The role of Substance P in chronic traumatic encephalopathy

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.

Author dc:creator

• McAteer, Kelly Marie

Advisors dc:contributor.advisor

• Turner, Renee Jade
• Vink, Robert
• Corrigan, Frances

• Mild traumatic brain injury
• traumatic brain injury
• Substance P
• tau
• phosphorylated tau
• concussion
• NK1
• TRPV1

Handle dc:identifier.uri

http://hdl.handle.net/2440/115184

OAI identifier oai:identifier

oai:digital.library.adelaide.edu.au:2440/115184