1] Department of Physiology, Loma Linda University, Loma Linda, California, USA [2] Department of Pediatrics, Loma Linda University Medical Center, Loma Linda, California, USA.
J Cereb Blood Flow Metab. 2013 Oct;33(10):1621-32. doi: 10.1038/jcbfm.2013.118. Epub 2013 Jul 31.
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.
创伤性脑损伤（TBI）在幼儿和青少年中很常见，与长期残疾和死亡率有关。儿童 TBI 引起的神经病理学后果是一系列复杂的事件，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 的新型治疗方法以减少水肿，可能会减轻神经病理学后果。我们假设，在儿童 TBI 后通过注射靶向 AQP4 的小干扰 RNA（siRNA）（siAQP4）抑制 AQP4 表达，将减少水肿形成、神经炎症、神经元细胞死亡并改善神经功能结局。在出生后第 17 天的大鼠中，在皮质撞击伤后将 siAQP4 或无 RNA 诱导沉默复合物（RISC）的对照 siRNA（siGLO）注射到损伤侧。进行磁共振成像、神经学测试和免疫组织化学检测以评估结果。与 siGLO 处理的动物相比，接受 siAQP4 治疗的幼鼠在急性（损伤后 3 天）和长期（损伤后 60 天）的运动功能和空间记忆方面均有改善。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。我们的治疗方案的有效性与注射部位 AQP4 表达降低 30%有关。
