with neurodevelopmental impairment. Decreased levels of circulating insulin-like growth factor 1 (IGF-1) are associated with decreased cerebellar volume. The relationship between preterm birth, circulating IGF-1, and key cell populations supporting cerebellar proliferation is unknown. The aim of this study was to evaluate the effect of preterm birth on postnatal growth, circulating IGF-1, and cerebellar maturation in a preterm rabbit pup model. Preterm rabbit pups (PT) were delivered by cesarean section at day 29 of gestation, cared for in closed incubators with humidified air, and gavage fed with formula. Control term pups (T) delivered by spontaneous vaginal delivery at day 32 of gestation were housed and fed by their lactating doe. In vivo perfusion-fixation for immunohistochemical evaluation of cerebellar proliferation, cell maturation, and apoptosis was performed at repeated time points in PT and T pups. Results show that the mean weight of the pups and circulating IGF-1 protein levels were lower in the PT group at all time points (p < 0.05) than in the T group. Postnatal weight development correlated with circulating IGF-1 (r2 = 0.89) independently of gestational age at birth and postnatal age. The proliferative (Ki-67-positive) portion of the external granular layer (EGL) was decreased in the PT group at postnatal day 2 (P2) compared to in the T group (p = 0.01). Purkinje cells exhibited decreased calbindin staining at P0 (p = 0.003), P2 (p = 0.004), and P5 (p = 0.04) in the PT group compared to in the T group. Staining for sonic hedgehog was positive in neuronal EGL progenitors and Purkinje cells at early time points but was restricted to a well-defined Purkinje cell monolayer at later time points. Preterm birth in rabbit pups is associated with lower circulating levels of IGF-1, decreased postnatal growth, and decreased cerebellar EGL proliferation and Purkinje cell maturation. The preterm rabbit pup model exhibits important characteristics of human preterm birth, and may thus be suitable for the evaluation of interventions aiming to modify growth and cerebellar development in the preterm population.

Project description:Background: Recombinant human IGF-1/binding protein-3 (rhIGF-1/BP-3) is currently tested as a therapy in preterm infants but possible effects on the gut, including necrotizing enterocolitis (NEC), have not been tested. The aim of this study was to evaluate if rhIGF-1/BP-3 supplementation in the first days after birth negatively affects clinical variables like growth, physical activity, blood chemistry and hematology and gut maturation (e.g., intestinal permeability, morphology, enzyme activities, cytokine levels, enterocyte proliferation, NEC lesions), using NEC-sensitive preterm pigs as a model for preterm infants. Methods: Preterm pigs were given twice daily subcutaneous injections of rhIGF-1/BP-3 or vehicle. Blood was collected for IGF-1 measurements and gut tissue for NEC evaluation and biochemical analyses on day 5. Results: Baseline circulating IGF-1 levels were low in preterm pigs compared with near-term pigs reared by their mother (<20 vs. 70 ng/ml). Injection with rhIGF-1/BP-3 resulted in increased plasma IGF-1 levels for up to 6 h after injection (>40 ng/mL). rhIGF-1/BP-3 treatment reduced the incidence of severe NEC lesions (7/24 vs.16/24, p = 0.01) and overall NEC severity (1.8 ± 0.2 vs. 2.6 ± 0.3, p < 0.05, with most lesions occurring in colon). In the small intestine, villi length (405 ± 25 vs. 345 ± 33 ?m) and activities of the brush border peptidases aminopeptidase N and dipeptidylpeptidase IV were increased in rhIGF-1/BP-3 treated pigs, relative to control pigs (+31-44%, both p < 0.05). The treatment had no effects on body weight, blood chemistry or hematology, except for an increase in blood leucocyte and neutrophil counts (p < 0.05, i.e., reduced neonatal neutropenia). Likewise, rhIGF-1/BP-3 treatment did not affect intestinal tissue cytokine levels (IL-1?, IL-6, IL-8, TNF?,), enterocyte proliferation, goblet cell density, permeability or bacterial translocation to the bone marrow. Conclusion: Supplemental rhIGF-1/BP-3 did not negatively affect any of the measured variables of clinical status or gut maturation in preterm pigs. Longer-term safety and efficacy of exogenous rhIGF-1/BP-3 to support maturation of the gut and other critical organs in preterm newborns remain to be investigated in both pigs and infants.

Project description:In some induced-ovulating species, beta nerve growth factor (?-NGF) has important roles in ovulation, though data for rabbits are still inconclusive. In this study we first synthesized functional recombinant ?-NGF from rabbit tissue (rr?-NGF) to address the following objectives: 1) to compare rabbit ?-NGF amino acid sequence with those of other induced- or spontaneous-ovulating species; 2) to assess the effects of rr?-NGF on rabbit sperm viability and motility, and 3) to examine the in vivo ovulation inducing effect of rr?-NGF added to the seminal dose in rabbit does. The NGF gene in rabbit prostate tissue was sequenced by Rapid Amplification of cDNA Ends and annotated in GenBank (KX528686). Recombinant r?-NGF was produced in CHO cells and purified by affinity chromatography. Once confirmed by Western blotting and mass spectrometry (MALDI-TOF) that the amino acid sequence of the recombinant protein corresponded to ?-NGF, its functionality was validated in PC12 cells in a successful dose-response study over 8 days. The amino acid sequence of prostate rabbit NGF differed to that of other species mainly in its receptor binding sites. In all the spontaneous ovulating species examined, compared with rabbit, alanine and proline residues, which interact with the high-affinity receptor, were replaced by a serine. In rabbits, asparagine and methionine were substituted by lysine at the low-affinity receptor binding site. In time- and dose-response experiments, the in vitro addition of rr?-NGF to the ejaculate did not affect sperm viability whereas sperm motility parameters were enhanced by the addition of 1 ?g/mL of the neuropeptide. Addition of this same concentration of rr?-NGF to the seminal dose administered via the intravaginal route in does induced ovulation with a delayed LH peak, leading to a plasma progesterone increase, gestation and delivery. Our findings suggest that rr?-NGF could be a useful option for biotechnological and reproduction assisted techniques in rabbits but further studies are needed.

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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.

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