Strategies for working with a preterm rabbit model of glycerol-induced intraventricular hemorrhage: strengths and limitations

Ballabh, Praveen; LaGamma, Edmund F.

doi:10.1038/pr.2014.111

Cited by 7 publications

(4 citation statements)

References 9 publications

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“…The utility of the early neurobehavioral assessment to detect a functional deficit was confirmed, as noted in other rabbit models that studied the perinatal effect of hypoxia-ischemia 17 , intraventricular hemorrhage 20 and intrauterine growth restriction 33 . These motor deficits form a major part of the clinical context of EoP 5 and it is imperative for any preclinical model to correlate functional neurological outcomes to the underlying neuropathology processes if any mechanism will be investigated to modulate the insult.…”

Section: Discussionmentioning

confidence: 56%

“…Lately, the rabbit has been widely employed for modeling brain damage after perinatal injury in models of cerebral palsy 16,17 , hypoxia-ischemia 18 , intraventricular hemorrhage 19,20 and intrauterine infection 21–23 . The rabbit seems best suited to bridge the gap between small and large animals being widely available, having low housing needs, a short reproductive cycle, timed gestation with large litters and placental development close to human 24,25 .…”

Section: Introductionmentioning

confidence: 99%

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Early neuropathological and neurobehavioral consequences of preterm birth in a rabbit model

Merwe

Veeken

Ferraris

et al. 2019

Sci Rep

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Preterm birth is the most significant problem in contemporary obstetrics accounting for 5–18% of worldwide deliveries. Encephalopathy of prematurity encompasses the multifaceted diffuse brain injury resulting from preterm birth. Current animal models exploring the underlying pathophysiology of encephalopathy of prematurity employ significant insults to generate gross central nervous system abnormalities. To date the exclusive effect of prematurity was only studied in a non-human primate model. Therefore, we aimed to develop a representative encephalopathy of prematurity small animal model only dependent on preterm birth. Time mated New-Zealand white rabbit does were either delivered on 28 (pre-term) or 31 (term) postconceptional days by caesarean section. Neonatal rabbits underwent neurobehavioral evaluation on 32 days post conception and then were transcardially perfuse fixed. Neuropathological assessments for neuron and oligodendrocyte quantification, astrogliosis, apoptosis and cellular proliferation were performed. Lastly, ex-vivo high-resolution Magnetic Resonance Imaging was used to calculate T1 volumetric and Diffusion Tensor Imaging derived fractional anisotropy and mean diffusivity. Preterm birth was associated with a motoric (posture instability, abnormal gait and decreased locomotion) and partial sensory (less pain responsiveness and failing righting reflex) deficits that coincided with global lower neuron densities, less oligodendrocyte precursors, increased apoptosis and less proliferation. These region-specific histological changes corresponded with Magnetic Resonance Diffusion Tensor Imaging differences. The most significant differences were seen in the hippocampus, caudate nucleus and thalamus of the preterm rabbits. In conclusion this model of preterm birth, in the absence of any other contributory events, resulted in measurable neurobehavioral deficits with associated brain structural and Magnetic Resonance Diffusion Tensor Imaging findings.

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Section: Discussionmentioning

confidence: 56%

Section: Introductionmentioning

confidence: 99%

Early neuropathological and neurobehavioral consequences of preterm birth in a rabbit model

Merwe

Veeken

Ferraris

et al. 2019

Sci Rep

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“…Two animal models of IVH are previously reported: (a) injection of exogenous blood into the ventricles of newborn rodents [8][9][10][11] and (b) our model of intraperitoneal glycerolinduced endogenous IVH in premature rabbit pups. [12][13][14][15][16] We prefer the glycerol-induced endogenous IVH model as rabbit brains closely approximate human stages [17,18] as well as replicate many of the clinical manifestations of IVH seen in premature human neonates including hypomyelination, gliosis, pro-inflammatory cytokines, apoptosis as well as spastic diplegia, neurodegeneration, and cognitive delays. [13,14,19,20] Prior preclinical investigations using mesenchymal stem cells (MSCs) in the injected exogenous blood rodent model of IVH showed improved myelination, neuroprotection.…”

Section: Introductionmentioning

confidence: 99%

Human Cord Blood-Derived Unrestricted Somatic Stem Cell Infusion Improves Neurobehavioral Outcome in a Rabbit Model of Intraventricular Hemorrhage

