Partial white and grey matter protection with prolonged infusion of recombinant human erythropoietin after asphyxia in preterm fetal sheep

Wassink, Guido; Davidson, J.; Dhillon, Simerdeep K; Fraser, Mhoyra; Galinsky, Robert; Gunn, Alistair J.

doi:10.1177/0271678x16650455

Cited by 39 publications

(48 citation statements)

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“…Our findings suggest that the amplified proinflammatory cytokine response to VIBI observed previously is likely due to the high dose (5,000 IU/kg) used or may be due to the timing of administration. High-dose EPO has been demonstrated previously to be neuroprotective in preterm lamb models of endotoxin-induced brain injury [35] and asphyxia [36] . Ventilation of preterm lambs with a high V T injurious ventilation strategy produces diffuse white matter injury [5] .…”

Section: Discussionmentioning

confidence: 95%

“…We have only investigated gene expression because of the acute nature of our protocol; further studies with longer durations are required to accurately determine whether increased cell death marker gene expression correlates with functional protein changes and apoptosis. A recent study which administered a bolus dose (5,000 IU) of EPO after asphyxia followed by 72 h of continuous infusion (832.5 IU/h) has demonstrated a reduced number of activated caspase-3-positive cells in preterm fetal sheep [36] .…”

Section: Discussionmentioning

confidence: 99%

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Optimizing the Dose of Erythropoietin Required to Prevent Acute Ventilation-Induced Cerebral White Matter Injury in Preterm Lambs

et al. 2017

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Erythropoietin (EPO) is being trialed in preterm neonates for neuroprotection. We have recently demonstrated that a single high bolus dose (5,000 IU/kg) of recombinant human EPO amplified preterm lung and brain ventilation-induced injury. We aimed to determine the optimal dose of EPO to reduce ventilation-induced cerebral white matter inflammation and injury in preterm lambs. Lambs (0.85 gestation) were ventilated with an injurious strategy for 15 min followed by conventional ventilation for 105 min. Lambs were randomized to no treatment (VENT; n = 8) or received a bolus dose of EPO (EPREX®): 300 IU/kg (EPO 300; n = 5), 1,000 IU/kg (EPO 1,000; n = 5), or 3,000 IU/kg (EPO 3,000; n = 5). Physiological parameters were measured throughout the study. After 2 h, brains were collected for analysis; real-time quantitative polymerase chain reaction and immunohistochemistry were used to assess inflammation, cell death, and vascular leakage in the periventricular and subcortical white matter (PVWM; SCWM). Molecular and histological inflammatory indices in the PVWM were not different between groups. EPO 300 lambs had higher IL-6 (p = 0.006) and caspase-3 (p = 0.025) mRNA expression in the SCWM than VENT lambs. Blood-brain barrier (BBB) occludin mRNA levels were higher in EPO 3,000 lambs in the PVWM and SCWM than VENT lambs. The number of blood vessels with protein extravasation in the SCWM was lower in EPO 1,000 (p = 0.010) and EPO 3,000 (p = 0.025) lambs compared to VENT controls but not different between groups in the PVWM. Early administration of EPO at lower doses neither reduced nor exacerbated cerebral white matter inflammation or injury. 3,000 IU/kg EPO may provide neuroprotection by improving BBB integrity.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Optimizing the Dose of Erythropoietin Required to Prevent Acute Ventilation-Induced Cerebral White Matter Injury in Preterm Lambs

et al. 2017

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“…; Wassink et al . ). Diffuse white matter injury evolves over time involving degenerative, proliferative and arrested maturation processes.…”

Section: The Global Burden Of Hypoxic–ischaemic Brain Injurymentioning

confidence: 97%

The fetus at the tipping point: modifying the outcome of fetal asphyxia

Dhillon

Lear

Galinsky

et al. 2018

The Journal of Physiology

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Brain injury around birth is associated with nearly half of all cases of cerebral palsy. Although brain injury is multifactorial, particularly after preterm birth, acute hypoxia-ischaemia is a major contributor to injury. It is now well established that the severity of injury after hypoxia-ischaemia is determined by a dynamic balance between injurious and protective processes. In addition, mothers who are at risk of premature delivery have high rates of diabetes and antepartum infection/inflammation and are almost universally given treatments such as antenatal glucocorticoids and magnesium sulphate to reduce the risk of death and complications after preterm birth. We review evidence that these common factors affect responses to fetal asphyxia, often in unexpected ways. For example, glucocorticoid exposure dramatically increases delayed cell loss after acute hypoxia-ischaemia, largely through secondary hyperglycaemia. This critical new information is important to understand the effects of clinical treatments of women whose fetuses are at risk of perinatal asphyxia.

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“…Multiple experimental studies have reported rEpo‐mediated neuroprotection with improved long‐term outcomes after HI (as reviewed by Wu & Gonzalez, ). For example, in preterm fetal sheep, rEpo infusion from 30 min until 72 h after asphyxia improved neuronal and oligodendroglial loss, and electrophysiological restoration (Wassink et al . 2017).…”

Section: The Mechanisms Of Hypothermic Neuroprotectionmentioning

confidence: 99%

A working model for hypothermic neuroprotection

Wassink

Davidson

Lear

et al. 2018

The Journal of Physiology

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Therapeutic hypothermia significantly improves survival without disability in near-term and full-term newborns with moderate to severe hypoxic-ischaemic encephalopathy. However, hypothermic neuroprotection is incomplete. The challenge now is to find ways to further improve outcomes. One major limitation to progress is that the specific mechanisms of hypothermia are only partly understood. Evidence supports the concept that therapeutic cooling suppresses multiple extracellular death signals, including intracellular pathways of apoptotic and necrotic cell death and inappropriate microglial activation. Thus, the optimal depth of induced hypothermia is that which effectively suppresses the cell death pathways after hypoxia-ischaemia, but without inhibiting recovery of the cellular environment. Thus mild hypothermia needs to be continued until the cell environment has recovered until it can actively support cell survival. This review highlights that key survival cues likely include the inter-related restoration of neuronal activity and growth factor release. This working model suggests that interventions that target overlapping mechanisms, such as anticonvulsants, are unlikely to materially augment hypothermic neuroprotection. We suggest that further improvements are most likely to be achieved with late interventions that maximise restoration of the normal cell environment after therapeutic hypothermia, such as recombinant human erythropoietin or stem cell therapy.

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Partial white and grey matter protection with prolonged infusion of recombinant human erythropoietin after asphyxia in preterm fetal sheep

Cited by 39 publications

References 50 publications

Optimizing the Dose of Erythropoietin Required to Prevent Acute Ventilation-Induced Cerebral White Matter Injury in Preterm Lambs

Optimizing the Dose of Erythropoietin Required to Prevent Acute Ventilation-Induced Cerebral White Matter Injury in Preterm Lambs

The fetus at the tipping point: modifying the outcome of fetal asphyxia

A working model for hypothermic neuroprotection

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