Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/115184
Type: Theses
Title: The role of Substance P in chronic traumatic encephalopathy
Author: McAteer, Kelly Marie
Issue Date: 2018
School/Discipline: Adelaide Medical School
Abstract: Chronic traumatic encephalopathy (CTE) is believed to be a neurodegenerative disease associated with contact sports and exposure to repetitive mild traumatic brain injury (rmTBI). CTE has attracted significant attraction over the past few years due to the high incidence of sports-related head injuries and the emergence of dementia-like symptoms many years following active play. In addition, patients with suspected CTE display a very unique pattern of hyperphosphorylated tau deposition post-mortem, with accumulation located at the base of the cortical sulci. To date, the link between exposure to rmTBI and the development of both dementia-like symptoms and post-mortem pathology associated with CTE has not been ascertained, highlighting the need for the study of potential mechanisms driving these processes. Substance P (SP) is a neuropeptide involved in the process of neurogenic inflammation, which has been shown previously to be involved in many processes within the brain following traumatic brain injury (TBI) including blood brain barrier disruption and development of oedema. Significantly increased levels of SP have also been frequently observed following TBI, as well as other studies showing that SP release can increase with the application of more frequent and intense stimuli, such as that observed in rmTBI. It could therefore be that SP may contribute to the long term behavioural and pathological changes observed in CTE. Therefore the overall aims of this thesis were to fully ascertain the role of SP release following rmTBI and to determine whether the changes observed following rmTBI can be attenuated with a therapeutic intervention. Significant increases in SP concentrations were observed following both rmTBI and severe TBI in the cortical regions in the acute phases of injury, although this did not appear to have a pronounced effect on tau as analysed by Western Blot (WB). However when analysed using immunohistochemistry changes in tau deposition were observed at the same timepoints. To further analyse the role that SP may play in these injury processes, blockade of the TRPV₁ receptor, where SP is believed to be released from when mechanically stimulated, was performed prior to injury. Administration of a TRPV₁ antagonist both prior to and following injury prevented SP release in severely injured animals. However in rmTBI animals, SP release was only attenuated in those pre-treated with a TRPV₁ antagonist. Therefore to further assess the effects of SP release following rmTBI, administration of an NK₁ antagonist, which is known to block the effects of SP release, was employed following injury. It was found that the antagonists may have had an effect on the acute release of SP following rmTBI, however this did not translate to changes in long term outcomes. Overall the effects on tau phosphorylation were believed to be negligible in this study and the SP/NK₁ system did not appear to be involved. To summarise, it is believed that SP release is indeed affected following rmTBI. However, it does not appear to be involved in the phosphorylation of tau in the acute or chronic phases of injury. However, there is still much to be discovered about the role of the SP/NK1 system and its potential involvement following rmTBI and these studies provide the groundwork for future developments in this area.
Advisor: Turner, Renee Jade
Vink, Robert
Corrigan, Frances
Dissertation Note: Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 2018
Keywords: Mild traumatic brain injury
traumatic brain injury
Substance P
tau
phosphorylated tau
concussion
NK1
TRPV1
Provenance: This electronic version is made publicly available by the University of Adelaide in accordance with its open access policy for student theses. Copyright in this thesis remains with the author. This thesis may incorporate third party material which has been used by the author pursuant to Fair Dealing exceptions. If you are the owner of any included third party copyright material you wish to be removed from this electronic version, please complete the take down form located at http://www.adelaide.edu.au/legals
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