Role for Selective Sphingosine 1-Phosphate Receptor 1 Modulation During Acute Ischemic Injury in an Experimental Male and Female Mouse Stroke Model

Abstract

Acute ischemic stroke (AIS) is a neurological disease caused by cessation of blood flow to the brain. Globally, AIS is the second leading cause of death in addition to being the leading cause of long term disability. Effective treatment strategies for ischemic stroke are limited; novel effective therapies are in great demand. Stroke pathophysiology is characterized by an initial ischemic event followed by a deluge of typical secondary responses including inflammation and vascular endothelial dysfunction. Recently the endogenous sphingolipid pathway has emerged as possible therapeutic target for attenuating ischemic brain damage. The sphingosine signaling pathway comprises of sphingosine-1-phosphate as well as its associated receptors that regulate a wide variety of physiological mechanisms, some of which are involved in AIS pathophysiology. In this thesis I will review the sphingosine signaling pathway biology as well as relevant effects on vascular function and inflammation. In addition, I will present and discuss data gathered during my thesis studies investigating sphingosine 1-phosphate receptor modulation in an experimental male and female mouse model of ischemic stroke and reperfusion.