Hypothermia is partially neuroprotective after neonatal
hypoxic-ischemic encephalopathy. Blockade of
connexin hemichannels can improve recovery of brain activity and cell survival after
ischemia in near-term fetal sheep. In this study, we investigated whether combining delayed
hypothermia with
connexin hemichannel blockade with
intracerebroventricular infusion of a mimetic
peptide can further improve outcomes after
cerebral ischemia. Fetal sheep (0.85 gestation) received 30 minutes of
cerebral ischemia followed by a 3-hour recovery period before treatment was started. Fetuses were randomized to one of the following treatment groups: normothermia (n=8),
hypothermia for 3 days (n=8),
connexin hemichannel blockade (50 μmol/L intracerebroventricular over 1 hour followed by 50 μmol/L over 24 hours, n=8) or
hypothermia plus hemichannel blockade (n=7). After 7 days recovery,
hypothermia was associated with reduced seizure burden, improved electroencephalographic (EEG) power, and a significant increase in neuronal and oligodendrocyte survival and reduced induction of Iba1-positive microglia. In contrast, although hemichannel blockade reduced seizure burden, there was no effect on EEG power or histology (P<0.05). There was no further improvement in outcomes with combined
hypothermia plus hemichannel blockade. In conclusion, these data show that there is no additive neuroprotection with combined
hypothermia and hemichannel blockade after
cerebral ischemia in near-term fetal sheep.