A Ferret Model of Inflammation-sensitized Late Preterm Hypoxic-ischemic Brain Injury

Wood, Thomas H.; Moralejo, Daniel H.; Corry, Kylie A.; Fisher, Cole; Snyder, Jessica M.; Acuna, Vivienne; Holden-Hunt, Alair; Virk, Simar; White, Olivia; Law, Janessa; Parikh, Pratik; Juul, Sandra E.

doi:10.3791/60131

Cited by 9 publications

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“…The dose and timing of Epo may also play a critical role in the outcomes seen, with the important caveats that i) not all the preclinical data has found a neuroprotective effect of Epo in the developing brain, and ii) most preclinical studies involve a single injurious event rather than the confluence of heterogeneous factors associated with preterm brain injury [49]. Indeed, the difference between expected and measured outcomes may be due to a different magnitude of anti-inflammatory effect of Epo in extremely preterm human infants, a population that is difficult to model in the laboratory [50,51]. Epo may also have a greater effect on cytokines not measured in the Epo cohort such as IL-1b.…”

Section: Discussionmentioning

confidence: 99%

Early Biomarkers of Hypoxia and Inflammation and Two-Year Neurodevelopmental Outcomes in the Preterm Erythropoietin Neuroprotection (PENUT) Trial

et al. 2021

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Background In the Preterm Erythropoietin (Epo) NeUroproTection (PENUT) Trial, potential biomarkers of neurological injury were measured to determine their association with outcomes at two years of age and whether Epo treatment decreased markers of inflammation in extremely preterm (<28 weeks’ gestation) infants. Methods Plasma Epo was measured (n=391 Epo, n=384 placebo) within 24h after birth (baseline), 30min after study drug administration (day 7), 30min before study drug (day 9), and on day 14. A subset of infants (n=113 Epo, n=107 placebo) had interferon-gamma (IFN-γ), Interleukin (IL)-6, IL-8, IL-10, Tau, and tumour necrosis factor-α (TNF-α) levels evaluated at baseline, day 7 and 14. Infants were then evaluated at 2 years using the Bayley Scales of Infant and Toddler Development, 3rd Edition (BSID-III). Findings Elevated baseline Epo was associated with increased risk of death or severe disability (BSID-III Motor and Cognitive subscales <70 or severe cerebral palsy). No difference in other biomarkers were seen between treatment groups at any time, though Epo appeared to mitigate the association between elevated baseline IL-6 and lower BSID-III scores in survivors. Elevated baseline, day 7 and 14 Tau concentrations were associated with worse BSID-III Cognitive, Motor, and Language skills at two years. Interpretation Elevated Epo at baseline and elevated Tau in the first two weeks after birth predict poor outcomes in infants born extremely preterm. However, no clear prognostic cut-off values are apparent, and further work is required before these biomarkers can be widely implemented in clinical practice. Funding PENUT was funded by the National Institute of Neurological Disorders and Stroke (U01NS077955 and U01NS077953).

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Section: Discussionmentioning

confidence: 99%

Early Biomarkers of Hypoxia and Inflammation and Two-Year Neurodevelopmental Outcomes in the Preterm Erythropoietin Neuroprotection (PENUT) Trial

et al. 2021

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“…Kits were removed from the nest and placed in a heated chamber for 1 h prior to all testing. The tests were modified from rodent reflex testing and performed as previously published [ 7 , 11 ]. The tests included negative geotaxis (NG), cliff aversion (CA), and righting reflex (RR).…”

Section: Methodsmentioning

confidence: 99%

“…Gait characteristics were assessed using the CatWalkXT system (Noldus Information Technology, Wageningen, Netherlands). The protocol for kit handling, experiment setup, and testing process has been previously published [ 11 ]. On P42, three compliant runs were collected from each animal.…”

Section: Methodsmentioning

confidence: 99%

“…Postnatal ferret brain development is histologically similar to the rapid brain maturation that occurs in the second half of human gestation [ 9 , 10 ]. Our group recently published a protocol utilizing lipopolysaccharide (LPS) inflammation presensitized hypoxia-ischemia plus hyperoxia (HIH) to model hypoxic-ischemic (HI) brain injury in the near-term (P17) ferret [ 11 ]. The P17 ferret brain developmentally correlates to an infant at 32–36 week’s gestation [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

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Evaluating Neuroprotective Effects of Uridine, Erythropoietin, and Therapeutic Hypothermia in a Ferret Model of Inflammation-Sensitized Hypoxic-Ischemic Encephalopathy

