PRO-INFLAMMATORY TRANSFORMING GROWTH FACTOR BETA SIGNALLING AS A THERAPEUTIC TARGET FOR REPETITIVE MILD TRAUMATIC BRAIN INJURY

Abstract

Traumatic brain injury (TBI) occurs in an estimated 50-60 million people annually, making it a major global health concern. Despite growing awareness of the risks associated with repetitive mild traumatic brain injury (rmTBI) and concussion, there remain significant unknowns regarding the mechanisms underlying the acute and delayed complications of these events. Moreover, there are currently no approved therapies for the treatment or prevention of the pathological sequelae of rmTBI.

This thesis sought to investigate the role of pro-inflammatory transforming growth factor beta (TGFβ) signalling in rmTBI and evaluate its potential as a novel treatment strategy for rmTBI-associated complications. To address these questions, I established and characterized a rodent model of rmTBI that recapitulates the clinical spectrum of outcomes that are commonly observed following concussion and mild brain trauma (Chapter 2). To further characterize this heterogeneity, retrospective grouping of animals as “sensitive” to the acute neurological consequences of rmTBI versus those “resilient” to these effects was performed. This approach revealed that acute neurological outcomes of rmTBI were not predictive of delayed deterioration, suggesting that the mechanisms underlying chronic neurological consequences of rmTBI occur in the absence of overt acute neurological signs. In Chapter 3, the mechanisms underlying acute sensitivity to rmTBI were explored. I showed that pathological increases in blood-brain barrier dysfunction (BBBD), TGFβ signalling, reactive gliosis, and neuroinflammation following rmTBI are associated with a more severe clinical outcome (sensitivity) during the acute phases of injury. Thus, I tested the effect of two TGFβ antagonists, IPW and losartan, as therapeutic approaches for the treatment and prevention of rmTBI-associated complications (Chapter 4). While slight differences in effects were observed for each of these treatments, I found that antagonism of TGFβ signalling was successful in improving acute outcomes, including post-impact convulsions and early recovery following injury. Further, antagonism of TGFβ signalling protected the integrity of the blood-brain barrier and prevented delayed neurological and cognitive complications of repetitive injury. Together, my findings highlight the potential of TGFβ antagonism as a future therapeutic strategy for complications of rmTBI.