scholarly journals Non-Additive Effects of Delayed Connexin Hemichannel Blockade and Hypothermia after Cerebral Ischemia in Near-Term Fetal Sheep

2015 ◽  
Vol 35 (12) ◽  
pp. 2052-2061 ◽  
Author(s):  
Joanne O Davidson ◽  
Alexandra L Rout ◽  
Guido Wassink ◽  
Caroline A Yuill ◽  
Frank G Zhang ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Brain Activity ◽  
Recovery Period ◽  
Fetal Sheep ◽  
Treatment Groups ◽  
Intracerebroventricular Infusion ◽  
Eeg Power ◽  
Near Term ◽  
Connexin Hemichannel ◽  
Ischemic Encephalopathy

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 umol/L intracerebroventricular over 1 hour followed by 50 umol/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.

scholarly journals Limited benefit of slow rewarming after cerebral hypothermia for global cerebral ischemia in near-term fetal sheep

2018 ◽  
Vol 39 (11) ◽  
pp. 2246-2257 ◽  
Author(s):  
Joanne O Davidson ◽  
Guido Wassink ◽  
Vittoria Draghi ◽  
Simerdeep K Dhillon ◽  
Laura Bennet ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Therapeutic Hypothermia ◽  
Optimal Rate ◽  
Global Cerebral Ischemia ◽  
Preclinical Studies ◽  
Critical Determinant ◽  
Fetal Sheep ◽  
Eeg Power ◽  
Near Term ◽  
Ischemic Encephalopathy

The optimal rate of rewarming after therapeutic hypothermia for neonatal hypoxic–ischemic encephalopathy is unknown, although it is widely suggested that slow rewarming is beneficial. Some preclinical studies suggest better outcomes with slower rewarming, but did not control for the duration of hypothermia. In this study, near-term fetal sheep (0.85 gestation) received 30 min cerebral ischemia followed by normothermia, 48 h hypothermia with rapid rewarming over 1 h, 48-h hypothermia with slow rewarming over 24 h, or 72-h hypothermia with rapid rewarming. Slow rewarming after 48 h of hypothermia improved recovery of EEG power compared with rapid rewarming ( p < 0.05), but was not different from rapid rewarming after 72 h of hypothermia. At seven days recovery, neuronal survival was partially improved by both fast and slow rewarming after 48-h hypothermia, but less than 72-h hypothermia in the cortex and CA4 ( p < 0.05). In conclusion, although electrographic recovery was partially improved by slow rewarming over 24 h following cerebral hypothermia for 48 h, optimal neuroprotection was seen with hypothermia for 72 h with rapid rewarming, suggesting that the overall duration of cooling was the critical determinant of outcomes after therapeutic hypothermia.

Connexin hemichannel blockade is neuroprotective after, but not during, global cerebral ischemia in near-term fetal sheep

2013 ◽  
Vol 248 ◽  
pp. 301-308 ◽  
Author(s):  
J.O. Davidson ◽  
C.R. Green ◽  
L.F.B. Nicholson ◽  
L. Bennet ◽  
A.J. Gunn
Keyword(s):  
Cerebral Ischemia ◽  
Global Cerebral Ischemia ◽  
Fetal Sheep ◽  
Near Term ◽  
Connexin Hemichannel

scholarly journals Connexin Hemichannel Mimetic Peptide Attenuates Cortical Interneuron Loss and Perineuronal Net Disruption Following Cerebral Ischemia in Near-Term Fetal Sheep

2020 ◽  
Vol 21 (18) ◽  
pp. 6475
Author(s):  
Panzao Yang ◽  
Joanne O. Davidson ◽  
Tania M. Fowke ◽  
Robert Galinsky ◽  
Guido Wassink ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Perineuronal Nets ◽  
Perinatal Hypoxia ◽  
Perineuronal Net ◽  
Fetal Sheep ◽  
Mimetic Peptide ◽  
Intracerebroventricular Infusion ◽  
Bilateral Carotid ◽  
Cortical Interneurons ◽  
Hypoxia Ischemia

