Vascular Permeability Normalization in Ischemic Stroke

DESCRIPTION (provided by applicant): Stroke is the third leading cause of death in the United States and is the number one cause of adult disability. It is estimated that this clinical condition results in a cost of $30-40 billion in the U.S alone. While a large number of therapeutic agents have been investigated for the treatment of ischemic stroke, only one agent is currently approved for marketing in the United States. This agent, tissue plasminogen activator, functions by dissolving clots that prevent perfusion to the effected portion of the brain. Consequently, the agent must be administered rapidly following the onset of stroke symptoms for effectiveness. Many patients do not reach treatment facilities in adequate time to benefit from this therapy. 2,3-DABA represents a novel mechanism of action that may prevent brain damage associated with edema and swelling by reducing microvascular permeability. This type of agent should be effective for an extended period of time following the onset of ischemic stroke, and function by preventing the tissue damage seen following the stroke, addressing a huge unmet medical need. In previous experiments involving three independent animal models of increased pulmonary vascular permeability, it was demonstrated that 2,3-DABA is effective in significantly reducing the degree of permeability increase. The precise mechanisms by which 2,3-DABA may be exerting these effects are currently under investigation, however, these results have encouraged us to search for additional applications of these permeability decreasing properties. Following this reasoning, the specific aims of this proposal are the following: 1. To investigate the protective effect of 2,3-DABA on the permeability increases seen in an in vitro primary endothelial cell culture model of the blood brain barrier interface, both prior to and following the induction of oxygen and glucose deprivation. 2. To utilize an in vivo model of transient focal ischemia in rats to investigate the protective effect of 2,3-DABA on the permeability of the blood brain barrier both prior to and following the onset of ischemia. Evans blue dye extravasation and brain water content will be the outcome measurements employed as direct indicators of the reduction or prevention of cerebral ischemic injury.