Neuroprotection with Hemoglobin-based Oxygen Carriers in Ischemic Stroke: A Narrative Review of Preclinical Studies

While the establishment of endovascular thrombectomy has markedly improved outcomes in acute ischemic stroke, ineffective reperfusion remains a major challenge. Despite extensive preclinical research on neuroprotective strategies, this challenge persists, likely due to the inability to effectively address the no-reflow phenomenon, characterized by microvascular luminal narrowing that impedes red blood cell passage. Hemoglobin-based oxygen carriers (HBOCs), with particle sizes significantly smaller than red blood cells, offer a unique advantage over other neuroprotective agents: they can deliver oxygen to brain tissue and exert neuroprotective effects even under no-reflow conditions. This review provides a comprehensive overview of preclinical studies investigating the therapeutic application of various HBOCs in ischemic stroke and discusses future research directions in this promising field. Because most studies on the neuroprotective effects of HBOCs in cerebral ischemia have employed rodent middle cerebral artery occlusion models, this narrative review primarily focuses on studies using comparable rodent ischemic models to evaluate differences in efficacy. Although many HBOCs have demonstrated neuroprotective potential in experimental models, their clinical translatability remains limited, particularly regarding optimal dosage and administration timing. Among the HBOCs investigated, polynitroxylated PEGylated hemoglobin and hemoglobin nanoparticles have shown particularly promising neuroprotective effects when administered intravenously at low doses at or after reperfusion onset. These specific HBOCs possess antioxidant properties that inhibit methemoglobin formation, thereby preserving oxygen transport capacity. Furthermore, these antioxidant properties may directly confer neuroprotective effects. Additionally, by binding carbon monoxide (CO) instead of oxygen, they may elicit multiple protective effects similar to those observed with low-dose CO exposure. By simultaneously addressing the no-reflow phenomenon through oxygen delivery and activating multiple neuroprotective mechanisms, HBOCs hold significant promise as a multi-targeted therapeutic strategy for ischemic stroke.