Blood-Brain Barrier Pathology as a Bio-Marker and Target for Treatment of Traumatic Brain Injury and Post-Traumatic Epilepsy

Abstract

TBI is currently the leading cause of death and disability. Although moderate TBI only accounts for 10% of all TBIs worldwide, approximately 450 Canadians suffer a moderate brain injury every day and less than 30% of survivors show neurological improvements. Additionally, TBI survivors often face challenging prognoses and are at risk for long-term neurological sequelae including cognitive decline and post traumatic epilepsy (PTE). Despite growing awareness of these complications, the risks remain relatively high and there are no approved prevention treatments.

This thesis sought to investigate the suppression of pro-inflammatory transforming growth factor beta (TGFβ) signaling after moderate TBI as a treatment strategy to prevent PTE. To do this, I first established a rodent model of moderate TBI that induces blood-brain barrier dysfunction (BBBD) and reproduces outcomes that resemble clinical symptoms such as neurological and cognitive deficits (Chapter 2). Next, I characterized PTE in our model and assessed potential electrocorticographic (ECoG) diagnostic biomarkers (Chapter 3). The results of chapter 3 revealed that PTE is common after moderate TBI and seizures are related to an underlying slowing of cortical networks known as paroxysmal slow wave events (PSWEs). Furthermore, I showed that PSWEs serve as a good diagnostic biomarker for seizure activity and should therefore be considered in clinical settings. In chapter 4, I tested the effect IPW, a TGFβ antagonist, as a therapeutic intervention for complications associated with moderate TBI and a prevention strategy for PTE. I found that IPW successfully protected against blood-brain barrier (BBB) opening and improved neurological and cognitive deficits associated with head trauma. Importantly, I demonstrated the potential for IPW treatment to prevent PTE and reduce cortical slowing activity even several months after drug withdrawal. Together, my findings suggest future preclinical and clinical trials targeting TGF signaling may be of interest for patients at risk of developing PTE.