Intranasal IGF-1 Reduced Rat Pup Germinal Matrix Hemorrhage

Lekic, Tim; Flores, Jerry; Klebe, Damon; Doycheva, Desislava; Rolland, William; Tang, Jiping; Zhang, Junyi

doi:10.1007/978-3-319-18497-5_37

Cited by 11 publications

(8 citation statements)

References 23 publications

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“…10,14 In addition, IGF-1 is neuroprotective in rat pups affected by germinal matrix hemorrhage. 15 Together, these data suggest that ROP, BPD, brain injury/neurodevelopmental impairment, and growth restriction could be ameliorated by supplementing postnatal serum IGF-1 to corresponding fetal levels in extremely preterm infants.…”

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confidence: 80%

rhIGF-1/rhIGFBP-3 in Preterm Infants: A Phase 2 Randomized Controlled Trial

Ley

Hallberg

Hansen‐Pupp

et al. 2019

The Journal of Pediatrics

118

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Objective To investigate recombinant human insulin-like growth factor 1 complexed with its binding protein (rhIGF-1/rhIGFBP-3) for the prevention of retinopathy of prematurity (ROP) and other complications of prematurity among extremely preterm infants. Study design This phase 2 trial was conducted from September 2014 to March 2016. Infants born at a gestational age of 23 0/7 weeks to 27 6/7 weeks were randomly allocated to rhIGF-1/rhIGFBP-3 (250 μ g/kg/24 hours, continuous intravenous infusion from <24 hours of birth to postmenstrual age 29 6/7 weeks) or standard neonatal care, with follow-up to a postmenstrual age of 40 4/7 weeks. Target exposure was ≥70% IGF-1 measurements within 28–109 μ g/L and ≥70% intended therapy duration. The primary endpoint was maximum severity of ROP. Secondary endpoints included time to discharge from neonatal care, bronchopulmonary dysplasia, intraventricular hemorrhage, and growth measures. Results Overall, 61 infants were allocated to rhIGF-1/rhIGFBP-3, 60 to standard care (full analysis set); 24 of 61 treated infants achieved target exposure (evaluable set). rhIGF-1/rhIGFBP-3 did not decrease ROP severity or ROP occurrence. There was, however, a 53% decrease in severe bronchopulmonary dysplasia in the full analysis set (21.3% treated vs 44.9% standard care), and an 89% decrease in the evaluable set (4.8% vs 44.9%; P = .04 and P = .02, respectively) for severity distribution between groups. There was also a nonsignificant trend toward decrease in grades 3–4 intraventricular hemorrhage in the full analysis set (13.1% vs 23.3%) and in the evaluable set (8.3% vs 23.3%). Fatal serious adverse events were reported in 19.7% of treated infants (12/61) and 11.7% of control infants (7/60). No effect was observed on time to discharge from neonatal care/growth measures. Conclusions rhIGF-1/rhIGFBP-3 did not affect development of ROP, but decreased the occurrence of severe bronchopulmonary dysplasia, with a nonsignificant decrease in grades 3–4 intraventricular hemorrhage. Trial registration ClinicalTrials.gov : NCT01096784 .

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mentioning

confidence: 80%

rhIGF-1/rhIGFBP-3 in Preterm Infants: A Phase 2 Randomized Controlled Trial

Ley

Hallberg

Hansen‐Pupp

et al. 2019

The Journal of Pediatrics

118

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“…In recent reports, intranasal administered insulin‐like growth factor 1 or osteopontin significantly reduced brain edema at 72 h post‐GMH, which was associated with improved long‐term neurofunctional outcomes (Lekic et al . ; Malaguit et al . ).…”

Section: Discussionmentioning

confidence: 99%

Fingolimod confers neuroprotection through activation of Rac1 after experimental germinal matrix hemorrhage in rat pups

