Cell adhesion molecules and ischemic stroke

Abstract

Objective: To describe the role of adhesion molecules in ischemic stroke.

Methods: A PubMed search of literature pertaining to this study was conducted in April 2008 using specific keyword search terms pertaining to stroke and various listed subtopics related to adhesion molecules.

Results: An important contribution of beta2-integrins (CD11/CD18), intercellular adhesion molecule and P-selectin in the recruitment of leukocytes as well as platelets in the post-ischemic cerebral microvasculature has been defined in related studies. Immunoblockade or genetic deletion of these adhesion molecules has been shown to reduce infarct volume, edema, behavioral deficits and/or mortality in different animal models of ischemic stroke. Anti-adhesion agents also appear to widen the therapeutic window for thrombolytic therapy in these experimental models. An emerging role of inflammatory signaling pathways has also been addressed in modulating adhesion properties of post-ischemic cerebral microvasculature. Despite the promising data obtained from animal studies, few clinical trials assessing anti-adhesion therapy in ischemic stroke have failed to show efficacy.

Discussion: Several experiments using cell surface adhesion molecules as targets of stroke therapy are promising yet inadequate. Clinical trials using immune blockade of adhesion molecules by antibodies have failed due to immune reactions of the host. Further clinical trials are needed to test the efficacy of humanized antibodies or non-immunogenic agents that interfere with cell adhesion mechanisms. Adhesion blocking strategies seem to be effective particularly at reperfusion and use of these strategies with thrombolytic therapies justifies a continued effort to define the role of adhesion molecules in the pathophysiology of cerebral ischemia-reperfusion.

Figure 1

Adhesion of leukocytes and platelets into cerebral microvessels following cerebral ischemia reperfusion (I/R). I/R triggers activation of leukocytes and platelets and expression of adhesion molecules on cerebral endothelium (EC). Initially polymorphonuclear cells (PMN) roll and attach to endothelial cells. Platelets (PLT) adhere directly to endothelial cells or to PMN adhering to cerebral endothelium. At late phases of reperfusion mononuclear cell (MN) adhesion predominates. Adhesion of circulating cells further exacerbates the cerebral injury.