Abstract TP120: Complement Activation Contributes to Malignant Transformation of Stroke and Limits Cognitive Recovery After Reperfusion Therapy

Abstract

Introduction: Ischemic stroke involves an ischemic event followed by post-ischemic neuroinflammation, leading to acute mortality, neuronal loss, and impaired recovery. Standard of care reperfusion therapy (thrombolysis or thrombectomy) has a limited treatment window due to risk of hemorrhage, and leads to functional independence in only a subset of patients. We studied the role of complement and neuroinflammation in the pathophysiology behind the major clinical challenges of reperfusion therapy; the risk of hemorrhage and limited cognitive recovery. Methods: We used 3 stroke models, namely transient middle cerebral artery occlusion (MCAO), permanent MCAO and microembolic models, to investigate the effects of t-PA, mechanical reperfusion, rehabilitation therapy, and complement inhibition in mice. We used B4-Crry, a site-targeted inhibitor of C3 activation that specifically localizes to neoepitopes expressed in the post-ischemic brain following its intravenous administration. A retrospective analysis was also performed for cognitive and motor recovery in human patients following reperfusion therapy. Results: Complement inhibition with B4-Crry improved the safety, efficacy and treatment window of reperfusion therapy, decreased hemorrhagic transformation, and improved cognitive recovery. Despite reperfusion with t-PA, there was ongoing complement-dependent microglial activation and phagocytosis of hippocampal synapses for at least 30 days leading to pronounced long-term cognitive deficits. Administration of B4Crry, alone or in combination with thrombolytic therapy, limited complement deposition in the perilesional brain, and reduced microgliosis and synaptic uptake. Reperfusion therapy alone did not improve cognitive outcomes, even when combined with rehabilitation therapy. Reperfusion therapy did not improve cognitive outcomes in stroke patients. Conclusions: Although post-stroke reperfusion therapy limits the size of injury and improves motor deficits, post-reperfusion complement activation and neuroinflammation contribute to the malignant transformation of stroke acutely and seeds a chronic neurodegenerative inflammatory response. Complement modulation may be a promising adjuvant to reperfusion therapy.