Perinatal hypoxia-ischemia is associated with disruption of cortical gamma-aminobutyric acid (GABA)ergic interneurons and their surrounding perineuronal nets, which may contribute to persisting neurological deficits. Blockade of connexin43 hemichannels using a mimetic peptide can alleviate seizures and injury after hypoxia-ischemia. In this study, we tested the hypothesis that connexin43 hemichannel blockade improves the integrity of cortical interneurons and perineuronal nets. Term-equivalent fetal sheep received 30 min of bilateral carotid artery occlusion, recovery for 90 min, followed by a 25-h intracerebroventricular infusion of vehicle or a mimetic peptide that blocks connexin hemichannels or by a sham ischemia + vehicle infusion. Brain tissues were stained for interneuronal markers or perineuronal nets. Cerebral ischemia was associated with loss of cortical interneurons and perineuronal nets. The mimetic peptide infusion reduced loss of glutamic acid decarboxylase-, calretinin-, and parvalbumin-expressing interneurons and perineuronal nets. The interneuron and perineuronal net densities were negatively correlated with total seizure burden after ischemia. These data suggest that the opening of connexin43 hemichannels after perinatal hypoxia-ischemia causes loss of cortical interneurons and perineuronal nets and that this exacerbates seizures. Connexin43 hemichannel blockade may be an effective strategy to attenuate seizures and may improve long-term neurological outcomes after perinatal hypoxia-ischemia.

scholarly journals Window of Opportunity of Cerebral Hypothermia for Postischemic White Matter Injury in the Near-Term Fetal Sheep

2004 ◽  
Vol 24 (8) ◽  
pp. 877-886 ◽  
Author(s):  
Vincent Roelfsema ◽  
Laura Bennet ◽  
Sherly George ◽  
David Wu ◽  
Jian Guan ◽  
...  
Keyword(s):  
White Matter ◽  
Cerebral Ischemia ◽  
Caspase 3 ◽  
Basic Protein ◽  
White Matter Injury ◽  
Window Of Opportunity ◽  
Reactive Microglia ◽  
Fetal Sheep ◽  
Near Term ◽  
Protein Density

Postresuscitation cerebral hypothermia is consistently neuroprotective in experimental preparations; however, its effects on white matter injury are poorly understood. Using a model of reversible cerebral ischemia in unanesthetized near-term fetal sheep, we examined the effects of cerebral hypothermia (fetal extradural temperature reduced from 39.4±0.1°C to between 30 and 33°C), induced at different times after reperfusion and continued for 72 hours after ischemia, on injury in the parasagittal white matter 5 days after ischemia. Cooling started within 90 minutes of reperfusion was associated with a significant increase in bioactive oligodendrocytes in the intragyral white matter compared with sham cooling (41±20 vs 18±11 per field, P < 0.05), increased myelin basic protein density and reduced expression of activated caspase-3 (14±12 vs 91±51, P < 0.05). Reactive microglia were profoundly suppressed compared with sham cooling (4±6 vs 38±18 per field, P < 0.05) with no effect on numbers of astrocytes. When cooling was delayed until 5.5 hours after reperfusion there was no significant effect on loss of oligodendrocytes (24±12 per field). In conclusion, hypothermia can effectively protect white matter after ischemia, but only if initiated early after the insult. Protection was closely associated with reduced expression of both activated caspase-3 and of reactive microglia.

scholarly journals How long is sufficient for optimal neuroprotection with cerebral cooling after ischemia in fetal sheep?

