From the Department of Anesthesia and Intensive Care Medicine, Akita University Graduate School of Medicine, Akita, Akita, Japan.
Division of Dentistry and Oral Surgery, Akita University Hospital, Akita, Akita, Japan.
Anesth Analg. 2018 Mar;126(3):815-823. doi: 10.1213/ANE.0000000000002602.
Excessive Rho/Rho-kinase pathway activation occurs subsequent to stroke. We examined the neuroprotective effects of pre- and posttreatment with fasudil (a Rho-kinase inhibitor) in a rat transient spinal cord ischemia-reperfusion model under normothermic conditions.
After approval by our animal research committee, male Sprague-Dawley rats were assigned to 1 of 6 groups: pre- and postcontrol (C); pre- and postfasudil (F); and pre- and postsham (S). Fasudil (10 mg/kg) or normal saline was administered intravenously over 30 minutes before ischemia in the pre-F or pre-C groups, and over 30 minutes after reperfusion in the post-F or post-C groups. Sham groups were not subjected to ischemia. Ischemia was induced by aortic occlusion using a balloon catheter combined with hypotension for 10 minutes. Neurologic deficit scores (NDS; 0-8 points) were assessed 1, 7, and 14 days after ischemia, and then histopathologic outcomes were assessed.
NDS 7 and 14 days after ischemia in the pre-F group (median [range]; 3.5 [2-6] and 2.5 [0-6]) were lower than those in the pre-C group (5.5 [4-7] and 4.5 [4-6]; P = .046 and P = .049), whereas NDS in the post-F group and in the post-C group were not different. The numbers of intact neurons in the gray matter in the pre- and post-F groups (mean ± standard deviation [95% confidence interval]: 25 ± 7 [20-30] and 16 ± 5 [12-19]) were greater than those in the pre- and post-C groups (11 ± 5 [7-14] and 9 ± 3 [7-11]; P < .001 and P = .002). The number of intact neurons in the post-F group (16 ± 5 [12-19]) was lower than the number in the post-S group (26 ± 2 [24-29]; P < .001). The percentages of vacuolation in the white matter in the pre- and post-F groups (21.5 ± 8.4 [15.5-27.5] and 13.6 ± 7.4 [8.3-18.9]) were lower than those in the pre- and post-C groups (43.7 ± 10.4 [36.3-51.1] and 40.6 ± 12.3 [31.8-49.4]; P < .001 and P < .001).
Our results demonstrated that intravenous fasudil administered before ischemia improved both neurologic and histopathologic outcomes even 14 days after ischemia, while fasudil administered postinsult improved histopathologic outcomes only in normothermic rats. Fasudil may be a relevant pretreatment paradigm for planned procedures at risk for spinal cord ischemia.
过度的 Rho/Rho-激酶途径激活发生在中风之后。我们在常温脊髓缺血再灌注模型中研究了 fasudil（Rho-激酶抑制剂）预处理和后处理对大鼠的神经保护作用。
在获得我们的动物研究委员会批准后，雄性 Sprague-Dawley 大鼠被分配到 6 个组中的 1 个：预处理和对照组（C）；预处理和 fasudil 组（F）；预处理和假手术组（S）。在预-F 或预-C 组中，在缺血前 30 分钟内静脉给予 fasudil（10mg/kg）或生理盐水，在 post-F 或 post-C 组中，在再灌注后 30 分钟内给予 fasudil 或生理盐水。假手术组不进行缺血。通过球囊导管联合低血压诱导缺血 10 分钟。缺血后 1、7 和 14 天评估神经功能缺损评分（NDS；0-8 分），然后评估组织病理学结果。
缺血后 7 天和 14 天，预-F 组的 NDS（中位数[范围]；3.5[2-6]和 2.5[0-6]）低于预-C 组（5.5[4-7]和 4.5[4-6]；P=0.046 和 P=0.049），而 post-F 组和 post-C 组的 NDS 无差异。预-F 组和 post-F 组的灰质中完整神经元数量（平均值±标准差[95%置信区间]：25±7[20-30]和 16±5[12-19]）大于预-C 组和 post-C 组（11±5[7-14]和 9±3[7-11]；P<0.001 和 P=0.002）。Post-F 组（16±5[12-19]）的完整神经元数量低于 post-S 组（26±2[24-29]；P<0.001）。预-F 组和 post-F 组的白质空泡化百分比（21.5±8.4[15.5-27.5]和 13.6±7.4[8.3-18.9]）低于预-C 组和 post-C 组（43.7±10.4[36.3-51.1]和 40.6±12.3[31.8-49.4]；P<0.001 和 P<0.001）。
我们的结果表明，缺血前静脉给予 fasudil 可改善神经功能和组织病理学结果，即使在缺血后 14 天也是如此，而缺血后给予 fasudil 仅改善常温大鼠的组织病理学结果。Fasudil 可能是计划进行脊髓缺血风险手术的相关预处理方案。
