The protective function of blood-borne monocytes/macrophages after delayed recanalization in a permanent MCAO rodent model

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ABSTRACT Ischemic stroke, which accounts for 87% of all strokes, is associated with high mortality and disability rates bringing a heavy burden to the society and families. Focal cerebral ischemia, due to large vessel occlusion (LVO) of the middle cerebral artery and internal carotid artery, accounts for 40-50% ischemic stroke patients. Thrombolytic therapy has been the preferred method of early treatment for patients with ischemic stroke, however, only 15% of those patients are treated with rtPA and 2.6-4% are treated with mechanical embolectomy. This leaves 88-98% of stroke patients with permanent occlusion without treatment options. The main challenge is the narrow therapeutic window beyond which patients with ischemic stroke are unable to receive treatment. Recent clinical trials have prompted changes in treatment guidelines, which now suggest recanalization can be performed up to 24 hours after stroke in select patients. Furthermore, there is evidence from several clinical studies and case reports showing that delayed recanalization even 3 days or later after symptom onset can improve clinical outcomes in ischemic stroke patients. However, recanalization beyond 24 hours is not routinely practiced, which we propose to study. We will focus on the pathological and neurological outcomes after delayed recanalization using a clinically relevant rat model of permanent middle cerebral artery occlusion (pMCAO). Our corollary hypothesis is that delayed recanalization will result in a massive infiltration of blood-borne immune cells into the brain, with monocyte/macrophages representing a large subset of these immune cells. Macrophages can undergo re-programming in the brain, thus driving them to assume efferocytic and anti-inflammatory roles, thereby alleviating the pathological and neurological deficits after pMCAO. Two specific aims have been proposed to characterize and determine the roles of these macrophages in ischemic core and penumbra after delayed recanalization. We will also determine how blood-borne macrophages re- program to assume efferocytic and anti-inflammatory phenotypes that exert a protective function after delayed recanalization. The long-term goal of this project is to establish delayed recanalization as a novel therapeutic approach for patients that have missed the conventional therapeutic window to receive rtPA.