Beneficial effect of dipyridyl, a liposoluble iron chelator against focal cerebral ischemia:: In vivo and in vitro evidence of protection of cerebral endothelial cells
Beneficial effect of dipyridyl, a liposoluble iron chelator against focal cerebral ischemia:: In vivo and in vitro evidence of protection of cerebral endothelial cells
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DOI：
10.1016/j.brainres.2007.11.063
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发表时间：
2008-02-08
期刊：
影响因子：
2.9
通讯作者：
Marie, Christine
中科院分区：
文献类型：
--
作者：
Megthy, Delphine;Bertrand, Nathalie;Marie, Christine
尽管铁螯合剂显示出诱导针对脑损伤的神经保护，但铁螯合剂对缺血诱导的脑内皮损伤的作用在很大程度上是未知的。我们的目的是探讨亲脂性铁螯合剂联吡啶（DP）的内皮保护作用（i）在体外对脑内皮细胞（CEC）死亡的细胞内铁负荷和（ii）在体内缺血诱导的血脑屏障（BBB）破坏。当铁暴露或脑缺血后不久给予DP时，DP分别防止CEC死亡和减少BBB破坏，而延迟给予DP与较低的CEC保护相关。有趣的是，当预防性给予时，DP还消除了CEC的死亡并减少了BBB破坏。然而，DP治疗和铁暴露之间的长时间延迟导致更高的保护，这表明DP的预处理效果。因此，通过铁螯合防止羟基自由基形成不能单独解释预防性DP治疗的有益效果。我们的研究结果表明，DP未能诱导潜在的细胞保护蛋白，血红素加氧酶-1和锰超氧化物歧化酶，表明其他蛋白参与DP的预处理效果。综上所述，DP的治疗和预防作用在这项研究中证明，铁螯合治疗是一个有利的和有效的方法，以增加血脑屏障抵抗缺血性损伤。(C)2007 Elsevier B. V.保留所有权利。
Whereas iron chelators were shown to induce neuroprotection against brain injury, the effect of iron chelators on ischemia-induced damage of cerebral endothelium is largely unknown. Our objective was to explore the endothelioprotective effect of the lipophilic iron chelator dipyridyl (DP) (i) in vitro on the death of cerebral endothelial cells (CECs) subjected to intracellular iron loading and (ii) in vivo on the ischemia-induced blood-brain barrier (BBB) disruption. When given shortly after iron exposure or brain ischemia, DP prevented the death of CECs and diminished BBB disruption, respectively, whereas a delayed administration of DP was associated with a lower CECs protection. Interestingly, when given preventively, DP also abrogated the death of CECs and reduced BBB disruption. However, a long delay between DP treatment and iron exposure led to a higher protection, suggesting a preconditioning effect of DP. Accordingly, prevention of hydroxyl radical formation through iron chelation cannot explain alone the beneficial effect of preventive DP treatment. Our findings showing that DP failed to induce the potentially cytoprotective proteins, heme oxygenase-1 and manganese superoxide dismutase, suggest that other proteins participate to the preconditioning effect of DP. To conclude, the curative and preventive effects of DP evidenced in this study suggest that iron chelation therapy represents a favorable and effective approach to increase BBB resistance towards ischemic injury. (C) 2007 Elsevier B.V. All rights reserved.