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 Perinatal hypoxic-ischemic brain injury in large animal models: Relevance to human neonatal encephalopathy

2018 ◽  
Vol 38 (12) ◽  
pp. 2092-2111 ◽  
Author(s):  
Raymond C Koehler ◽  
Zeng-Jin Yang ◽  
Jennifer K Lee ◽  
Lee J Martin
Keyword(s):  
Brain Injury ◽  
Animal Models ◽  
Cerebral Hypoperfusion ◽  
Large Animal ◽  
Perinatal Hypoxia ◽  
Cellular Mechanisms ◽  
Fetal Sheep ◽  
Newborn Piglets ◽  
Large Animal Models ◽  
Hypoxia Ischemia

Perinatal hypoxia-ischemia resulting in death or lifelong disabilities remains a major clinical disorder. Neonatal models of hypoxia-ischemia in rodents have enhanced our understanding of cellular mechanisms of neural injury in developing brain, but have limitations in simulating the range, accuracy, and physiology of clinical hypoxia-ischemia and the relevant systems neuropathology that contribute to the human brain injury pattern. Large animal models of perinatal hypoxia-ischemia, such as partial or complete asphyxia at the time of delivery of fetal monkeys, umbilical cord occlusion and cerebral hypoperfusion at different stages of gestation in fetal sheep, and severe hypoxia and hypoperfusion in newborn piglets, have largely overcome these limitations. In monkey, complete asphyxia produces preferential injury to cerebellum and primary sensory nuclei in brainstem and thalamus, whereas partial asphyxia produces preferential injury to somatosensory and motor cortex, basal ganglia, and thalamus. Mid-gestational fetal sheep provide a valuable model for studying vulnerability of progenitor oligodendrocytes. Hypoxia followed by asphyxia in newborn piglets replicates the systems injury seen in term newborns. Efficacy of post-insult hypothermia in animal models led to the success of clinical trials in term human neonates. Large animal models are now being used to explore adjunct therapy to augment hypothermic neuroprotection.

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 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.

Oxygen treatment after perinatal hypoxia-ischemia reduces neuronal damage at short survival times, but worsens injury with long-term survival

2005 ◽  
Vol 25 (1_suppl) ◽  
pp. S444-S444 ◽  
Author(s):  
Kristin M Noppens ◽  
J Regino Perez-Polo ◽  
David K Rassin ◽  
Karin N Westlund ◽  
Roderic Fabian ◽  
...  
Keyword(s):  
Neuronal Damage ◽  
Perinatal Hypoxia ◽  
Survival Times ◽  
Term Survival ◽  
Long Term Survival ◽  
Short Survival ◽  
Oxygen Treatment ◽  
Hypoxia Ischemia

scholarly journals NIR Laser Photobiomodulation Induces Neuroprotection in an In Vitro Model of Cerebral Hypoxia/Ischemia

2021 ◽  
Author(s):  
Elisabetta Gerace ◽  
Francesca Cialdai ◽  
Elettra Sereni ◽  
Daniele Lana ◽  
Daniele Nosi ◽  
...  
Keyword(s):  
Laser Radiation ◽  
Cerebral Ischemia ◽  
Molecular Mechanisms ◽  
Hippocampal Slices ◽  
Treatment Protocol ◽  
Synaptic Activity ◽  
Laser Source ◽  
Therapeutic Window ◽  
Hypoxia Ischemia ◽  
Nir Laser

AbstractBrain photobiomodulation (PBM) is an innovative treatment for a variety of neurological conditions, including cerebral ischemia. However, the capability of PBM for ischemic stroke needs to be further explored and its mechanisms of action remain currently unclear. The aim of the present research was to identify a treatment protocol capable of inducing neuroprotection and to investigate the molecular mechanisms activated by a dual-wavelength near infrared (NIR) laser source in an organotypic hippocampal slice model of hypoxia/ischemia. Hippocampal slices were exposed to oxygen and glucose deprivation (OGD) for 30 min followed by NIR laser light (fluence 3.71, 7.42, or 14.84 J/cm2; wavelengths 808 nm and 905 nm) delivered immediately or 30 min or 60 min after OGD, in order to establish a therapeutic window. Neuronal injury was assessed by propidium iodide fluorescence 24 h later. Our results show that NIR laser irradiation attenuates OGD neurotoxicity once applied immediately or 30 min after OGD. Western blot analysis of proteins involved in neuroinflammation (iNOS, COX-2, NFkB subunit p65, and Bcl-2) and in glutamatergic-mediated synaptic activity (vGluT1, EAAT2, GluN1, and PSD95) showed that the protein modifications induced by OGD were reverted by NIR laser application. Moreover, CA1 confocal microscopy revealed that the profound morphological changes induced by OGD were reverted by NIR laser radiation. In conclusion, NIR laser radiation attenuates OGD neurotoxicity in organotypic hippocampal slices through attenuation of inflammatory mechanisms. These findings shed light on molecular definition of NIR neuroprotective mechanisms, thus underlining the potential benefit of this technique for the treatment of cerebral ischemia.

