Bioactive Glycerophospholipids and Their Role in Modulating Neuronal Vulnerability Following Cerebral Ischemia

Abstract

Stroke is a devastating and debilitating condition resulting from a blockage or hemorrhage in the vasculature of the brain. Despite extensive research, the etiology and pathophysiology of the disease at the level of the cell membrane are poorly understood, and effective treatment has been elusive. Though much research has shown marked increases in lipid metabolism following stroke, the impact of these changes have often been overlooked given the technical challenges associated with identifying regionally specific changes in degenerating tissue. The advent of lipidomics – a systems biology approach to the large-scale profiling of individual lipid species in tissues – has renewed interest in understanding the role of membrane lipids and their metabolites in the cell and in ischemic injury. In this thesis, I have used an unbiased LC-ESI-MS-based lipidomic approach to profile the small molecular weight glycerophosphocholine second messenger lipidome in anterior and posterior regions of cortex and striatum in the forebrain of wild-type and platelet activating factor receptor (PAFR) null-mutant mice before and after middle cerebral artery occlusion (MCAO). From these profiles, I have outlined the potential use of lipid second messenger distribution as topographic landmarks to identify functional subdomains within neural tissue. Further, I have demonstrated that ischemia does not simply disrupt lipid second messenger metabolism globally but produces regionally specific changes in discrete species and that these changes are altered by the loss of lipid regulatory effectors (i.e., PAFR null mutation). Based on the lipid species identified in this profile of healthy and ischemic tissue, I proposed that tight regulation of PC(O-22:6/2:0) homeostasis by PAFR-expressing microglia is ii required for proper dopaminergic signaling in prefrontal cortex. Finally, I have outlined a model whereby increased PAF synthesis following ischemia contributes the inflammatory response by promoting blood-brain barrier permeability, microglial activation and immune cell infiltration in a PAFR-dependent manner.