Corry

White

Shearlock

et al. 2021

IJMS

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Perinatal hypoxic-ischemic (HI) brain injury, often in conjunction with an inflammatory insult, is the most common cause of death or disability in neonates. Therapeutic hypothermia (TH) is the standard of care for HI encephalopathy in term and near-term infants. However, TH may not always be available or efficacious, creating a need for novel or adjunctive neurotherapeutics. Using a near-term model of inflammation-sensitized HI brain injury in postnatal day (P) 17 ferrets, animals were randomized to either the control group (n = 43) or the HI-exposed groups: saline vehicle (Veh; n = 42), Ur (uridine monophosphate, n = 23), Epo (erythropoietin, n = 26), or TH (n = 24) to test their respective therapeutic effects. Motor development was assessed from P21 to P42 followed by analysis of cortical anatomy, ex vivo MRI, and neuropathology. HI animals took longer to complete the motor assessments compared to controls, which was exacerbated in the Ur group. Injury resulted in thinned white matter tracts and narrowed cortical sulci and gyri, which was mitigated in Epo-treated animals in addition to normalization of cortical neuropathology scores to control levels. TH and Epo treatment also resulted in region-specific improvements in diffusion parameters on ex vivo MRI; however, TH was not robustly neuroprotective in any behavioral or neuropathological outcome measures. Overall, Ur and TH did not provide meaningful neuroprotection after inflammation-sensitized HI brain injury in the ferret, and Ur appeared to worsen outcomes. By comparison, Epo appears to provide significant, though not complete, neuroprotection in this model.

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“…More recently, a ferret model of LPS sensitised HI brain jury has been developed, where postnatal day 17 ferrets receive an intraperitoneal injection of LPS 4 h before hypoxia. This models a late preterm human insult ( Wood et al, 2019 ). The injured ferrets display variable degrees of damage in the cortical gyri and associated sulci, as well as behavioural deficits.…”

Section: Animal Models Of Infection-sensitised Hypoxia–ischaemiamentioning

confidence: 99%

Current Therapies for Neonatal Hypoxic–Ischaemic and Infection-Sensitised Hypoxic–Ischaemic Brain Damage

Tetorou

Sisa

Iqbal

et al. 2021

Front. Synaptic Neurosci.

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Neonatal hypoxic–ischaemic brain damage is a leading cause of child mortality and morbidity, including cerebral palsy, epilepsy, and cognitive disabilities. The majority of neonatal hypoxic–ischaemic cases arise as a result of impaired cerebral perfusion to the foetus attributed to uterine, placental, or umbilical cord compromise prior to or during delivery. Bacterial infection is a factor contributing to the damage and is recorded in more than half of preterm births. Exposure to infection exacerbates neuronal hypoxic–ischaemic damage thus leading to a phenomenon called infection-sensitised hypoxic–ischaemic brain injury. Models of neonatal hypoxia–ischaemia (HI) have been developed in different animals. Both human and animal studies show that the developmental stage and the severity of the HI insult affect the selective regional vulnerability of the brain to damage, as well as the subsequent clinical manifestations. Therapeutic hypothermia (TH) is the only clinically approved treatment for neonatal HI. However, the number of HI infants needed to treat with TH for one to be saved from death or disability at age of 18–22 months, is approximately 6–7, which highlights the need for additional or alternative treatments to replace TH or increase its efficiency. In this review we discuss the mechanisms of HI injury to the immature brain and the new experimental treatments studied for neonatal HI and infection-sensitised neonatal HI.

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A Ferret Model of Inflammation-sensitized Late Preterm Hypoxic-ischemic Brain Injury

Cited by 9 publications

References 0 publications

Early Biomarkers of Hypoxia and Inflammation and Two-Year Neurodevelopmental Outcomes in the Preterm Erythropoietin Neuroprotection (PENUT) Trial

Early Biomarkers of Hypoxia and Inflammation and Two-Year Neurodevelopmental Outcomes in the Preterm Erythropoietin Neuroprotection (PENUT) Trial

Evaluating Neuroprotective Effects of Uridine, Erythropoietin, and Therapeutic Hypothermia in a Ferret Model of Inflammation-Sensitized Hypoxic-Ischemic Encephalopathy

Current Therapies for Neonatal Hypoxic–Ischaemic and Infection-Sensitised Hypoxic–Ischaemic Brain Damage

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