{"id":{"repo_id":"auckland-ms","oai_identifier":"oai:researchspace.auckland.ac.nz:2292/61103"},"canonical_url":"https://search.dev.ndltd.org/etd/auckland-ms/oai:researchspace.auckland.ac.nz:2292/61103","repository":{"repo_id":"auckland-ms","name":"University of Auckland","base_url":"https://researchspace.auckland.ac.nz/server/oai/request"},"display":{"title":"Perinatal hypoxic-ischemic brain injury – characterization, mechanisms and treatment","abstract":"The overarching aim of this thesis was to investigate the molecular mechanisms underlying the spread of perinatal hypoxic-ischemic brain injury, particularly connexin hemichannels, pannexin channels and purinergic signaling, as well as to identify mechanisms of injury that are poorly attenuated by therapeutic hypothermia in order to find suitable additive treatments, such as Exendin-4. I showed that global cerebral ischemia was associated with a striking increase in concentration of adenosine triphosphate in the cerebrospinal fluid at 6 hours in near-term fetal sheep. Curiously, the increase in adenosine triphosphate occurred despite no change in the expression or cell type distribution of connexin 43 hemichannels and pannexin 1 channels at this time. Although hypothermia significantly reduced cortical and white matter lesions and axonal and myelin injury, evidence of axonopathy persisted in the white matter after treatment with hypothermia after ischemia in near-term fetal sheep. Hypothermia was associated with only partial reduction in microgliosis and astrogliosis. Elevated microglial number was inversely correlated with recovery of electroencephalogram activity on day 7. Furthermore, hypothermia only partially reduced the ratio of “pro-inflammatory” to “anti-inflammatory microglia”. Taken together, these studies suggest that white matter injury and persistent neuroinflammation are potential targets to further improve neuroprotection in addition to hypothermia. Finally, I investigated whether targeting neuroinflammation with Exendin-4 will have additive neuroprotective effects with hypothermia after global cerebral ischemia in near-term fetal sheep. I showed that Exendin-4 infusion alone was highly neuroprotective and that the combination of Exendin-4 and hypothermia was associated with better neuronal survival, compared with hypothermia alone. In summary, this thesis furthered our understanding of the mechanisms underlying the spread of perinatal hypoxic-ischemic brain injury. I showed for the first time in a perinatal model that profound release of adenosine triphosphate occurs during the latent phase, highlighting abnormal purinergic signaling as a future direction of research. My research also suggested that targeting neuroinflammation and persistent white matter injury may be useful strategies to improve neuroprotection with hypothermia. I showed that Exendin-4 is a promising treatment, both alone and in combination with therapeutic hypothermia to reduce brain injury in a translational model of perinatal hypoxia ischemia.","abstract_html":"The overarching aim of this thesis was to investigate the molecular mechanisms underlying the spread of perinatal hypoxic-ischemic brain injury, particularly connexin hemichannels, pannexin channels and purinergic signaling, as well as to identify mechanisms of injury that are poorly attenuated by therapeutic hypothermia in order to find suitable additive treatments, such as Exendin-4. I showed that global cerebral ischemia was associated with a striking increase in concentration of adenosine triphosphate in the cerebrospinal fluid at 6 hours in near-term fetal sheep. Curiously, the increase in adenosine triphosphate occurred despite no change in the expression or cell type distribution of connexin 43 hemichannels and pannexin 1 channels at this time. Although hypothermia significantly reduced cortical and white matter lesions and axonal and myelin injury, evidence of axonopathy persisted in the white matter after treatment with hypothermia after ischemia in near-term fetal sheep. Hypothermia was associated with only partial reduction in microgliosis and astrogliosis. Elevated microglial number was inversely correlated with recovery of electroencephalogram activity on day 7. Furthermore, hypothermia only partially reduced the ratio of “pro-inflammatory” to “anti-inflammatory microglia”. Taken together, these studies suggest that white matter injury and persistent neuroinflammation are potential targets to further improve neuroprotection in addition to hypothermia. Finally, I investigated