A novel apoE-derived therapeutic reduces vasospasm and improves outcome in a murine model of subarachnoid hemorrhage
A novel apoE-derived therapeutic reduces vasospasm and improves outcome in a murine model of subarachnoid hemorrhage
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DOI：
10.1385/ncc:4:1:025
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发表时间：
2006-02-01
影响因子：
3.5
通讯作者：
Laskowitz, Daniel T.
中科院分区：
文献类型：
--
作者：
Gao, Junling;Wang, Haichen;Laskowitz, Daniel T.
前言：最近的临床观察表明，APOE4基因增加了动脉瘤性蛛网膜下腔出血(SAH)后迟发性脑缺血的发生和预后。在目前的研究中，我们使用仅表达人apoE3或apoE4的靶向替换小鼠来模拟SAH后apoE的异构体特异性效应。然后，我们验证了载脂蛋白E衍生的治疗性多肽在SAH后减少血管痉挛和促进功能恢复的假设。方法：在APOE3和APOE4靶向替换小鼠中诱导实验性SAH。伤后3d，每日进行功能评定。然后处死小鼠，对脑血管进行可视化，以量化血管痉挛。在另一项单独的实验中，C57BL/6小鼠在SAH后每12小时静脉注射一次载脂蛋白E模拟肽、低剂量或高剂量apoE模拟肽，连续3天。结果：与表达apoE4亚型的小鼠相比，表达apoE4亚型的小鼠具有更高的功能缺陷、死亡率、脑水肿和血管痉挛。与赋形剂治疗的小鼠相比，接受apoE类似肽治疗的小鼠死亡率、功能缺陷和血管痉挛的组织学证据都有所减少。结论：与临床文献一致，apoE4亚型与实验性SAH后血管痉挛的发生率增加和功能恢复不良有关。载脂蛋白E衍生的多肽代表了一种治疗SAH的新方法。
Introduction: Recent clinical observations demonstrate that the APOE4 genotype increases the development of delayed ischemic deficit and worsens prognosis following aneurysmal subarachnoid hemorrhage (SAH). In the current study, we use targeted replacement mice expressing only human apoE3 or apoE4 to model the isoform-specific effects of apoE following SAH. We then test the hypothesis that an apoE-derived therapeutic peptide reduces vasospasm and improves functional recovery after SAH.Methods: Experimental SAH was induced in APOE3- and APOE4-targeted replacement mice. For 3 days following injury, daily functional assessments were made. Mice were then sacrificed and the cerebral vasculature visualized to quantify vasospasm. In a separate experiment, C57Bl/6 mice were treated with intravenous injection of vehicle, low-dose, or high-dose apoE-mimetic peptide every 12 hours for 3 days post-SAH. Functional endpoints were assessed on a daily basis, followed by measurement of middle cerebral artery diameter.Results: Mice expressing the apoE4 isoform had greater functional deficit, mortality, cerebral edema, and vasospasm as compared with their apoE3 counterparts. Mice treated with the apoE-mimetic peptide had decreased mortality, functional deficits, and histological evidence of vasospasm as compared with vehicle-treated animals.Conclusion: Consistent with the clinical literature, the apoE4 isoform is associated with an increased incidence of vasospasm and poor functional recovery after experimental SAH. An apoE-derived peptide represents a novel therapeutic approach for the treatment of SAH.