ACUTE ALTERATIONS IN BLOOD-BRAIN BARRIER PERMEABILITY FOLLOWING BIOMECHANICAL INSULTS OF DIFFERENT SEVERITIES

Blood-brain barrier (BBB) disruption is a major consequence of traumatic brain injuries (TBI). Additionally, alterations in BBB tight-junction proteins, neuroinflammation and perivascular aggregation of the dementia-associated protein, p-tau, have been implicated in TBI-related neurodegenerative conditions. Therapeutic strategies focused at strengthening the BBB are gaining traction to counter TBI-induced neuroinflammation and neurodegeneration. Thus, to delineate this evolution of BBB dysfunction, two pre-clinical models, a single controlled cortical impact (CCI) and a 5-hit repeated head trauma (5xRHT), were compared. Increased permeability of the BBB was evident at 1-3 days post-injury (dpi) but not at 7dpi as assessed by the extravasation of the physiologically impermeable Evans blue dye. Interestingly, fibrinogen deposits were observed at 1dpi after both the types of TBI. Cerebrovascular changes were also assessed by diffusion-weighted imaging after 5xRHT. Concomitantly, loss of tight junction proteins, claudin-5 and Zo-1, peaked at 3 and 7dpi, respectively, and was negatively associated with vascular inflammation as indicated by ICAM-1. Flow cytometry further revealed the sub-acute infiltration of myeloid cells and lymphocytes, and a decrease in endothelial cells. Altogether, our study indicates that understanding the acute BBB dynamics after distinct biomechanical insults could help identify the right time-window for early neurovascular interventions.