Vinukonda

Liao

et al. 2019

Stem Cells Translational Medicine

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Intraventricular hemorrhage (IVH) is a severe complication of preterm birth, which leads to hydrocephalus, cerebral palsy, and mental retardation. There are no available therapies to cure IVH, and standard treatment is supportive care. Unrestricted somatic stem cells (USSCs) from human cord blood have reparative effects in animal models of brain and spinal cord injuries. USSCs were administered to premature rabbit pups with IVH and their effects on white matter integrity and neurobehavioral performance were evaluated. USSCs were injected either via intracerebroventricular (ICV) or via intravenous (IV) routes in 3 days premature (term 32d) rabbit pups, 24 hours after glycerol‐induced IVH. The pups were sacrificed at postnatal days 3, 7, and 14 and effects were compared to glycerol‐treated but unaffected or nontreated control. Using in vivo live bioluminescence imaging and immunohistochemical analysis, injected cells were found in the injured parenchyma on day 3 when using the IV route compared to ICV where cells were found adjacent to the ventricle wall forming aggregates; we did not observe any adverse events from either route of administration. The injected USSCs were functionally associated with attenuated microglial infiltration, less apoptotic cell death, fewer reactive astrocytes, and diminished levels of key inflammatory cytokines (TNFα and IL1β). In addition, we observed better preservation of myelin fibers, increased myelin gene expression, and altered reactive astrocyte distribution in treated animals, and this was associated with improved locomotor function. Overall, our findings support the possibility that USSCs exert anti‐inflammatory effects in the injured brain mitigating many detrimental consequences associated with IVH. stem cells translational medicine 2019;8:1157–1169

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“…The rabbit has been widely employed in perinatal neurobehavioral research, simulating cerebral palsy [13], hypoxia-ischemia [14], intraventricular hemorrhage [15] and intrauterine infection [16]. The rabbit seems best suited to bridge the gap between small and large animals being widely available, having low housing needs, a short reproductive cycle, timed gestation with large litters and placental development close to human [17].…”

Section: Introductionmentioning

confidence: 99%

Earlier preterm birth is associated with a worse neurocognitive outcome in a rabbit model

et al. 2021

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Background Preterm birth (PTB) and particularly late preterm PTB has become a research focus for obstetricians, perinatologists, neonatologists, pediatricians and policy makers alike. Translational models are useful tools to expedite and guide clinical but presently no model exists that contextualizes the late PTB scenario. Herein we aimed to develop a rabbit model that echo’s the clinical neurocognitive phenotypes of early and late PTB. Methods Time mated rabbit does underwent caesarean delivery at a postconceptional age (PCA) of either 28 (n = 6), 29 (n = 5), 30 (n = 4) or 31 (n = 4) days, term = 31 d. Newborn rabbits were mixed and randomly allocated to be raised by cross fostering and underwent short term neurobehavioral testing on corrected post-natal day 1. Open field (OFT), spontaneous alteration (TMT) and novel object recognition (NORT) tests were subsequently performed at 4 and 8 weeks of age. Results PTB was associated with a significant gradient of short-term mortality and morbidity inversely related to the PCA. On postnatal day 1 PTB was associated with a significant sensory deficit in all groups but a clear motor insult was only noted in the PCA 29d and PCA 28d groups. Furthermore, PCA 29d and PCA 28d rabbits had a persistent neurobehavioral deficit with less exploration and hyperanxious state in the OFT, less alternation in TMT and lower discriminatory index in the NORT. While PCA 30d rabbits had some anxiety behavior and lower spontaneous alteration at 4 weeks, however at 8 weeks only mild anxiety driven behavior was observed in some of these rabbits. Conclusions In this rabbit model, delivery at PCA 29d and PCA 28d mimics the clinical phenotype of early PTB while delivery at PCA 30d resembles that of late PTB. This could serve as a model to investigate perinatal insults during the early and late preterm period.

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Strategies for working with a preterm rabbit model of glycerol-induced intraventricular hemorrhage: strengths and limitations

Cited by 7 publications

References 9 publications

Early neuropathological and neurobehavioral consequences of preterm birth in a rabbit model

Early neuropathological and neurobehavioral consequences of preterm birth in a rabbit model

Human Cord Blood-Derived Unrestricted Somatic Stem Cell Infusion Improves Neurobehavioral Outcome in a Rabbit Model of Intraventricular Hemorrhage

Earlier preterm birth is associated with a worse neurocognitive outcome in a rabbit model

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