whether targeting neuroinflammation with Exendin-4 will have additive neuroprotective effects with hypothermia after global cerebral ischemia in near-term fetal sheep. I showed that Exendin-4 infusion alone was highly neuroprotective and that the combination of Exendin-4 and hypothermia was associated with better neuronal survival, compared with hypothermia alone. In summary, this thesis furthered our understanding of the mechanisms underlying the spread of perinatal hypoxic-ischemic brain injury. I showed for the first time in a perinatal model that profound release of adenosine triphosphate occurs during the latent phase, highlighting abnormal purinergic signaling as a future direction of research. My research also suggested that targeting neuroinflammation and persistent white matter injury may be useful strategies to improve neuroprotection with hypothermia. I showed that Exendin-4 is a promising treatment, both alone and in combination with therapeutic hypothermia to reduce brain injury in a translational model of perinatal hypoxia ischemia.","abstract_has_math":false,"creators":["Zhou, Qishan (Kelly)"],"institution":"ResearchSpace@Auckland","degree_name":"PhD","degree_level":"Doctoral","degree_discipline":"Biomedical Science","degree_department":null,"school":null,"contributors":[],"advisors":["Davidson, Joanne","Gunn, Alistair","Green, Colin"],"committee_chairs":[],"committee_members":[],"year":2022,"date_issued":"2022","date_published":"2022","updated_at":"2026-07-24T01:06:48Z","subjects":[],"languages":[],"rights":["Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated."],"rights_urls":["https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm"],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/2292/61103","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Davidson, Joanne","Gunn, Alistair","Green, Colin"]},{"key":"dc:creator","label":"Author","values":["Zhou, Qishan (Kelly)"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2022-09-09T01:46:58Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2022-09-09T01:46:58Z"]},{"key":"dc:date.issued","label":"Date","values":["2022"]},{"key":"dc:publisher","label":"Institution","values":["ResearchSpace@Auckland"]},{"key":"dc:relation.isreferencedby","label":"Dc Relation Isreferencedby","values":["UoA"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Biomedical Science"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Doctoral"]},{"key":"thesis:degree_name","label":"Degree Name","values":["PhD"]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["The University of Auckland"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:rights","label":"Dc Rights","values":["Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated."]},{"key":"dc:rights.uri","label":"Rights URI","values":["https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://hdl.handle.net/2292/61103"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["The overarching aim of this thesis was to investigate the molecular mechanisms underlying the spread of perinatal hypoxic-ischemic brain injury, particularly connexin hemichannels, pannexin channels and purinergic signaling, as well as to identify mechanisms of injury that are poorly attenuated by therapeutic hypothermia in order to find suitable additive treatments, such as Exendin-4. I showed that global cerebral ischemia was associated with a striking increase in concentration of adenosine triphosphate in the cerebrospinal fluid at 6 hours in near-term fetal sheep. Curiously, the increase in adenosine triphosphate occurred despite no change in the expression or cell type distribution of connexin 43 hemichannels and pannexin 1 channels at this time. Although hypothermia significantly reduced cortical and white matter lesions and axonal and myelin injury, evidence of axonopathy persisted in the white matter after treatment with hypothermia after ischemia in near-term fetal sheep. Hypothermia was associated with only partial reduction in microgliosis and astrogliosis. Elevated microglial number was inversely correlated with recovery of electroencephalogram activity on day 7. Furthermore, hypothermia only partially reduced the ratio of “pro-inflammatory” to “anti-inflammatory microglia”. Taken together, these studies suggest that white matter injury and persistent neuroinflammation are potential targets to further improve neuroprotection in addition to hypothermia. Finally, I investigated whether targeting neuroinflammation with Exendin-4 will have additive neuroprotective effects with hypothermia