E-Selectin in Focal Cerebral Ischemia and Reperfusion in the Rat

Abstract

Summary:The selectin family of glycoproteins facilitates the early phase of polymorphonuclear leukocyte adhesion to the endothelial cell and, thus, may promote ischemic cell damage, To evaluate E-selectin in the pathogenesis of focal cerebral ischemia and reperfusion injury, we cloned rat E-selectin cDNA and measured the temporal profiles E-selectin mRNA (Northern blot) and protein (immunohistochemistry) during (1 h of ischemia) and after (up to 1 week) transient (2 h) middle cerebral artery (MCA) occlusion in the male Wistar rat We also tested the effect on these rats of administration of CY-1503, an analog of sialyl Lewisx (SLeX), on ischemia cell dam age, mRNA for E-seJectin was first detected in the ischemic hemisphere at 2 h of reperfusion and persisted to 46 h of reperLeukocytes contribute to cerebral ischemic cell dam age (Hallenbeck et aI., 1986;del Zoppo et al., 1991; Garcia et a1., 1994; Zhang RL et aI., 1994a), Accumu lation of leukocytes in an ischemic lesion is a dynamic process that is sequentially regulated by selectin, integrin and immunoglobulin families of related adhesion mol ecules (Patarroyo et aI., 1990;Butcher, 1991; Bevilac qua, 1993). The initial leukocyte endothelial low-affinity interaction promoting leukocyte rolling is mediated by the se1ectin family, including L-selectin, P-selectin, and E-selectin, Subsequently, a high-affinity interaction be-

Postischemic Cerebrovascular E-Selectin Expression Mediates Tissue Injury in Murine Stroke

“…Unfortunately, conclusions regarding the functional significance of E-selectin blockade alone were obscured by the use of controversial end points and nonselective agents. 12,13 In addition to these data, recent murine knockout data raise further questions, with mice expressing neither P-nor E-selectin being every bit as stroke-prone as wild-type littermate cousins. 11 In these latter experiments, the deletionally mutant strain also suffered the same degree of no-reflow phenomenon as the intact mice, leading the authors to suggest that compensatory upregulation of ICAM-1 and Mac-1 may have been responsible.…”

“…Others have shown that E-selectin is upregulated after focal cerebral ischemia in a variety of animal models 7-10; nonetheless, the functional significance of this upregulation remains incompletely understood. [11][12][13] To explore the pathophysiological role of E-selectin in reperfused stroke, we used a murine model of transient focal middle cerebral artery occlusion (MCAO). Using this model, we tested the hypothesis that E-selectin expression is increased and contributes to leukocyte recruitment, postischemic hypoperfusion, and tissue injury in stroke.…”

Mucosal Tolerization to E-Selectin Protects against Memory Dysfunction and White Matter Damage in a Vascular Cognitive Impairment Model

“…E-selectin is a glycoprotein adhesion molecule that is specifically expressed on endothelial cells (Bevilacqua et al, 1989), but it is only expressed when endothelium becomes activated (Bevilacqua, 1993). E-selectin becomes expressed in experimental (Zhang et al, 1996) and clinical (Fassbender et al, 1999) brain ischemia. Recombinant E-selectin can, therefore, serve as an immunological tolerization antigen, which can focus immunomodulation to regions of the vascular tree in which thrombosis or hemorrhage are threatened.…”

Therapeutic inhibition of carbohydrate-protein interactions in vivo.

“…Similar results with sialyl Lewis x type oligosaccharides have been reported in dog (28) and rat (29) myocardial reperfusion injury models, where, like in the cat, P-and L-selectin-dependent neutrophil recruitment contributes substantially to injury. Reductions in tissue injury have also been achieved with this glycan in a rat model of E-selectin-dependent cerebral ischemia and reperfusion injury (30). It remains to be determined if the protective effects of selectin antagonism will be as effective in humans, especially in the context of reperfusion injury associated with thrombolytic therapy for stroke or myocardial infarction.…”