Huang Xian-Jian, Li Wei-Ping, Lin Yong, Feng Jun-Feng, Jia Feng, Mao Qing, Jiang Ji-Yao
1 Department of Neurosurgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai, China .
J Neurotrauma. 2014 Feb 15;31(4):346-57. doi: 10.1089/neu.2013.2899. Epub 2013 Dec 6.
Excessive active voltage-gated sodium channels are responsible for the cellular abnormalities associated with secondary brain injury following traumatic brain injury (TBI). We previously presented evidence that significant upregulation of Nav1.3 expression occurs in the rat cortex at 2 h and 12 h post-TBI and is correlated with TBI severity. In our current study, we tested the hypothesis that blocking upregulation of Nav1.3 expression in vivo in the acute stage post-TBI attenuates the secondary brain injury associated with TBI. We administered either antisense oligodeoxynucleotides (ODN) targeting Nav1.3 or artificial cerebrospinal fluid (aCSF) at 2 h, 4 h, 6 h, and 8 h following TBI. Control sham animals received aCSF administration at the same time points. At 12 h post-TBI, Nav1.3 messenger ribonucleic acid (mRNA) levels in bilateral hippocampi of the aCSF group were significantly elevated, compared with the sham and ODN groups (p<0.01). However, the Nav1.3 mRNA levels in the uninjured contralateral hippocampus of the ODN group were significantly lowered, compared with the sham group (p<0.01). Treatment with antisense ODN significantly decreased the number of degenerating neurons in the ipsilateral hippocampal CA3 and hilar region (p<0.01). A set of left-to-right ratio value analyzed by magnetic resonance imaging T2 image on one day, three days, and seven days post-TBI showed marked edema in the ipsilateral hemisphere of the aCSF group, compared with that of the ODN group (p<0.05). The Morris water maze memory retention test showed that both the aCSF and ODN groups took longer to find a hidden platform, compared with the sham group (p<0.01). However, latency in the aCSF group was significantly higher than in the ODN group (p<0.05). Our in vivo Nav1.3 inhibition studies suggest that therapeutic strategies to block upregulation of Nav1.3 expression in the brain may improve outcomes following TBI.
过度活跃的电压门控钠通道是创伤性脑损伤（TBI）后继发性脑损伤相关细胞异常的原因。我们之前提供的证据表明，在TBI后2小时和12小时，大鼠皮质中Nav1.3表达显著上调，且与TBI严重程度相关。在我们当前的研究中，我们测试了这样一个假设：在TBI急性期体内阻断Nav1.3表达的上调可减轻与TBI相关的继发性脑损伤。我们在TBI后2小时、4小时、6小时和8小时给予靶向Nav1.3的反义寡脱氧核苷酸（ODN）或人工脑脊液（aCSF）。对照假手术动物在相同时间点接受aCSF给药。TBI后12小时，与假手术组和ODN组相比，aCSF组双侧海马中Nav1.3信使核糖核酸（mRNA）水平显著升高（p<0.01）。然而，与假手术组相比，ODN组未受伤的对侧海马中Nav1.3 mRNA水平显著降低（p<0.01）。反义ODN治疗显著减少了同侧海马CA3和门区变性神经元的数量（p<0.01）。通过磁共振成像T2图像在TBI后一天、三天和七天分析的一组左右比值显示，与ODN组相比，aCSF组同侧半球有明显水肿（p<0.05）。莫里斯水迷宫记忆保持测试表明，与假手术组相比，aCSF组和ODN组找到隐藏平台的时间都更长（p<0.01）。然而，aCSF组的潜伏期显著高于ODN组（p<0.05）。我们的体内Nav1.3抑制研究表明，阻断大脑中Nav1.3表达上调的治疗策略可能改善TBI后的预后。
