Ischemic stroke is a leading cause of death and disability, for which treatment options are very limited. The therapeutic dilemma created by the opposing goals of achieving rapid reperfusion and preventing intracerebral hemorrhage (ICH), has led us to consider the utility of targeting an inflammatory paradigm, the complement cascade, for inhibition in ischemic stroke. Studies are driven by the hypothesis that complement activation contributes directly to cerebral injury in stroke and may indirectly reduce the efficacy of tPA due to plasmin-dependent activation of complement. Preliminary data in a model of stroke using gene deficient mice have pointed to the critical deleterious role for leukocyte recruitment via the P- and E-selectin and ICAM-1 glycoprotein adhesion receptors. More recently, we have shown that ischemia triggers neurons to express an early complement component (C1q, thereby potentially flagging themselves for lysis or receptor mediated immune clearance. C1q-expressing, ischemically injured neurons bind a soluble truncated form of the extracellular domain of the complement receptor 1 (sCR1), which inhibits local complement activation and confers partial cerebral protection in stroke. When this complement-inhibitory protein is covalently modified by sLex- glycosylation to additionally inhibit selectin-mediated events, striking gains are observed in terms of reducing leukocyte and platelet recruitment, leading to a safe, durable protection even with delayed treatment. Preliminary data in our new primate (baboon) model of reperfused stroke demonstrate similar upregulation of cerebral microvascular selectin and neuronal C1q expression in the ischemic zone. In a double-blind placebo-controlled trial of baboon stroke we have just completed, a humanized anti-P-/E-selectin antibody demonstrated moderate cerebral protective efficacy. Together, these data lead us to hypothesize that selectin- and complement-mediated immune-inflammatory mechanisms are pathophysiologically relevant in stroke, and that simultaneous inhibition of both mechanisms may provide a novel and useful therapeutic target. Furthermore, given that plasmin may activate complement, and anti-complement approach might be especially useful in stroke to increase the efficacy of and therapeutic window for rtPA. These data lead directly to the Specific Aims, which are: (1) demonstrate the role of C1q expression in murine stroke using C1qa -/- mice and determine whether the effect of c1q expression is injurious via activation of the complement cascade and/or via local binding of transmembrane and cytosolic receptors leading to enhanced oxidative stress and phagocytosis; (2) determine whether thrombolysis with tPA activates complement, thereby diminishing it's capacity to protect the brain in stroke; and (3) determine the pathophysiological contribution of C1q expression in primate stroke using complement blockade (with sCR1) strategy as well as a combined anti-adhesion receptor, anti-complement strategy (sCR1/SLex).
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