scholarly journals A Model of Global Cerebral Ischemia in C57 BL/6 Mice

2004 ◽  
Vol 24 (2) ◽  
pp. 151-158 ◽  
Author(s):  
Ichiro Yonekura ◽  
Nobutaka Kawahara ◽  
Hirofumi Nakatomi ◽  
Kazuhide Furuya ◽  
Takaaki Kirino
Keyword(s):  
Cerebral Ischemia ◽  
Genetic Background ◽  
Neuronal Degeneration ◽  
Neuronal Damage ◽  
Neuronal Injury ◽  
Genetically Engineered ◽  
Global Cerebral Ischemia ◽  
Vessel Occlusion ◽  
Bilateral Carotid ◽  
The Mean

A reproducible model of global cerebral ischemia in mice is essential for elucidating the molecular mechanism of ischemic neuronal injury. Such a model is particularly important in the mouse because many genetically engineered mutant animals are available. In C57BL/6 and SV129/EMS mice, we evaluated a three-vessel occlusion model. Occlusion of the basilar artery with a miniature clip was followed by bilateral carotid occlusion. The mean cortical cerebral blood flow was reduced to less than 10% of the preischemic value, and the mean anoxic depolarization was attained within 1 minute. In C57BL/6 mice, there was CA1 hippocampal neuronal degeneration 4 days after ischemia. Neuronal damage depended upon ischemic duration: the surviving neuronal count was 78.5 ± 8.5% after 8-minute ischemia and 8.4 ± 12.7% after 14-minute ischemia. In SV129/EMS mice, similar neuronal degeneration was not observed after 14-minute ischemia. The global ischemia model in C57BL/6 mice showed high reproducibility and consistent neuronal injury in the CA1 sector, indicating that comparison of ischemic outcome between wild-type and mutant mice could provide meaningful data using the C57BL/6 genetic background. Strain differences in this study highlight the need for consideration of genetic background when evaluating ischemia experiments in mice.

scholarly journals Loss of interneurons and disruption of perineuronal nets in the cerebral cortex following hypoxia-ischaemia in near-term fetal sheep

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Tania M. Fowke ◽  
Robert Galinsky ◽  
Joanne O. Davidson ◽  
Guido Wassink ◽  
Rashika N. Karunasinghe ◽  
...  
Keyword(s):  
Cerebral Cortex ◽  
Perineuronal Nets ◽  
Fetal Sheep ◽  
Near Term

scholarly journals Proteolytic Remodeling of Perineuronal Nets: Effects on Synaptic Plasticity and Neuronal Population Dynamics

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
P. Lorenzo Bozzelli ◽  
Seham Alaiyed ◽  
Eunyoung Kim ◽  
Sonia Villapol ◽  
Katherine Conant
Keyword(s):  
Population Dynamics ◽  
Synaptic Plasticity ◽  
Synaptic Input ◽  
Neuronal Plasticity ◽  
Population Level ◽  
Gamma Oscillations ◽  
Brain Regions ◽  
Neuronal Population ◽  
Perineuronal Nets ◽  
Perineuronal Net

The perineuronal net (PNN) represents a lattice-like structure that is prominently expressed along the soma and proximal dendrites of parvalbumin- (PV-) positive interneurons in varied brain regions including the cortex and hippocampus. It is thus apposed to sites at which PV neurons receive synaptic input. Emerging evidence suggests that changes in PNN integrity may affect glutamatergic input to PV interneurons, a population that is critical for the expression of synchronous neuronal population discharges that occur with gamma oscillations and sharp-wave ripples. The present review is focused on the composition of PNNs, posttranslation modulation of PNN components by sulfation and proteolysis, PNN alterations in disease, and potential effects of PNN remodeling on neuronal plasticity at the single-cell and population level.

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