Free Radical Scavenger Edaravone Administration Protects against Tissue Plasminogen Activator Induced Oxidative Stress and Blood Brain Barrier Damage
Free Radical Scavenger Edaravone Administration Protects against Tissue Plasminogen Activator Induced Oxidative Stress and Blood Brain Barrier Damage
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DOI：
10.2174/156720210793180747
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发表时间：
2010-11-01
影响因子：
2.1
通讯作者：
Abe, Koji
中科院分区：
文献类型：
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作者：
Lukic-Panin, Violeta;Deguchi, Kentaro;Abe, Koji
组织纤溶酶原激活剂(t-PA)是治疗急性脑缺血的药物之一。在3小时后使用t-PA会增加出血的几率，涉及多种机制。为了阐明t-PA毒性的可能机制和自由基清除剂依达拉奉的作用，我们在完整的大鼠皮质内分别给予赋形剂、纤溶酶和t-PA，并静脉注射依达拉奉。纤溶酶和t-PA对大鼠脑组织造成损伤，t-PA组4-HNE、HEL和8-OHdG免疫组化染色显示t-PA组损伤最明显。T-PA+依达拉奉组脑损伤明显减轻。在神经血管单位免疫染色方面，单一纤溶酶或t-PA组血管闭合素和IV型胶原表达减少，t-PA+依达拉奉组有所恢复。而基质金属蛋白酶-9在t-PA组表达最强，在纤溶酶中表达较弱，在t-PA+依达拉奉组中表达最弱。体外实验结果显示，两种给药组的紧密连接均有明显损伤，而血管内皮细胞(NAGO)和血管周围组织(GFAP)染色无明显变化。T-PA+依达拉奉组在钠-荧光素通透性测定中恢复了类似的紧密连接损伤。给予t-PA可引起脂质、蛋白质和DNA的氧化应激损伤，并导致神经血管单位外层的破坏，其作用大于纤溶酶。添加剂依达拉奉通过保护血脑屏障外层(体内)和紧密连接(体外)来改善t-PA造成的这种氧化损伤。
One of the therapeutics for acute cerebral ischemia is tissue plasminogen activator (t-PA). Using t-PA after 3 hour time window increases the chances of hemorrhage, involving multiple mechanisms. In order to show possible mechanisms of t-PA toxicity and the effect of the free radical scavenger edaravone, we administered vehicle, plasmin, and t-PA into intact rat cortex, and edaravone intravenously. Plasmin and t-PA damaged rat brain with the most prominent injury in t-PA group on 4-HNE, HEL, and 8-OHdG immunostainings. Such brain damage was strongly decreased in t-PA plus edaravone group. For the neurovascular unit immunostainings, occludin and collagen IV expression was decreased in single plasmin or t-PA group, which was recovered in t-PA plus edaravone group. In contrast, matrix metalloproteinase-9 intensity was the strongest in t-PA group, less in plasmin, and was the least prominent in t-PA plus edaravone group. In vitro data showed a strong damage to tight junctions for occludin and claudin 5 in both administration groups, while there were no changes for endothelial (NAGO) and perivascular (GFAP) stainings. Such damage to tight junctions was recovered in t-PA plus edaravone group with similar recovery in Sodium-Fluorescein permeability assay. Administration of t-PA caused oxidative stress damage to lipids, proteins and DNA, and led to disruption of outer parts of neurovascular unit, greater than the effect in plasmin administration. Additive edaravone ameliorated such an oxidative damage by t-PA with protecting outer layers of blood-brain barrier (in vivo) and tight junctions (in vitro).