Roles of inflammation and the activated protein C pathway in the brain edema associated with cerebral venous sinus thrombosis

Abstract

BACKGROUND AND PURPOSE-: Increased blood-brain barrier (BBB) permeability, brain edema, and hemorrhage are important consequences of cerebral venous sinus thrombosis (CVST). The objective of this study was to define the role of the protein C pathway in the BBB permeability and edema elicited by experimental CVST. The role of neutrophil recruitment was also evaluated. METHODS-: Edema, BBB permeability, leukocyte-endothelial cell adhesion (LECA) and inflammatory cytokine levels were monitored in a murine model of CVST. The role of activated protein C (APC) was assessed in wild type mice (WT) receiving APC neutralizing antibody and in endothelial protein C receptor overexpressing mice (EPCR-tg). Neutrophil involvement was evaluated using an anti-CD18 antibody (Ab) and antineutrophil serum. RESULTS-: Brain edema and increases in BBB permeability and LECA were noted 48 hours after CVST. APC immunoblockade exacerbated these responses, while EPCR-tg exhibited blunted responses, as did WT treated with either antineutrophil serum or the CD18 Ab. CONCLUSIONS-: The protein C pathway protects the brain against the deleterious microvascular responses to CVST, a response that appears to be linked to the recruitment of inflammatory cells. © 2009 American Heart Association, Inc.