Novel Hemoglobin-Based Oxygen Carrier Bound With Albumin Shows Neuroprotection With Possible Antioxidant Effects
Novel Hemoglobin-Based Oxygen Carrier Bound With Albumin Shows Neuroprotection With Possible Antioxidant Effects
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DOI：
10.1161/strokeaha.118.021467
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发表时间：
2018-08-01
期刊：
影响因子：
8.3
通讯作者：
Houkin, Kiyohiro
中科院分区：
文献类型：
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作者：
Gekka, Masayuki;Abumiya, Takeo;Houkin, Kiyohiro
背景与目的血红蛋白-白蛋白簇（HemoAct）是一种血红蛋白氧载体，由1个血红蛋白核和3个白蛋白壳共价结合而成。我们的目的是探讨神经保护HemoAct在短暂性脑缺血和阐明其潜在mechanism.Methods雄性大鼠进行2小时短暂性大脑中动脉闭塞，然后给予HemoAct transarterially在再灌注的发病。再灌注24小时后检查神经学和病理学结果，以确定HemoAct的神经保护作用。间歇测量皮质血流量和氧含量，并在再灌注早期对大鼠进行组织病理学分析，以评估HemoAct的治疗机制。此外，HemoAct的抗氧化作用在缺氧/复氧处理的大鼠脑微血管内皮cells.Results的神经功能恶化，梗死和水肿的发展，和MMP-9（基质金属蛋白酶-9）的激活和脂质过氧化作用后24小时的再灌注显着改善HemoAct治疗。6小时再灌注后皮质半影区血流量和组织氧分压的降低通过HemoAct治疗显著改善。皮质半暗带的组织病理学分析显示，HemoAct处理大鼠中的HemoAct显示出上级未处理大鼠中的自体红细胞的微血管灌注，微血管狭窄变化减轻。尽管HemoAct与血清蛋白一起外渗到缺血核心中，但其并未诱导缺血核心中血清外渗或活性氧产生增加。在体外实验中，大鼠脑微血管内皮细胞显示，HemoAct显着抑制细胞活性氧的产生缺氧/复氧处理cells，类似于albumin.Conclusions HemoAct发挥强大的神经保护作用，在短暂性脑缺血。具有氧气输送能力和可能的抗氧化作用的上级微血管灌注似乎是潜在的神经保护机制。
Background and Purpose A hemoglobin-albumin cluster, 1 core of hemoglobin covalently bound with 3 shell albumins, designated as HemoAct was developed as a hemoglobin-based oxygen carrier. We aim to investigate neuroprotection by HemoAct in transient cerebral ischemia and elucidate its underlying mechanisms.Methods Male rats were subjected to 2-hour transient middle cerebral artery occlusion and were then administered HemoAct transarterially at the onset of reperfusion. Neurological and pathological findings were examined after 24 hours of reperfusion to identify neuroprotection by HemoAct. Intermittent measurements of cortical blood flow and oxygen content were performed, and a histopathologic analysis was conducted on rats during the early phase of reperfusion to assess the therapeutic mechanism of HemoAct. In addition, the antioxidant effects of HemoAct were examined in hypoxia/reoxygenation-treated rat brain microvascular endothelial cells.Results Neurological deterioration, infarct and edema development, and the activation of MMP-9 (matrix metalloprotease-9) and lipid peroxidation after 24 hours of reperfusion were significantly ameliorated by the HemoAct treatment. Reductions in blood flow and tissue partial oxygen pressure in the cortical penumbra after 6 hours of reperfusion were significantly ameliorated by the HemoAct treatment. The histopathologic analysis of the cortical penumbra revealed that HemoAct in HemoAct-treated rats showed superior microvascular perfusion with the mitigation of microvascular narrowing changes than autologous erythrocytes in nontreated rats. Although HemoAct extravasated into the ischemic core with serum protein, it did not induce an increase in serum extravasation or reactive oxygen species production in the ischemic core. In vitro experiments with rat brain microvascular endothelial cells revealed that HemoAct significantly suppressed cellular reactive oxygen species production in hypoxia/reoxygenation-treated cells, similar to albumin.Conclusions HemoAct exerted robust neuroprotection in transient cerebral ischemia. Superior microvascular perfusion with an oxygen delivery capability and possible antioxidant effects appear to be the underlying neuroprotective mechanisms.