Gao Junling, Wang Haichen, Sheng Huaxin, Lynch John R, Warner David S, Durham Lori, Vitek Michael P, Laskowitz Daniel T
Multidisciplinary Neuroprotection Laboratories, Durham, NC, USA.
Neurocrit Care. 2006;4(1):25-31. doi: 10.1385/NCC:4:1:025.
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.
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.
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.
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.
最近的临床观察表明，APOE4基因型会增加动脉瘤性蛛网膜下腔出血（SAH）后迟发性缺血性神经功能缺损的发生，并使预后恶化。在本研究中，我们使用仅表达人载脂蛋白E3（apoE3）或载脂蛋白E4（apoE4）的靶向替代小鼠来模拟SAH后载脂蛋白E的异构体特异性作用。然后，我们检验了一种源自载脂蛋白E的治疗性肽可减轻SAH后血管痉挛并改善功能恢复的假设。
在APOE3和APOE4靶向替代小鼠中诱导实验性SAH。损伤后的3天内，每天进行功能评估。然后处死小鼠，观察脑血管系统以量化血管痉挛情况。在另一项实验中，C57Bl/6小鼠在SAH后3天内每12小时静脉注射一次溶媒、低剂量或高剂量的载脂蛋白E模拟肽。每天评估功能终点，随后测量大脑中动脉直径。
与表达apoE3的小鼠相比，表达apoE4异构体的小鼠具有更严重的功能缺损、更高的死亡率、脑水肿和血管痉挛。与接受溶媒治疗的动物相比，接受载脂蛋白E模拟肽治疗的小鼠死亡率降低、功能缺损减轻，且有血管痉挛的组织学证据。
与临床文献一致，apoE4异构体与实验性SAH后血管痉挛发生率增加及功能恢复不良相关。一种源自载脂蛋白E的肽代表了一种治疗SAH的新型治疗方法。