after global cerebral ischemia in near-term fetal sheep. I showed that Exendin-4 infusion alone was highly neuroprotective and that the combination of Exendin-4 and hypothermia was associated with better neuronal survival, compared with hypothermia alone. In summary, this thesis furthered our understanding of the mechanisms underlying the spread of perinatal hypoxic-ischemic brain injury. I showed for the first time in a perinatal model that profound release of adenosine triphosphate occurs during the latent phase, highlighting abnormal purinergic signaling as a future direction of research. My research also suggested that targeting neuroinflammation and persistent white matter injury may be useful strategies to improve neuroprotection with hypothermia. I showed that Exendin-4 is a promising treatment, both alone and in combination with therapeutic hypothermia to reduce brain injury in a translational model of perinatal hypoxia ischemia."]},{"key":"dc:title","label":"Title","values":["Perinatal hypoxic-ischemic brain injury – characterization, mechanisms and treatment"]}]}],"canonical_facts":{"dc:contributor.advisor":["Davidson, Joanne","Gunn, Alistair","Green, Colin"],"dc:creator":["Zhou, Qishan (Kelly)"],"dc:date.accessioned":["2022-09-09T01:46:58Z"],"dc:date.available":["2022-09-09T01:46:58Z"],"dc:date.issued":["2022"],"dc:description.abstract":["The overarching aim of this thesis was to investigate the molecular mechanisms underlying the spread of perinatal hypoxic-ischemic brain injury, particularly connexin hemichannels, pannexin channels and purinergic signaling, as well as to identify mechanisms of injury that are poorly attenuated by therapeutic hypothermia in order to find suitable additive treatments, such as Exendin-4. I showed that global cerebral ischemia was associated with a striking increase in concentration of adenosine triphosphate in the cerebrospinal fluid at 6 hours in near-term fetal sheep. Curiously, the increase in adenosine triphosphate occurred despite no change in the expression or cell type distribution of connexin 43 hemichannels and pannexin 1 channels at this time. Although hypothermia significantly reduced cortical and white matter lesions and axonal and myelin injury, evidence of axonopathy persisted in the white matter after treatment with hypothermia after ischemia in near-term fetal sheep. Hypothermia was associated with only partial reduction in microgliosis and astrogliosis. Elevated microglial number was inversely correlated with recovery of electroencephalogram activity on day 7. Furthermore, hypothermia only partially reduced the ratio of “pro-inflammatory” to “anti-inflammatory microglia”. Taken together, these studies suggest that white matter injury and persistent neuroinflammation are potential targets to further improve neuroprotection in addition to hypothermia. Finally, I investigated whether targeting neuroinflammation with Exendin-4 will have additive neuroprotective effects with hypothermia after global cerebral ischemia in near-term fetal sheep. I showed that Exendin-4 infusion alone was highly neuroprotective and that the combination of Exendin-4 and hypothermia was associated with better neuronal survival, compared with hypothermia alone. In summary, this thesis furthered our understanding of the mechanisms underlying the spread of perinatal hypoxic-ischemic brain injury. I showed for the first time in a perinatal model that profound release of adenosine triphosphate occurs during the latent phase, highlighting abnormal purinergic signaling as a future direction of research. My research also suggested that targeting neuroinflammation and persistent white matter injury may be useful strategies to improve neuroprotection with hypothermia. I showed that Exendin-4 is a promising treatment, both alone and in combination with therapeutic hypothermia to reduce brain injury in a translational model of perinatal hypoxia ischemia."],"dc:identifier.uri":["https://hdl.handle.net/2292/61103"],"dc:publisher":["ResearchSpace@Auckland"],"dc:relation.isreferencedby":["UoA"],"dc:rights":["Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated."],"dc:rights.uri":["https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm"],"dc:title":["Perinatal hypoxic-ischemic brain injury – characterization, mechanisms and treatment"],"dc:type":["Thesis"],"thesis:degree_discipline":["Biomedical Science"],"thesis:degree_level":["Doctoral"],"thesis:degree_name":["PhD"],"thesis:institution_name":["The University of Auckland"]},"updated_at":"2026-07-24T01:06:48Z"}