Mechanisms of Blood Brain Barrier Dysfunction in Stroke: A Therapeutic Opportunity

Stroke is the 5th leading cause of death in the United States according to the 2019 CDC Mortality Data. There are ~795,000 new incidences of stroke each year, and this prevalence is increasing in correlation with the aging population of the United States [159]. At 4-6 hours post-stroke, there is breakdown of the blood brain barrier (BBB). The BBB is comprised of brain microvascular endothelial cells that line the cerebral microvasculature. Functionally, the BBB provides a physical and biochemical barrier between the brain and the systemic circulation. Barrier properties of the BBB are provided by tight junctions and transporters that control selective passage of substances into the brain. During stroke, tight junction integrity and transporter expression is considerably altered, leading to significant leakage of substances from the systemic circulation. Of particular significance, BBB dysfunction also results in edema and swelling in the brain. Following the leak is a generalized immune response that exacerbates the ischemic insult in the brain [236]. Neurons start to die because of the inflammation. If this edema is not controlled within the first 24 hours, cognitive damage is permanent, and death may result [160]. Thus, preservation of the BBB during ischemic injury is critical to maintaining the health of the individual and preventing BBB dysfunction. Due to the limited therapeutic options available, it is critical to discover novel strategies for treatment of stroke and preservation of BBB integrity. In this dissertation, stroke pathophysiology is reviewed with an emphasis on BBB dysfunction. Research methods that can be used to identify new stroke therapeutics that have vascular protective properties will also be highlighted. This discussion will focus on statins, a class of therapeutics that are commonly administered to stroke patients due to their known ability to improve post-stroke neurological outcomes