Posttraumatic reduction of edema with aquaporin-4 RNA interference improves acute and chronic functional recovery
Posttraumatic reduction of edema with aquaporin-4 RNA interference improves acute and chronic functional recovery
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DOI：
10.1038/jcbfm.2013.118
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发表时间：
2013-10-01
影响因子：
6.3
通讯作者：
Badaut, Jerome
中科院分区：
文献类型：
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作者：
Fukuda, Andrew M.;Adami, Arash;Badaut, Jerome
创伤性脑损伤（TBI）在幼儿和青少年中很常见，并与长期残疾和死亡率有关。青少年创伤性脑损伤的神经病理后遗症是一个复杂的级联事件，包括水肿形成和脑肿胀。脑水通道蛋白-4 （AQP4）在水肿形成中起关键作用。因此，开发针对AQP4的新型治疗方法可以减轻水肿的神经病理后遗症。我们假设，通过注射靶向AQP4 （siAQP4）的小干扰RNA （siRNA）抑制青少年TBI后AQP4的表达，可以减少水肿形成、神经炎症、神经元细胞死亡，改善神经预后。在出生后第17天，将siAQP4或不含rna诱导沉默复合物（RISC）的对照siRNA （siGLO）注射到创伤部位外侧。通过磁共振成像、神经系统测试和免疫组织化学来评估结果。与sigo处理的动物相比，siAQP4处理的幼鼠在运动功能和长期空间记忆方面（损伤后3天）表现出急性改善（损伤后60天）。这些改善与水肿形成减少、小胶质细胞激活增加、血脑屏障破坏减少、星形胶质细胞增生和神经元细胞死亡减少有关。我们的治疗模式的有效性与注射部位AQP4表达降低30%相关。
Traumatic brain injury (TBI) is common in young children and adolescents and is associated with long-term disability and mortality. The neuropathologic sequelae that result from juvenile TBI are a complex cascade of events that include edema formation and brain swelling. Brain aquaporin-4 (AQP4) has a key role in edema formation. Thus, development of novel treatments targeting AQP4 to reduce edema could lessen the neuropathologic sequelae. We hypothesized that inhibiting AQP4 expression by injection of small-interfering RNA (siRNA) targeting AQP4 (siAQP4) after juvenile TBI would decrease edema formation, neuroinflammation, neuronal cell death, and improve neurologic outcomes. The siAQP4 or a RNA-induced silencing complex (RISC)-free control siRNA (siGLO) was injected lateral to the trauma site after controlled cortical impact in postnatal day 17 rats. Magnetic resonance imaging, neurologic testing, and immunohistochemistry were performed to assess outcomes. Pups treated with siAQP4 showed acute (3 days after injury) improvements in motor function and in spatial memory at long term (60 days after injury) compared with siGLO-treated animals. These improvements were associated with decreased edema formation, increased microglial activation, decreased blood-brain barrier disruption, reduced astrogliosis and neuronal cell death. The effectiveness of our treatment paradigm was associated with a 30% decrease in AQP4 expression at the injection site.