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Severe intraventricular hemorrhage causes long-lasting structural damage in a preterm rabbit pup model

Romantsik, Olga LU ; Ross-Munro, Emily ; Grönlund, Susanne LU ; Holmqvist, Bo ; Brinte, Anders ; Gerdtsson, Erik ; Vallius, Suvi LU ; Bruschettini, Matteo LU orcid ; Wang, Xiaoyang LU and Fleiss, Bobbi , et al. (2022) In Pediatric Research 92(2). p.403-414
Abstract

Background: Intraventricular hemorrhage causes significant lifelong mortality and morbidity, especially in preterm born infants. Progress in finding an effective therapy is stymied by a lack of preterm animal models with long-term follow-up. This study addresses this unmet need, using an established model of preterm rabbit IVH and analyzing outcomes out to 1 month of age. Methods: Rabbit pups were delivered preterm and administered intraperitoneal injection of glycerol at 3 h of life and approximately 58% developed IVH. Neurobehavioral assessment was performed at 1 month of age followed by immunohistochemical labeling of epitopes for neurons, synapses, myelination, and interneurons, analyzed by means of digital quantitation and assessed... (More)

Background: Intraventricular hemorrhage causes significant lifelong mortality and morbidity, especially in preterm born infants. Progress in finding an effective therapy is stymied by a lack of preterm animal models with long-term follow-up. This study addresses this unmet need, using an established model of preterm rabbit IVH and analyzing outcomes out to 1 month of age. Methods: Rabbit pups were delivered preterm and administered intraperitoneal injection of glycerol at 3 h of life and approximately 58% developed IVH. Neurobehavioral assessment was performed at 1 month of age followed by immunohistochemical labeling of epitopes for neurons, synapses, myelination, and interneurons, analyzed by means of digital quantitation and assessed via two-way ANOVA or Student’s t test. Results: IVH pups had globally reduced myelin content, an aberrant cortical myelination microstructure, and thinner upper cortical layers (I–III). We also observed a lower number of parvalbumin (PV)-positive interneurons in deeper cortical layers (IV–VI) in IVH animals and reduced numbers of neurons, synapses, and microglia. However, there were no discernable changes in behaviors. Conclusions: We have established in this preterm pup model that long-term changes after IVH include significant wide-ranging alterations to cortical organization and microstructure. Further work to improve the sensitivity of neurocognitive testing in this species at this age may be required. Impact: This study uses an established animal model of preterm birth, in which the rabbit pups are truly born preterm, with reduced organ maturation and deprivation of maternally supplied trophic factors.This is the first study in preterm rabbits that explores the impacts of severe intraventricular hemorrhage beyond 14 days, out to 1 month of age.Our finding of persisting but subtle global changes including brain white and gray matter will have impact on our understanding of the best path for therapy design and interventions.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Pediatric Research
volume
92
issue
2
pages
403 - 414
publisher
International Pediatric Foundation Inc.
external identifiers
  • scopus:85129273696
  • pmid:35505079
ISSN
0031-3998
DOI
10.1038/s41390-022-02075-y
language
English
LU publication?
yes
id
faefc4fa-5ba3-4926-99fe-d7ddffe8cef7
date added to LUP
2022-08-15 15:08:10
date last changed
2024-12-28 15:20:18
@article{faefc4fa-5ba3-4926-99fe-d7ddffe8cef7,
  abstract     = {{<p>Background: Intraventricular hemorrhage causes significant lifelong mortality and morbidity, especially in preterm born infants. Progress in finding an effective therapy is stymied by a lack of preterm animal models with long-term follow-up. This study addresses this unmet need, using an established model of preterm rabbit IVH and analyzing outcomes out to 1 month of age. Methods: Rabbit pups were delivered preterm and administered intraperitoneal injection of glycerol at 3 h of life and approximately 58% developed IVH. Neurobehavioral assessment was performed at 1 month of age followed by immunohistochemical labeling of epitopes for neurons, synapses, myelination, and interneurons, analyzed by means of digital quantitation and assessed via two-way ANOVA or Student’s t test. Results: IVH pups had globally reduced myelin content, an aberrant cortical myelination microstructure, and thinner upper cortical layers (I–III). We also observed a lower number of parvalbumin (PV)-positive interneurons in deeper cortical layers (IV–VI) in IVH animals and reduced numbers of neurons, synapses, and microglia. However, there were no discernable changes in behaviors. Conclusions: We have established in this preterm pup model that long-term changes after IVH include significant wide-ranging alterations to cortical organization and microstructure. Further work to improve the sensitivity of neurocognitive testing in this species at this age may be required. Impact: This study uses an established animal model of preterm birth, in which the rabbit pups are truly born preterm, with reduced organ maturation and deprivation of maternally supplied trophic factors.This is the first study in preterm rabbits that explores the impacts of severe intraventricular hemorrhage beyond 14 days, out to 1 month of age.Our finding of persisting but subtle global changes including brain white and gray matter will have impact on our understanding of the best path for therapy design and interventions.</p>}},
  author       = {{Romantsik, Olga and Ross-Munro, Emily and Grönlund, Susanne and Holmqvist, Bo and Brinte, Anders and Gerdtsson, Erik and Vallius, Suvi and Bruschettini, Matteo and Wang, Xiaoyang and Fleiss, Bobbi and Ley, David}},
  issn         = {{0031-3998}},
  language     = {{eng}},
  number       = {{2}},
  pages        = {{403--414}},
  publisher    = {{International Pediatric Foundation Inc.}},
  series       = {{Pediatric Research}},
  title        = {{Severe intraventricular hemorrhage causes long-lasting structural damage in a preterm rabbit pup model}},
  url          = {{http://dx.doi.org/10.1038/s41390-022-02075-y}},
  doi          = {{10.1038/s41390-022-02075-y}},
  volume       = {{92}},
  year         = {{2022}},
}