Effects of novel pharmacological agents on markers of cellular and molecular health in a preclinical model of mild traumatic brain injury

Background: Mild traumatic brain injuries (mTBI) are events with potentially debilitating short- and longterm consequences and may lead to neurodegenerative diseases such as chronic traumatic encephalopathy (CTE). An incomplete understanding of the mechanisms of disease progression has led to difficulty in identifying diagnostic and prognostic markers of mTBI and CTE, while treatment therapies remain elusive. Lines of evidence suggest that the antiinflammatory and neuroprotective agents celecoxib and minocycline may mitigate the injury processes initiated by mTBI, however a thorough investigation of these compounds in this context has not been undertaken. Accordingly, the aims of this research project were to: (i) investigate the behavioural, biochemical and molecular changes that are representative of repetitive mTBI and chronic neurodegeneration; and (ii) assess the implementation of minocycline and celecoxib in the inflammatory and excitotoxic pathways that are induced following mTBI. Methods: To meet these project aims, a series of reviews were conducted to ascertain the current knowledge gaps in mTBI research. A systematic review analysed the parameters and outcomes of mTBI animal modelling. A review was also undertaken to assess the current status of blood biomarker research for mTBI and CTE, and a third review described therapeutic targets for neuroprotection following mTBI and corresponding pharmacological treatments that have been investigated. These reviews provided rationale for our series of murine studies addressing the aforementioned aims. Study 1 examined differing modelling parameters to further understand the clinical, biochemical, and gene expression response to injury. Studies 2 and 3 used the findings of Study 1 to investigate the effectiveness of minocycline and celecoxib in mitigating mTBI-induced detriment to molecular and cognitive function. Results: The systematic review identified relevant mTBI modelling platforms and reported on subsequent changes to cognitive performance, neurodegenerative proteins, and neurodestructive genes. Study 1 used cumulative impacts to replicate the mTBI pathophysiology and clinical features described in the systematic review. Our pharmacology treatment studies found molecular measures of excitotoxicity and neurodegeneration induced by repetitive mTBI showed similar patterns of neuroprotection from minocycline and celecoxib in the hippocampus and cortex. However, glial cell involvement and inflammation was normalised by celecoxib in both the acute and chronic phases of recovery, but only in the chronic phase by minocycline. Interestingly, it was observed that behavioural detriment associated with mTBI following celecoxib administration did not reflect the neuroprotective gene expression changes. Conclusion: These investigations provide novel mechanistic data regarding microglial activation, inflammation, excitotoxicity, and neurodegeneration following repetitive mTBI. This work suggests that the pathways effected by minocycline and celecoxib are of importance in the alleviation of mTBI pathophysiology at chronic recovery. In turn, these investigations may help identify reliable mTBI-related diagnostic and prognostic markers and in developing potential treatments to mitigate the harmful effects of mTBI.