2017 ◽  
Vol 38 (6) ◽  
pp. 1047-1059 ◽  
Author(s):  
Joanne O Davidson ◽  
Vittoria Draghi ◽  
Sean Whitham ◽  
Simerdeep K Dhillon ◽  
Guido Wassink ◽  
...  
Keyword(s):  
White Matter ◽  
Cerebral Ischemia ◽  
Myelin Basic Protein ◽  
Basic Protein ◽  
Close Association ◽  
Global Cerebral Ischemia ◽  
Fetal Sheep ◽  
Head Cooling ◽  
Improved Outcomes ◽  
Eeg Power

The optimal duration of mild “therapeutic” hypothermia for neonates with hypoxic-ischemic encephalopathy is surprisingly unclear. This study assessed the relative efficacy of cooling for 48 h versus 72 h. Fetal sheep (0.85 gestation) received sham ischemia (n = 9) or 30 min global cerebral ischemia followed by normothermia (n = 8) or delayed hypothermia from 3 h to 48 h (n = 8) or 72 h (n = 8). Ischemia was associated with profound loss of electroencephalogram (EEG) power, neurons in the cortex and hippocampus, and oligodendrocytes and myelin basic protein expression in the white matter, with increased Iba-1-positive microglia and proliferation. Hypothermia for 48 h was associated with improved outcomes compared to normothermia, but a progressive deterioration of EEG power after rewarming compared to 72 h of hypothermia, with impaired neuronal survival and myelin basic protein, and more microglia in the white matter and cortex. These findings show that head cooling for 48 h is partially neuroprotective, but is inferior to cooling for 72 h after cerebral ischemia in fetal sheep. The close association between rewarming at 48 h, subsequent deterioration in EEG power and increased cortical inflammation strongly suggests that deleterious inflammation can be reactivated by premature rewarming.

Glutamate Release from the Ovine Fetal Brain during Maternal Hemorrhage 

1995 ◽  
Vol 82 (2) ◽  
pp. 521-530 ◽  
Author(s):  
Donald H. Penning ◽  
David H. Chestnut ◽  
Franklin Dexter ◽  
James Hrdy ◽  
Dan Poduska ◽  
...  
Keyword(s):  
Parietal Cortex ◽  
Glutamate Release ◽  
Recovery Period ◽  
Fetal Brain ◽  
In Utero ◽  
Extracellular Glutamate ◽  
Microdialysis Probe ◽  
Fetal Sheep ◽  
Near Term ◽  
Ovine Fetal

Background Glutamate has been implicated in the pathophysiology of neuronal injury associated with cerebral hypoxia-ischemia. A model using chronic in utero microdialysis was developed to sample the extracellular space of the fetal brain. Using this model, we tested the hypothesis that glutamate efflux from the parasagittal parietal cortex of near-term fetuses would increase during maternal hemorrhage. Methods Twelve near-term fetal sheep were instrumented with vascular catheters, and a microdialysis probe(s) was implanted into the parasagittal parietal cortex. After a 3-day recovery period, the animals were subjected to maternal hemorrhage until either the fetal pH was &lt; 7.00 or the fetus died. The extracellular glutamate concentration in the collected dialysate was determined by high pressure liquid chromatography (HPLC). Results Maternal hemorrhage resulted in an 80-90% decrease in uterine blood flow, a decrease fetal po2, and a mixed metabolic and respiratory fetal acidosis. There were two groups of fetuses, survivors (n = 5) and nonsurvivors (n = 7). The nonsurvivor group showed a large increase (10-30-fold) in peak glutamate release (P = 0.0015). Survivors demonstrated a small (threefold) increase that was not statistically significant (P = 0.065), unless one animal with very low probe recovery was excluded (P = 0.0048). Conclusions Extracellular glutamate release from the fetal brain can occur during maternal hemorrhage with fetal acidemia. The pathophysiologic role (if any) of glutamate release in the survivors remains to be elucidated. Our results are consistent with the hypothesis that in utero release of glutamate occurs during periods of fetal asphyxia. This experimental preparation of chronic fetal brain microdialysis can be used to monitor the brain extracellular concentration of any dialyzable substance in response to stress, including maternal hemorrhage.

scholarly journals The Effect of Size, Maturation, Global Asphyxia, Cerebral Ischemia, and Therapeutic Hypothermia on the Pharmacokinetics of High-Dose Recombinant Erythropoietin in Fetal Sheep

