Regional cold perfusion and hemoglobin-based oxygen carrier administration both exert neuroprotective effects against cerebral ischemia reperfusion injury. We herein investigated whether the combination of these two therapies leads to stronger neuroprotective effects. Combination therapy was performed with the regional perfusion of cold HemoAct, a core-shell structured hemoglobin-albumin cluster, in a rat transient middle cerebral artery occlusion model. The effects of combination therapy, the intra-arterial administration of 10 °C HemoAct (10H) initiated at the onset of reperfusion, were compared with those of monotherapies, the intra-arterial administration of 10 °C saline (10S) and 37 °C HemoAct (37H), and an untreated control under the condition of 2-hour ischemia/24-hour reperfusion. The durability of therapeutic effects and the therapeutic time window of combination therapy were assessed based on comparisons with the 10H and control groups. Significantly better neurological findings and smaller infarct volumes were observed in the three treated (10S, 37H, and 10H) groups than in the control group. Among the 3 treated groups, only the 10H group showed significant improvements over the control group in the other items examined, including cerebral blood flow reduction, brain edema, and protein extravasation. The significant therapeutic effects of combination therapy on neurological disabilities and infarct volumes were confirmed at least until 7 days after reperfusion. Furthermore, combination therapy ameliorated neurological disabilities and hemorrhagic transformation in rats subjected to 4- and 5-hour ischemia/24-hour reperfusion. Since therapeutic effects may be expected until at least 5 h of complete ischemia and reperfusion, this combination therapy is a promising neuroprotective strategy against severe ischemic stroke.

区域冷灌注和基于血红蛋白的氧载体给药均对脑缺血再灌注损伤具有神经保护作用。我们在此调查了这两种疗法的组合是否会导致更强的神经保护作用。在大鼠暂时性大脑中动脉闭塞模型中，通过局部灌注冷 HemoAct（一种核壳结构的血红蛋白-白蛋白簇）进行联合治疗。在再灌注开始时动脉内给予 10 °C HemoAct (10H) 联合治疗的效果与单一疗法、10 °C 生理盐水 (10S) 和 37 °C 动脉内给药的效果进行比较HemoAct (37H)，以及在 2 小时缺血/24 小时再灌注条件下未经处理的对照。基于与 10H 组和对照组的比较，评估了治疗效果的持久性和联合治疗的治疗时间窗口。与对照组相比，在三个治疗组（10S、37H 和 10H）中观察到明显更好的神经学发现和更小的梗死体积。在3个治疗组中，只有10H组在其他检查项目（包括脑血流量减少、脑水肿和蛋白质外渗）方面比对照组有显着改善。联合治疗对神经功能障碍和梗死体积的显着治疗效果至少在再灌注后 7 天得到证实。此外，联合治疗改善了经受 4 和 5 小时缺血/24 小时再灌注的大鼠的神经功能障碍和出血性转化。由于在至少 5 小时的完全缺血和再灌注之前可能会出现治疗效果，因此这种联合疗法是一种有前景的针对严重缺血性中风的神经保护策略。