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.

scholarly journals Assessment of Postischemic Neurogenesis in Rats with Cerebral Ischemia and Propofol Anesthesia

2009 ◽  
Vol 110 (3) ◽  
pp. 529-537 ◽  
Author(s):  
Irina Lasarzik ◽  
Uta Winkelheide ◽  
Sonja Stallmann ◽  
Christian Orth ◽  
Astrid Schneider ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Spatial Learning ◽  
Neuronal Damage ◽  
Artery Occlusion ◽  
Carotid Artery Occlusion ◽  
High Dose ◽  
Sprague Dawley ◽  
Bilateral Carotid ◽  
Significant Difference ◽  
Treatment Naïve

Background Postischemic endogenous neurogenesis can be dose-dependently modulated by volatile anesthetics. The intravenous anesthetic propofol is used during operations with a risk of cerebral ischemia, such as neurosurgery, cardiac surgery, and vascular surgery. The effects of propofol on neurogenesis are unknown and, therefore, the object of this study. Methods Eighty male Sprague-Dawley rats were randomly assigned to treatment groups with propofol administration for 3 h: 36 mg x kg(-1) x h(-1) propofol with or without cerebral ischemia and 72 mg x kg(-1) x h(-1) propofol with or without cerebral ischemia. In addition, 7 rats with propofol administration for 6 h and 14 treatment-naive rats were investigated. Forebrain ischemia was induced by bilateral carotid artery occlusion and hemorrhagic hypotension. Animals received 5-bromo-2-deoxyuridine for 7 days. 5-Bromo-2-deoxyuridine-positive neurons were counted in the dentate gyrus after 9 and 28 days. Spatial learning in the Barnes maze and histopathologic damage of the hippocampus were analyzed. Results Propofol revealed no impact on basal neurogenesis. Cerebral ischemia increased the amount of new neurons. After 28 days, neurogenesis significantly increased in animals with low-dose propofol administered during cerebral ischemia compared with naive animals, whereas no significant difference was observed in animals with high-dose propofol during ischemia. Neuronal damage in the CA3 region was increased at 28 days with high-dose propofol. Postischemic deficits in spatial learning were not affected by propofol. Conclusions Independent effects of propofol are difficult to ascertain. Peri-ischemic propofol administration may exert secondary effects on neurogenesis by modulating the severity of histopathologic injury and thereby regenerative capacity of the hippocampus.

Spontaneous Pre-Existing Hypoxia Does Not Affect Brain Damage after Global Cerebral Ischaemia in Late-Gestation Fetal Sheep

2014 ◽  
Vol 37 (1) ◽  
pp. 56-65 ◽  
Author(s):  
Joanne O. Davidson ◽  
Caroline A. Yuill ◽  
Guido Wassink ◽  
Laura Bennet ◽  
Alistair J. Gunn
Keyword(s):  
Cerebral Ischaemia ◽  
Artery Occlusion ◽  
Carotid Artery Occlusion ◽  
Significant Loss ◽  
Late Gestation ◽  
Sleep State ◽  
Fetal Sheep ◽  
Bilateral Carotid ◽  
Global Cerebral Ischaemia ◽  
Bilateral Carotid Artery

There is considerable evidence that a mild, non-injurious insult can protect (precondition) against a subsequent injurious insult. Typically, protection is seen when the gap between insults is several days to a week. However, the effect of mild but persistent hypoxia is unknown. In this study we examined the hypothesis that mild pre-existing hypoxia (PaO2 <17 mm Hg) would reduce neural injury in chronically instrumented late-gestation (0.85 gestation) fetal sheep exposed to 30 min of global cerebral ischaemia induced by bilateral carotid artery occlusion (normoxia: n = 9 vs. pre-existing hypoxia: n = 9) or normoxia plus sham ischaemia (sham controls: n = 9). Histopathology was assessed after 7 days of recovery. Fetuses with pre-existing hypoxia had lower PaO2 values (16.1 ± 0.6 vs. 26.0 ± 1.1 mm Hg) and were lighter at post-mortem (4,033 ± 412 vs. 5,261 ± 238 g) compared to normoxic fetuses. Cerebral ischaemia was associated with secondary cortical oedema and seizures, reduced final EEG power, loss of sleep state cycling, and significant loss of neurons and oligodendrocytes, with no significant effect of pre-existing hypoxia. Pre-existing hypoxia was associated with a significantly attenuated rise in mean arterial pressure between 18 and 36 h and slower resolution of cortical oedema between 96 and 150 h after ischaemia. These data suggest that chronic hypoxia is not associated with a significant preconditioning effect.

scholarly journals Neurovascular Coupling Varies with Level of Global Cerebral Ischemia in a Rat Model

