Perinatal hypoxic-ischemic brain injury – characterization, mechanisms and treatment

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.

Name thesis:degree_name

PhD

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Biomedical Science

Grantor dc:publisher

ResearchSpace@Auckland

Year dc:date.issued

2022

Author dc:creator

• Zhou, Qishan (Kelly)

Advisors dc:contributor.advisor

• Davidson, Joanne
• Gunn, Alistair
• Green, Colin

Statement dc:rights

• Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

Licence dc:rights.uri

• https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm

Handle dc:identifier.uri

https://hdl.handle.net/2292/61103

OAI identifier oai:identifier

oai:researchspace.auckland.ac.nz:2292/61103