Connexin hemichannel blockade improves outcomes in a model of fetal ischemia
Article first published online: 24 JAN 2012
Copyright © 2011 American Neurological Association
Annals of Neurology
Volume 71, Issue 1, pages 121–132, January 2012
How to Cite
Davidson, J. O., Green, C. R., B. Nicholson, L. F., O'Carroll, S. J., Fraser, M., Bennet, L. and Jan Gunn, A. (2012), Connexin hemichannel blockade improves outcomes in a model of fetal ischemia. Ann Neurol., 71: 121–132. doi: 10.1002/ana.22654
- Issue published online: 24 JAN 2012
- Article first published online: 24 JAN 2012
- Accepted manuscript online: 31 OCT 2011 06:44AM EST
- Manuscript Accepted: 16 OCT 2011
- Manuscript Revised: 7 OCT 2011
- Manuscript Received: 19 APR 2011
- Health Research Council of New Zealand
- Bright Futures PhD Scholarship
- Tertiary Education Commission of New Zealand
Connexin hemichannels can open during ischemia, resulting in loss of membrane potential, calcium influx, and release of glutamate. In this study, we tested the hypothesis that opening of hemichannels after cerebral ischemia may contribute to delayed evolution of injury.
We infused a mimetic peptide that blocks connexin 43 hemichannels into the lateral ventricle of chronically instrumented fetal sheep in utero at 128 ± 1 days gestation (term is 147 days), starting 90 minutes after 30 minutes of severe ischemia induced by reversible bilateral carotid artery occlusion, for either 1 or 25 hours. Sheep were killed 7 days later.
Peptide infusion was associated with a graded improvement in recovery of electroencephalographic power after 7 days recovery, from −13 ± 1.9dB (n = 7) after ischemia–vehicle to −9 ± 1.6dB (n = 7) after ischemia–short infusion and −5 ± 1.6dB after ischemia–long infusion (n = 6, p < 0.05). Peptide infusion was associated with reduced seizure activity after ischemia, less frequent status epilepticus (p < 0.05), and earlier return of sleep state cycling (p < 0.05). Ischemia–long infusion (but not ischemia–short infusion) was associated with improved survival of oligodendrocytes in intragyral and periventricular white matter (p < 0.05) and increased brain weight (p < 0.05). Ischemia–long infusion was associated with an intermediate estimate of surviving neurons in the parasagittal cortex of 2.9 ± 0.8 × 106, in comparison to sham control (4.3 ± 0.9 × 106) or ischemia–vehicle (1.5 ± 0.4 × 106; p < 0.05 vs sham control).
These data support the hypothesis that opening of connexin hemichannels is a significant mediator of postischemic white and gray matter dysfunction and injury. ANN NEUROL 2012;71:121–132