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

Kyra Y.Y. Chan, Domenic A. Larosa, Mary Tolcos, Anqi Li, Valerie A. Zahra, Graeme R. Polglase, Samantha K. Barton

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)298-309
Number of pages12
JournalDevelopmental Neuroscience
Volume39
Issue number1-4
DOIs
Publication statusPublished - 1 Jul 2017

Keywords

  • Erythropoietin
  • Mechanical ventilation
  • Neonatal neuroprotection
  • Premature birth
  • Resuscitation
  • White matter injury

Cite this

Chan, Kyra Y.Y. ; Larosa, Domenic A. ; Tolcos, Mary ; Li, Anqi ; Zahra, Valerie A. ; Polglase, Graeme R. ; Barton, Samantha K. / Optimizing the Dose of Erythropoietin Required to Prevent Acute Ventilation-Induced Cerebral White Matter Injury in Preterm Lambs. In: Developmental Neuroscience. 2017 ; Vol. 39, No. 1-4. pp. 298-309.
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abstract = "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{\circledR}): 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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Optimizing the Dose of Erythropoietin Required to Prevent Acute Ventilation-Induced Cerebral White Matter Injury in Preterm Lambs. / Chan, Kyra Y.Y.; Larosa, Domenic A.; Tolcos, Mary; Li, Anqi; Zahra, Valerie A.; Polglase, Graeme R.; Barton, Samantha K.

In: Developmental Neuroscience, Vol. 39, No. 1-4, 01.07.2017, p. 298-309.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Optimizing the Dose of Erythropoietin Required to Prevent Acute Ventilation-Induced Cerebral White Matter Injury in Preterm Lambs

AU - Chan, Kyra Y.Y.

AU - Larosa, Domenic A.

AU - Tolcos, Mary

AU - Li, Anqi

AU - Zahra, Valerie A.

AU - Polglase, Graeme R.

AU - Barton, Samantha K.

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AB - 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.

KW - Erythropoietin

KW - Mechanical ventilation

KW - Neonatal neuroprotection

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KW - Resuscitation

KW - White matter injury

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