Therapeutic Target Identification, Validation and Drug Discovery for Traumatic Brain Injury

Morin, Alexander (2020). Therapeutic Target Identification, Validation and Drug Discovery for Traumatic Brain Injury. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.00010e32

Abstract

Traumatic Brain Injury (TBI) is a recognized cause of long-term disability worldwide with mild TBI accounting for 80% of all head traumas. Growing evidence links mTBI, and particularly repetitive mTBI (r-mTBI), with long lasting pathological and cognitive deficits that can serve as a risk factor for neurodegenerative disorders such as Alzheimer’s Disease, Parkinson’s Disease, Chronic Traumatic Encephalopathy and others. So far, there is no FDA-approved treatment to mitigate the consequences of r-mTBI, mainly due to the lack of an effective therapeutic target and a poor translatability of existing preclinical studies, which fail to mimic heterogeneous nature of TBI. In the current thesis, I used a mouse model of r-mTBI which was treated with two different drugs, nilvadipine and anatabine, that have been previously shown to decrease inflammation and neurodegenerative mechanisms and improve cognition. To address the heterogenous nature of r-mTBI, I used several cohorts of mice which vary in age at injury (young vs old), number of hits (5 vs 24), acute or chronic duration of treatment, and the time of the first treatment intervention post injury (immediate vs delayed). I have found that both nilvadipine and anatabine, in their respective treatment paradigms, improved cognitive deficits, decreased neuroinflammation, and reduced tau pathology. Moreover, nilvadipine was equally effective in both young and old 5-hit r-mTBI mice during the acute treatment. Anatabine was shown to be effective as a delayed treatment starting at 3 months after the last injury in r-mTBI mice with both 5 and 24 hits. We further conducted a phosphoproteome analysis to identify common alterations in response to r-mTBI and tested therapeutics. Despite a high heterogeneity of the phosphoproteome profile between the analyzed cohorts, our data identified several molecules (ARPP21, Syt-1) which were equally altered in response to treatment in all r-mTBI cohorts and may represent potential therapeutic targets that are effective across different models of r-mTBI. Future studies will focus on the total proteome analysis and a subsequent validation of these potential targets.

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