Cerebral ischemia initiates a cascade of events that can lead to secondary neuronal damage resulting in an increased extent of infarct and poorer clinical outcome. The restoration of blood flow to the area surrounding the infarct, although essential for patient recovery, elicits an inflammatory response that plays a significant role in secondary injury. The complement system plays a key role in the pathophysiology of many inflammatory and ischemic diseases, and clinical studies and interventional studies in experimental models indicate an important role for complement in neuronal injury following ischemic stroke. The long term goal of this project is to gain a better understanding of complement-dependent mechanisms involved in the pathogenesis of ischemic stroke, and to develop an efficacious and safe neuroprotective strategy based on attenuating complement-dependent injury. We will characterize the effects of various novel complement inhibitors that target either complement activation products or selectins. The role and relative contributions of P and E selectin in the context of complement activation will be investigated by the use of selectin targeting moieties with function blocking activity. The targeting strategies have been validated in other models of inflammation and ischemia and reperfusion injury, and we have shown that appropriate targeting of complement inhibitors not only markedly increases their bioavailability and efficacy, but obviates the need to systemically inhibit complement. Systemic complement inhibition and immunosupression is a potential concern with regard to the treatment of stroke patients, since infectious complications occur in a high proportion of patients within the first few days after stroke. The targeted complement inhibitors will be characterized in a murine model of transient focal cerebral ischemia. In addition to therapeutic determinations, we will elucidate pathophysiological mechanisms by investigating the roles and contributions of each selectin and different complement activation products in cerebral ischemia and reperfusion injury. To this end, we will determine in vivo relationships between neuronal injury, functional recovery, local and systemic complement inhibition, the generation of different complement activation products, P vs. E selectin antagonisms with and without complement inhibition, cytokine production, adhesion molecule expression, leukocyte infiltration and activation, and platelet adhesion and aggregation.
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