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Int. J. Mol. Sci. 2012, 13(5), 6303-6319; doi:10.3390/ijms13056303

Deleterious Effects of High Dose Connexin 43 Mimetic Peptide Infusion After Cerebral Ischaemia in Near-Term Fetal Sheep

Received: 9 April 2012 / Revised: 8 May 2012 / Accepted: 14 May 2012 / Published: 22 May 2012
(This article belongs to the Special Issue Neuroprotective Strategies 2012)
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Hypoxic-ischaemic brain injury at birth is associated with 1–3/1000 cases of moderate to severe encephalopathy. Previously, we have shown that connexin 43 hemichannel blockade, with a specific mimetic peptide, reduced the occurrence of seizures, improved recovery of EEG power and sleep state cycling, and improved cell survival following global cerebral ischaemia. In the present study, we examined the dose response for intracerebroventricular mimetic peptide infusion (50 µmol/kg/h for 1 h, followed by 50 µmol/kg/24 h (low dose) or 50 µmol/kg/h for 25 h (high dose) or vehicle only (control group), starting 90 min after the end of ischaemia), following global cerebral ischaemia, induced by 30 min bilateral carotid artery occlusion, in near-term fetal sheep (128 ± 1 days gestation). Both peptide infusion groups were associated with a transient significant increase in EEG power between 2–12 h after ischaemia. The ischaemia-low dose group showed a significant recovery of EEG power from day five compared to the ischaemia-vehicle and -high dose groups. In contrast, the high dose infusion was associated with greater secondary increase in impedance (brain cell swelling), as well as a trend towards a greater increase in lactate concentration and mortality. These data suggest that higher doses of connexin mimetic peptide are not beneficial and may be associated with adverse outcomes, most likely attributable to uncoupling of connexin 43 gap junctions leading to dysfunction of the astrocytic syncytium.
Keywords: fetus; ischaemia; hemichannels; gap junctions; connexins; mimetic peptide fetus; ischaemia; hemichannels; gap junctions; connexins; mimetic peptide
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Davidson, J.O.; Green, C.R.; Nicholson, L.F.B.; Bennet, L.; Gunn, A.J. Deleterious Effects of High Dose Connexin 43 Mimetic Peptide Infusion After Cerebral Ischaemia in Near-Term Fetal Sheep. Int. J. Mol. Sci. 2012, 13, 6303-6319.

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