Ikeno Yuki, Ghincea Christian V, Roda Gavriel F, Cheng Linling, Meng Xianzhong, Weyant Michael J, Cleveland Joseph C, Fullerton David A, Aftab Muhammad, Reece T Brett
Division of Cardiothoracic Surgery, Department of Surgery, University of Colorado, Aurora, Colorado.
Division of Cardiothoracic Surgery, Department of Surgery, University of Colorado, Aurora, Colorado.
Ann Thorac Surg. 2021 Jul;112(1):38-44. doi: 10.1016/j.athoracsur.2020.08.038. Epub 2020 Oct 22.
Spinal cord injury remains a devastating complication of thoracoabdominal aortic surgery. We previously demonstrated that pretreatment with nicorandil preserved motor function in a murine spinal cord injury model through mitochondrial adenosine triphosphate-sensitive potassium channel activation. We hypothesized that the neuroprotective effect of nicorandil is mediated by downstream generation of reactive oxygen species.
Spinal cord injury was induced by 7 minutes of thoracic aortic cross-clamping in adult male C57BL/6 mice. Five groups were evaluated: ischemic control (n = 19); nicorandil 1.0 mg/kg (n = 17); nicorandil 1.0 mg/kg plus N acetyl L-cysteine (NAC [reactive oxygen species scavenger, n = 18)]) 150 mg/kg; NAC 150 mg/kg (n = 13); and sham (n = 10). Limb motor function and the number of viable neurons within the anterior horn of the spinal cord were evaluated.
Mice in the sham group showed no functional deficits after surgery. Compared with ischemic control, motor function was significantly preserved in the nicorandil pretreatment group at every timepoint after ischemia. In the nicorandil plus NAC group, the motor-preserving effect of nicorandil was completely abolished (P < .001). Viable neuron quantification showed significant neuron preservation in the nicorandil group (29.± 2.6) compared with the ischemic control group (18.5 ± 2.1, P = .024) and nicorandil plus NAC group (14 ± 8.3, P = .001); no significant difference was observed between the ischemic control group and nicorandil plus NAC group (P = 0.768).
Reactive oxygen species generation plays a key role in the nicorandil-induced metabolic tolerance to spinal cord injury. Manipulation of mitochondrial adenosine triphosphate-sensitive potassium channels may lead to improvement in preventing spinal cord injury after thoracoabdominal aortic interventions.
脊髓损伤仍然是胸腹主动脉手术的一种毁灭性并发症。我们之前证明，在小鼠脊髓损伤模型中，尼可地尔预处理通过线粒体三磷酸腺苷敏感性钾通道激活来保留运动功能。我们假设尼可地尔的神经保护作用是由活性氧的下游生成介导的。
在成年雄性C57BL/6小鼠中，通过7分钟的胸主动脉交叉钳夹诱导脊髓损伤。评估五组：缺血对照组（n = 19）；尼可地尔1.0 mg/kg组（n = 17）；尼可地尔1.0 mg/kg加N-乙酰半胱氨酸（NAC[活性氧清除剂，n = 18]）150 mg/kg组；NAC 150 mg/kg组（n = 13）；假手术组（n = 10）。评估肢体运动功能和脊髓前角内的存活神经元数量。
假手术组小鼠术后无功能缺陷。与缺血对照组相比，尼可地尔预处理组在缺血后的每个时间点运动功能均得到显著保留。在尼可地尔加NAC组中，尼可地尔的运动保留作用完全被消除（P <.001）。存活神经元定量显示，与缺血对照组（18.5±2.1，P =.024）和尼可地尔加NAC组（14±8.3，P =.001）相比，尼可地尔组（29.±2.6）有显著的神经元保留；缺血对照组和尼可地尔加NAC组之间未观察到显著差异（P = 0.768）。
活性氧生成在尼可地尔诱导的脊髓损伤代谢耐受性中起关键作用。线粒体三磷酸腺苷敏感性钾通道的调控可能有助于改善胸腹主动脉干预后预防脊髓损伤的效果。
