This thesis concerns the investigation of the neuroprotective effects of the peptides relaxin-2 and relaxin-3. Previous studies have shown that intracerebral relaxin-2 reduces brain lesion size in an in vivo model of stroke, thereby providing evidence of a neuroprotective action of relaxin-2. This thesis set out to extend this work to determine whether or not relaxin-2 and relaxin-3 protected neural tissues from stroke in vivo and to determine the mechanisms by which relaxin-2 and relaxin-3 may protect astrocytes from injury by affecting migration, resistance to hypoxia and prevention of apoptosis.
The first set of experiments show that relaxin-2 and relaxin-3 pre- and post-treatments following stroke induction protect neural tissues from cerebral damage in vivo. The next experiments show that relaxin-2 and relaxin-3 increase astrocyte migration in vitro through nitric oxide, phosphoinositide 3-kinase and matrix metalloproteinase-mediated pathways. A third set of experiments show that relaxin-2 and relaxin-3 treated astrocytes exhibited a higher viability compared to untreated astrocytes when exposed to oxygen glucose deprivation for 24 hours. Astrocytes that were cultured with relaxin-2 or relaxin-3 also showed a lower production of reactive oxygen species compared to astrocytes that were exposed to oxygen glucose deprivation alone. Finally, relaxin-2 and relaxin-3 protected astrocytes from 24-hour apoptosis injury that was induced by tumor necrosis factor alpha and hydrogen peroxide.
Taken together these experiments provide evidence that relaxin-2 and relaxin-3 peptides protect neural tissues from the deleterious effects of cerebral ischemia in vivo and help elucidate some of the cellular mechanisms by which relaxin peptides might protect the brain. Furthermore, these data show that relaxin-2 and relaxin-3 act directly on astrocytes, the most numerous cell type in the brain, to increase astrocyte migration and to protect these cells from some of the deleterious effects of stroke, namely hypoxia and apoptosis.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:OGU.10214/5295 |
| Date | 11 January 2013 |
| Creators | Willcox, Jordan Mark |
| Contributors | Summerlee, Alastair |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Rights | http://creativecommons.org/licenses/by-nc-nd/2.5/ca/ |
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