Ischemic stroke results from the interruption of blood flow to the brain resulting in long-term motor and cognitive neurological deficits, and it is a leading cause of death and disability. Current interventions focus on the restoration of blood flow to limit neuronal death, but these treatments have a therapeutic window of only a few hours and do not address post-stroke cerebral inflammation. The complement system, a component of the innate immune system, is activated by natural immunoglobulin M (IgM) antibodies that recognize neoepitopes expressed in the brain after ischemic stroke. We took advantage of this recognition system to inhibit complement activation locally in the ischemic area in mice. A single chain antibody recognizing a post-ischemic neoepitope linked to a complement inhibitor (termed B4Crry) was administered systemically as a single dose after stroke and shown to specifically target the ischemic hemisphere and improve long-term motor and cognitive recovery. We show that complement opsonins guide microglial phagocytosis of stressed but salvageable neurons, and that by locally and transiently inhibiting complement deposition, B4Crry prevented phagocytosis of penumbral neurons and inhibited pathologic complement and microglial activation that otherwise persisted for several weeks after stroke. B4Crry was protective in adult, aged, male and female mice and had a therapeutic window of at least 24 hours after stroke. Furthermore, the epitope recognized by B4Crry in mice is overexpressed in the ischemic penumbra of acute stroke patients, but not in the contralateral tissue, highlighting the translational potential of this approach.

缺血性中风是由于流向大脑的血液中断导致长期的运动和认知神经功能缺损所致，是导致死亡和致残的主要原因。当前的干预措施集中在恢复血流以限制神经元死亡，但是这些治疗方法只有几个小时的治疗时间，无法解决卒中后脑部炎症。补体系统是先天免疫系统的组成部分，被天然免疫球蛋白M（IgM）抗体激活，该抗体可识别缺血性中风后大脑中表达的新表位。我们利用这种识别系统来抑制小鼠局部缺血区域的补体激活。脑卒中后以单剂量全身给药识别与补体抑制剂相连的缺血后新表位的单链抗体（称为B4Crry），并显示出可特异性靶向缺血半球并改善长期运动和认知恢复的能力。我们显示补体调理素可指导受压但可挽救的神经元的小胶质细胞吞噬作用，并且通过局部和暂时抑制补体沉积，B4Crry可以防止半影神经元的吞噬作用，并抑制病理性补体和小胶质细胞活化，否则在中风后可持续数周。B4Crry对成年，成年，雄性和雌性小鼠具有保护作用，并且在中风后至少24小时具有治疗范围。此外，