2012 ◽  
Vol 33 (1) ◽  
pp. 97-105 ◽  
Author(s):  
Wesley B Baker ◽  
Zhenghui Sun ◽  
Teruyuki Hiraki ◽  
Mary E Putt ◽  
Turgut Durduran ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Ischemia ◽  
Carotid Artery ◽  
Electrical Response ◽  
Artery Occlusion ◽  
Carotid Artery Occlusion ◽  
Laser Speckle ◽  
Global Cerebral Ischemia ◽  
Functional Responses ◽  
Bilateral Carotid

In this study, cerebral blood flow, oxygenation, metabolic, and electrical functional responses to forepaw stimulation were monitored in rats at different levels of global cerebral ischemia from mild to severe. Laser speckle contrast imaging and optical imaging of intrinsic signals were used to measure changes in blood flow and oxygenation, respectively, along with a compartmental model to calculate changes in oxygen metabolism from these measured changes. To characterize the electrical response to functional stimulation, we measured somatosensory evoked potentials (SEPs). Global graded ischemia was induced through unilateral carotid artery occlusion, bilateral carotid artery occlusion, bilateral carotid and right subclavian artery (SCA) occlusion, or carotid and SCA occlusion with negative lower body pressure. We found that the amplitude of the functional metabolic response remained tightly coupled to the amplitude of the SEP at all levels of ischemia observed. However, as the level of ischemia became more severe, the flow response was more strongly attenuated than the electrical response, suggesting that global ischemia was associated with an uncoupling between the functional flow and electrical responses.

scholarly journals Serine–Threonine Protein Kinase Akt does Not Mediate Ischemic Tolerance after Global Ischemia in the Gerbil

2000 ◽  
Vol 20 (9) ◽  
pp. 1301-1305 ◽  
Author(s):  
Shobu Namura ◽  
Izumi Nagata ◽  
Haruhiko Kikuchi ◽  
Michele Andreucci ◽  
Alessandro Alessandrini
Keyword(s):  
Protein Kinase ◽  
Ischemic Preconditioning ◽  
Neuronal Survival ◽  
Artery Occlusion ◽  
Carotid Artery Occlusion ◽  
Ischemic Tolerance ◽  
Early Reperfusion ◽  
Bilateral Carotid ◽  
Reperfusion Period ◽  
Protein Kinase Akt

The protein kinase Akt/PKB has been implicated in antiapoptosis and neuronal survival. The authors now show that Akt is phosphorylated in the hippocampus during the early reperfusion period after 3.5 minutes bilateral carotid artery occlusion (BCAO) in the gerbil. Repeated sublethal ischemia induces ischemic tolerance, which is known as ischemic preconditioning. Ischemic preconditioning does not affect the amount of Akt protein, but rather decreases the phosphorylation of Akt at Ser-473 after 10 minutes reperfusion after 3.5 minutes BCAO. These results suggest that although Akt may play a role in neuronal survival after ischemia, it may not play a role in ischemic tolerance by preconditioning.

scholarly journals Capillary Flow and Diameter Changes during Reperfusion after Global Cerebral Ischemia Studied by Intravital Video Microscopy

2004 ◽  
Vol 24 (4) ◽  
pp. 383-391 ◽  
Author(s):  
Erik F. Hauck ◽  
Sebastian Apostel ◽  
Julie F. Hoffmann ◽  
Axel Heimann ◽  
Oliver Kempski
Keyword(s):  
Cerebral Ischemia ◽  
Capillary Flow ◽  
Fluorescein Isothiocyanate ◽  
Artery Occlusion ◽  
Carotid Artery Occlusion ◽  
Global Cerebral Ischemia ◽  
Sham Operation ◽  
Cranial Window ◽  
Bilateral Carotid ◽  
Flow Velocities

The reaction of cerebral capillaries to ischemia is unclear. Based on Hossmann's observation of postischemic “delayed hypoperfusion,” we hypothesized that capillary flow is decreased during reperfusion because of increased precapillary flow resistance. To test this hypothesis, we measured cerebral capillary erythrocyte velocity and diameter changes by intravital microscopy in gerbils. A cranial window was prepared over the frontoparietal cortex in 26 gerbils anesthetized with halothane. The animals underwent either a sham operation or fifteen minutes of bilateral carotid artery occlusion causing global cerebral ischemia. Capillary flow velocities were measured by frame-to-frame tracking of fluorescein isothiocyanate labeled erythrocytes in 1800 capillaries after 1-hour reperfusion. Capillary flow velocities were decreased compared to control (0.25 ± 0.27mm/s vs. 0.76 ± 0.45 mm/s; P < 0.001). Precapillary arteriole diameters in reperfused animals were reduced to 76.3 ± 6.9% compared to baseline ( P < 0.05). Capillary diameters in reperfused animals (2.87 ± 0.97 μm) were reduced ( P < 0.001) compared to control (4.08 ± 1.19 μm). Similar reductions of precapillary (24%) and capillary vessel diameters (30%) and absolute capillary flow heterogeneity indicate that delayed (capillary) hypoperfusion occurs as a consequence of increased precapillary arteriole tone during reperfusion.

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.

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