2020 ◽  
Vol 21 (9) ◽  
pp. 3042 ◽  
Author(s):  
Simerdeep K. Dhillon ◽  
Guido Wassink ◽  
Christopher A. Lear ◽  
Joanne O. Davidson ◽  
Nicholas H.G. Holford ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Therapeutic Hypothermia ◽  
Combined Treatment ◽  
Full Term ◽  
Prolonged Treatment ◽  
High Dose ◽  
Recombinant Erythropoietin ◽  
Fetal Sheep ◽  
Gestation Age ◽  
Near Term

High-dose human recombinant erythropoietin (rEPO) is a promising potential neuroprotective treatment in preterm and full-term neonates with hypoxic-ischemic encephalopathy (HIE). There are limited data on the pharmacokinetics of high-dose rEPO in neonates. We examined the effects of body weight, gestation age, global asphyxia, cerebral ischemia, hypothermia and exogenous rEPO on the pharmacokinetics of high-dose rEPO in fetal sheep. Near-term fetal sheep on gestation day 129 (0.87 gestation) (full term 147 days) received sham-ischemia (n = 5) or cerebral ischemia for 30 min followed by treatment with vehicle (n = 4), rEPO (n = 8) or combined treatment with rEPO and hypothermia (n = 8). Preterm fetal sheep on gestation day 104 (0.7 gestation) received sham-asphyxia (n = 1) or complete umbilical cord occlusion for 25 min followed by i.v. infusion of vehicle (n = 8) or rEPO (n = 27) treatment. rEPO was given as a loading bolus, followed by a prolonged continuous infusion for 66 to 71.5 h in preterm and near-term fetuses. A further group of preterm fetal sheep received repeated bolus injections of rEPO (n = 8). The plasma concentrations of rEPO were best described by a pharmacokinetic model that included first-order and mixed-order elimination with linear maturation of elimination with gestation age. There were no detectable effects of therapeutic hypothermia, cerebral ischemia, global asphyxia or exogenous treatment on rEPO pharmacokinetics. The increase in rEPO elimination with gestation age suggests that to maintain target exposure levels during prolonged treatment, the dose of rEPO may have to be adjusted to match the increase in size and growth. These results are important for designing and understanding future studies of neuroprotection with high-dose rEPO.

scholarly journals How Long is Too Long for Cerebral Cooling after Ischemia in Fetal Sheep?

2015 ◽  
Vol 35 (5) ◽  
pp. 751-758 ◽  
Author(s):  
Joanne O Davidson ◽  
Guido Wassink ◽  
Caroline A Yuill ◽  
Frank G Zhang ◽  
Laura Bennet ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Therapeutic Hypothermia ◽  
Neuronal Survival ◽  
Artery Occlusion ◽  
Carotid Artery Occlusion ◽  
Fetal Sheep ◽  
Bilateral Carotid ◽  
Hypothermia Group ◽  
Near Term

Therapeutic hypothermia can partially reduce long-term death and disability in neonates after hypoxic-ischemic encephalopathy. The aim of this study was to determine whether prolonging the duration of cooling from 3 days to 5 days could further improve outcomes of cerebral ischemia in near-term fetal sheep. Fetal sheep (0.85 gestation) received 30 minutes bilateral carotid artery occlusion followed by 3 days of normothermia ( n = 8), 3 days of hypothermia ( n = 8), or 5 days of hypothermia ( n = 8) started 3 hours after ischemia. Sham controls received sham ischemia followed by normothermia ( n = 8). Cerebral ischemia was associated with profound loss of electroencephalography power and spectral edge, with greater and more rapid recovery in both hypothermia groups ( P < 0.05). Ischemia was associated with severe loss of neurons in the cortex, hippocampus and thalamus ( P < 0.05), with a significant improvement in both hypothermia groups. However, the ischemia-3-day hypothermia group showed greater neuronal survival in the cortex and dentate gyrus compared with ischemia-5-day hypothermia ( P < 0.05). Ischemia was associated with induction of iba1-positive microglia, which was attenuated in both hypothermia groups ( P < 0.05). Extending the duration of delayed therapeutic hypothermia from 3 to 5 days did not improve outcomes after severe ischemia, and was associated with reduced neuronal survival in some regions.

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