Macrophage Infiltration Reduces Neurodegeneration and Improves Stroke Recovery after Delayed Recanalization in Rats

Abstract

Background. Recent cerebrovascular recanalization therapy clinical trials have validated delayed recanalization in patients outside of the conventional window. However, a paucity of information on the pathophysiology of delayed recanalization and favorable outcomes remains. Since macrophages are extensively studied in tissue repair, we anticipate that they may play a critical role in delayed recanalization after ischemic stroke. Methods. In adult male Sprague-Dawley rats, two ischemic stroke groups were used: permanent middle cerebral artery occlusion (pMCAO) and delayed recanalization at 3 days following middle cerebral artery occlusion (rMCAO). To evaluate outcome, brain morphology, neurological function, macrophage infiltration, angiogenesis, and neurodegeneration were reported. Confirming the role of macrophages, after their depletion, we assessed angiogenesis and neurodegeneration after delayed recanalization. Results. No significant difference was observed in the rate of hemorrhage or animal mortality among pMCAO and rMCAO groups. Delayed recanalization increased angiogenesis, reduced infarct volumes and neurodegeneration, and improved neurological outcomes compared to nonrecanalized groups. In rMCAO groups, macrophage infiltration contributed to increased angiogenesis, which was characterized by increased vascular endothelial growth factor A and platelet-derived growth factor B. Confirming these links, macrophage depletion reduced angiogenesis, inflammation, neuronal survival in the peri-infarct region, and favorable outcome following delayed recanalization. Conclusion. If properly selected, delayed recanalization at day 3 postinfarct can significantly improve the neurological outcome after ischemic stroke. The sanguineous exposure of the infarct/peri-infarct to macrophages was essential for favorable outcomes after delayed recanalization at 3 days following ischemic stroke.

Delayed revascularization in acute ischemic stroke patients

“…Macrophage infiltration of the ischemic core has been shown to promote neurovascular remodeling in ischemic stroke ( Wang et al, 2020 ). Pang et al (2022) , in a study, showed that delayed recanalization at day 3 postinfarct improved vasculature of the ischemic core while reducing infarct volume and neurological outcomes. Their investigations revealed that macrophage infiltration after recanalization of middle cerebral artery occlusion (rMCAO) is responsible for increased neurovascular remodeling which was confirmed by the increased presence of vascular endothelial growth factor A and platelet-derived growth factor B—markers of pro-angiogenic activity.…”

“…Their investigations revealed that macrophage infiltration after recanalization of middle cerebral artery occlusion (rMCAO) is responsible for increased neurovascular remodeling which was confirmed by the increased presence of vascular endothelial growth factor A and platelet-derived growth factor B—markers of pro-angiogenic activity. The investigators further evaluated the responses of macrophage depletion and found significantly reduced levels of angiogenesis, inflammation, and neuronal survival which resulted in adverse outcomes following delayed recanalization ( Pang et al, 2022 ).…”