- Title
- Functional deficits after stroke: the key underlying mechanisms and the therapeutic potential of growth hormone
- Creator
- Sanchez Bezanilla, Sonia
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2020
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Background and aims: Stroke is currently the leading cause of long-term disability worldwide. Despite the efforts to minimise these negative outcomes, few treatments have been approved and have been mainly focused on the acute phase. This has led to a challenging situation where more than 90% of stroke survivors will experience long-lasting impairments in motor function and/or cognition. Therefore, clinical and pre-clinical research should focus on improving the understanding of underlying mechanisms contributing to neurological damage and functional impairment in later stages after stroke. One of the possible mechanisms that could explain these impairments is the development of secondary neurodegeneration (SND) in remote brain areas synaptically connected to the primary infarct site, such as the thalamus and hippocampus. This process is especially interesting because it occurs over a timescale of weeks to years after the primary infarct, providing a very interesting therapeutic target for chronic stroke treatment. This thesis focused on investigating the evolution of the functional outcomes after stroke and the mechanisms associated with these deficits (Chapter 3 and 4). Additionally, I was interested in studying a potential therapeutic intervention such as growth hormone (GH) to promote brain plasticity and alleviate motor and cognitive impairment (Chapter 5 and 6). Methods: The photothrombotic stroke model targeting the motor and sensory cortex was used to induce ischemia in mice. A touchscreen platform was used to analyse cognitive performance, and the grid walk and cylinder test were used to assess motor function. I also analysed the changes occurring after stroke in different brain areas (peri-infarct, thalamus and hippocampus) combining various molecular biology techniques such as Western Blot, immunohistochemistry, immunofluorescence and various histological stainings. In chapters 5 and 6, I used recombinant human GH (rhGH) delivered subcutaneously via a mini-osmotic pump for 28 days. Results: Stroke significantly impairs multiple cognitive domains and these deficits last for months after the primary infarction. Motor impairments were also long-lasting but a modest spontaneous recovery was observed over time. These deficits were associated with SND processes such as neuronal death, neuroinflammation (astrogliosis and microglia activation) and accumulation of neurotoxic proteins (amyloid-β and α-synuclein) in the thalamus and hippocampus (Chapters 3 and 4). Additionally, motor and cognitive impairment could be reversed by using GH as a therapeutic intervention. GH enhanced functional outcomes through a series of neurorestorative mechanisms including neurogenesis, synaptic plasticity and cerebrovascular remodelling (Chapters 5 and 6). Conclusion: Overall, in this thesis, I have deepened our understanding regarding cognitive and motor impairment after stroke and the mechanisms associated with these impairments. These important findings provide potential targets for translational medical research in the future. Finally, I have demonstrated that GH is an effective treatment following experimental stroke to promote brain plasticity and functional performance in the recovery phase after stroke. My results are encouraging and support the idea that GH represents a promising therapeutic intervention, which should be considered for clinical studies.
- Subject
- stroke; cognitive impairment; growth hormone; motor impairment; thesis by publication
- Identifier
- http://hdl.handle.net/1959.13/1424038
- Identifier
- uon:38016
- Rights
- Copyright 2020 Sonia Sanchez Bezanilla
- Language
- eng
- Full Text
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Thesis | 8 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 226 KB | Adobe Acrobat PDF | View Details Download |