Connexin hemichannel blockade is neuroprotective after asphyxia in preterm fetal sheep.

Joanne O Davidson,Louise F Nicholson,Paul P Drury,Colin R Green,Laura Bennet,Alistair J Gunn,Pierre Gressens

doi:10.1371/journal.pone.0096558

Joanne O Davidson, Louise F Nicholson + Show 5 more

Open Access

https://doi.org/10.1371/journal.pone.0096558

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Journal: PloS one	Publication Date: May 27, 2014
Citations: 108	License type: CC BY 4.0

Affiliation: University of Auckland

Abstract

Asphyxia around the time of preterm birth is associated with neurodevelopmental disability. In this study, we tested the hypothesis that blockade of connexin hemichannels would improve recovery of brain activity and reduce cell loss after asphyxia in preterm fetal sheep. Asphyxia was induced by 25 min of complete umbilical cord occlusion in preterm fetal sheep (103–104 d gestational age). Connexin hemichannels were blocked by intracerebroventricular infusion of mimetic peptide starting 90 min after asphyxia at a concentration of 50 µM/h for one hour followed by 50 µM/24 hour for 24 hours (occlusion-peptide group, n = 6) or vehicle infusion for controls (occlusion-vehicle group, n = 7). Peptide infusion was associated with earlier recovery of electroencephalographic power after asphyxia compared to occlusion-vehicle (p<0.05), with reduced neuronal loss in the caudate and putamen (p<0.05), but not in the hippocampus. In the intragyral and periventricular white matter, peptide administration was associated with an increase in total oligodendrocyte numbers (p<0.05) and immature/mature oligodendrocytes compared to occlusion-vehicle (p<0.05), with a significant increase in proliferation (p<0.05). Connexin hemichannel blockade was neuroprotective and reduced oligodendrocyte death and improved recovery of oligodendrocyte maturation in preterm fetuses after asphyxia.

Highlights

Preterm birth occurs in around 7 to 12% of all live births and is associated with a high level of neurodevelopmental disability and cerebral palsy [1]
The distribution of injury and particular vulnerability of specific cell types to ischemia varies considerably between the full-term and preterm neonate. It is unclear whether connexin hemichannels contribute to the spread of injury following asphyxia in the preterm fetus, when white matter is predominantly populated by oligodendrocyte progenitor cells at a stage when they are most vulnerable to injury [14]
There was no significant difference in any parameter during asphyxia or the recovery period between groups

Summary

Introduction

Preterm birth occurs in around 7 to 12% of all live births and is associated with a high level of neurodevelopmental disability and cerebral palsy [1]. Opening of connexin hemichannels has been associated with ischemia, as well as oxygen glucose deprivation, metabolic inhibition or low extracellular calcium ion (Ca2+) levels [4,5,6,7,8] This may cause disruption of the resting membrane potential, release of cytotoxic levels of ATP [9] and glutamate [10] and uptake of water, leading to cell swelling and death [11,12]. The distribution of injury and particular vulnerability of specific cell types to ischemia varies considerably between the full-term and preterm neonate It is unclear whether connexin hemichannels contribute to the spread of injury following asphyxia in the preterm fetus, when white matter is predominantly populated by oligodendrocyte progenitor cells at a stage when they are most vulnerable to injury [14]

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Conclusion