Traumatic Brain Injury: Novel Methods for in Vitro and in Vivo Assessment of Drug Candidates

Abstract Traumatic Brain Injury (TBI) is the leading cause of death and disability for people under 35 and over 65 in the United States. There are currently no approved pharmaceutical treatments for TBI, which represents a major unmet need. Recent statistics show there were about 2.5 million TBI-related emergency department (ED) visits, 282,000 hospitalizations, and 56,000 deaths in the United States. The total economic burden of TBI in 2017, including direct and indirect medical costs, is estimated at $86 billion. If the injury is not fatal, the extent of swelling in the brain (edema) is strongly associated with long lasting damage due to cytotoxic edema. In vivo studies show moderate and severe TBI disrupts the Blood Brain Barrier (BBB) which causes a surge in arginine vasopressin (AVP) secretion, a hormone concerned with water permeability and ion homeostasis. The increased exposure of cells to vasopressin leads to dysregulation of AQP4, a water channel protein found in the brain, which is strongly implicated in cytotoxic edema.