Rolland

Krafft

Lekic

et al. 2017

Journal of Neurochemistry

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Fingolimod, a sphingosine-1-phosphate receptor (S1PR) agonist, is clinically available to treat multiple sclerosis and is showing promise in treating stroke. We investigated if fingolimod provides long-term protection from experimental neonatal germinal matrix hemorrhage (GMH), aiming to support a potential mechanism of acute fingolimod-induced protection. GMH was induced in P7 rats by infusion of collagenase (0.3 U) into the right ganglionic eminence. Animals euthanized at four weeks post-GMH received low or high dose fingolimod (0.25 or 1.0 mg/kg) or vehicle, and underwent neurocognitive testing before histopathological evaluation. Subsequently, a cohort of animals euthanized at 72 hours post-GMH received 1.0 mg/kg fingolimod; the specific S1PR1 agonist, SEW2871; or fingolimod co-administered with the S1PR1/3/4 inhibitor, VPC23019, or the Rac1 inhibitor, EHT1864. All drugs were injected intraperitoneally 1, 24, and 48 hours post-surgery. At 72 hours post-GMH, brain water content, extravasated Evans blue dye, and hemoglobin were measured as well as the expression levels of phospho-Akt, Akt, GTP-Rac1, Total-Rac1, ZO1, occludin, and claudin-3 determined. Fingolimod significantly improved long-term neurocognitive performance and ameliorated brain tissue loss. At 72 hours post-GMH, fingolimod reduced brain water content and Evans blue dye extravasation as well as reversed GMH-induced loss of tight junctional proteins. S1PR1 agonism showed similar protection, whereas S1PR or Rac1 inhibition abolished the protective effect of fingolimod. Fingolimod treatment improved functional and morphological outcomes after GMH, in part, by tempering acute post-hemorrhagic blood-brain barrier disruption via the activation of the S1PR1/Akt/Rac1 pathway.

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“…It should also be mentioned that it has later been established that claudin-3 does not confer BBB properties to cerebral blood vessels, where claudin-5 is dominant, but its main sealing function is in epithelia [23]. They did see neuroprotection by both insulin-like growth factor 1 and fingolimod in this model with a reduction in BBB dysfunction showing that therapies directed towards the stabilisation of the cerebrovasculature could be beneficial in GMH [22,24] and supporting the idea that secondary changes to vascular integrity are a driver of pathogenesis.…”

Section: Discussionmentioning

confidence: 73%

Function and Biomarkers of the Blood-Brain Barrier in a Neonatal Germinal Matrix Haemorrhage Model

Andersson

Rocha‐Ferreira

Hagberg

et al. 2021

Cells

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Germinal matrix haemorrhage (GMH), caused by rupturing blood vessels in the germinal matrix, is a prevalent driver of preterm brain injuries and death. Our group recently developed a model simulating GMH using intrastriatal injections of collagenase in 5-day-old rats, which corresponds to the brain development of human preterm infants. This study aimed to define changes to the blood-brain barrier (BBB) and to evaluate BBB proteins as biomarkers in this GMH model. Regional BBB functions were investigated using blood to brain 14C-sucrose uptake as well as using biotinylated BBB tracers. Blood plasma and cerebrospinal fluids were collected at various times after GMH and analysed with ELISA for OCLN and CLDN5. The immunoreactivity of BBB proteins was assessed in brain sections. Tracer experiments showed that GMH produced a defined region surrounding the hematoma where many vessels lost their integrity. This region expanded for at least 6 h following GMH, thereafter resolution of both hematoma and re-establishment of BBB function occurred. The sucrose experiment indicated that regions somewhat more distant to the hematoma also exhibited BBB dysfunction; however, BBB function was normalised within 5 days of GMH. This shows that GMH leads to a temporal dysfunction in the BBB that may be important in pathological processes as well as in connection to therapeutic interventions. We detected an increase of tight-junction proteins in both CSF and plasma after GMH making them potential biomarkers for GMH.

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Intranasal IGF-1 Reduced Rat Pup Germinal Matrix Hemorrhage

Cited by 11 publications

References 23 publications

rhIGF-1/rhIGFBP-3 in Preterm Infants: A Phase 2 Randomized Controlled Trial

rhIGF-1/rhIGFBP-3 in Preterm Infants: A Phase 2 Randomized Controlled Trial

Fingolimod confers neuroprotection through activation of Rac1 after experimental germinal matrix hemorrhage in rat pups

Function and Biomarkers of the Blood-Brain Barrier in a Neonatal Germinal Matrix Haemorrhage Model

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