Wu Y, Satkunendrarajah K, Fehlings M G
Toronto Western Research Institute and Krembil Neuroscience Centre, University Health Network, University of Toronto, Canada.
Toronto Western Research Institute and Krembil Neuroscience Centre, University Health Network, University of Toronto, Canada; Division of Neurosurgery, University Health Network, University of Toronto, Canada.
Neuroscience. 2014 Apr 18;265:302-12. doi: 10.1016/j.neuroscience.2014.01.059. Epub 2014 Feb 6.
The spinal cord is vulnerable to ischemic injury due to trauma, vascular malformations and correction of thoracic aortic lesions. Riluzole, a sodium channel blocker and anti-glutamate drug has been shown to be neuroprotective in a model of ischemic spinal cord injury, although the effects in clinically relevant ischemia/reperfusion models are unknown. Here, we examine the effect of riluzole following ischemia-reperfusion injury to the spinal cord. Female rats underwent high thoracic aortic balloon occlusion to produce an ischemia/reperfusion injury. Tolerance to ischemia was evaluated by varying the duration of occlusion. Riluzole (8mg/kg) was injected intraperitoneally 4h after injury. Locomotor function (Basso, Beattie and Bresnahan (BBB) scale) was assessed at 4h, 1day, and 5days post-ischemia. Spinal cords were extracted and evaluated for neuronal loss using immunohistology (choline acetyltransferase (ChAT) and neuronal nuclei (NeuN)), inflammation (CD11b), astrogliosis (glial fibrillary acidic protein - GFAP) and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). Ischemic injury lasting between 5.5 and 6.75min resulted in delayed paraplegia, whereas longer ischemia induced immediate paraplegia. When riluzole was administered to rats that underwent 6min of occlusion, delayed paraplegia was prevented. The BBB score of riluzole-treated rats was 11.14±4.85 compared with 1.86±1.07 in control animals. Riluzole also reduced neuronal loss, infiltration of microglia/macrophages and astrogliosis in the ventral horn and intermediate zone of the gray matter. In addition, riluzole reduced apoptosis of neurons in the dorsal horn of the gray matter. Riluzole has a neuroprotective effect in a rat model of spinal cord injury/reperfusion when administered up to 4h post-injury, a clinically relevant therapeutic time window.
脊髓易因外伤、血管畸形和胸主动脉病变的矫正而发生缺血性损伤。利鲁唑是一种钠通道阻滞剂和抗谷氨酸药物，在缺血性脊髓损伤模型中已显示具有神经保护作用，尽管其在临床相关的缺血/再灌注模型中的效果尚不清楚。在此，我们研究利鲁唑在脊髓缺血-再灌注损伤后的作用。雌性大鼠接受高位胸主动脉球囊闭塞以产生缺血/再灌注损伤。通过改变闭塞持续时间来评估对缺血的耐受性。损伤后4小时腹腔注射利鲁唑（8mg/kg）。在缺血后4小时、1天和5天评估运动功能（Basso、Beattie和Bresnahan（BBB）评分）。提取脊髓并使用免疫组织学（胆碱乙酰转移酶（ChAT）和神经元细胞核（NeuN））、炎症（CD11b）、星形胶质细胞增生（胶质纤维酸性蛋白 - GFAP）和末端脱氧核苷酸转移酶介导的dUTP缺口末端标记（TUNEL）评估神经元损失。持续5.5至6.75分钟的缺血性损伤导致延迟性截瘫，而更长时间的缺血则导致立即截瘫。当给接受6分钟闭塞的大鼠施用利鲁唑时，可预防延迟性截瘫。利鲁唑治疗的大鼠的BBB评分为11.14±4.85，而对照动物为1.86±1.07。利鲁唑还减少了灰质腹角和中间带的神经元损失、小胶质细胞/巨噬细胞浸润和星形胶质细胞增生。此外，利鲁唑减少了灰质背角神经元的凋亡。在损伤后长达4小时（一个临床相关的治疗时间窗）给予利鲁唑，其在大鼠脊髓损伤/再灌注模型中具有神经保护作用。
