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摘要：
目的 评价κ‑阿片受体激动剂（kappa‑opioid receptor agonists, KORs）对CPB老年大鼠围手术期神经认知障碍（perioperative neurocognitive disorders, PND）的影响。 方法 清洁级老年SD大鼠60只，体重400~500 g，按随机数字表法分为5组（每组12只）：假手术组（S组）、CPB组（C组）、KORs+CPB组（U组）、KORs+CPB+κ‑阿片受体拮抗剂（Nor‑BNI）组（N组）、KORs+CPB+血红素加氧酶（heme oxygenase‑1, HO‑1）拮抗剂（ZnPP‑IX）组（Z组）。各组大鼠于CPB后1 d行水迷宫测试（记录潜伏期、穿越平台次数和目标象限游行距离）后，放血处死大鼠取海马，置于福尔马林和−80 ℃冰箱中待测。H‑E染色观察海马形态学变化，ELISA检测海马超氧化物歧化酶（superoxide dismutase, SOD）、丙二醛（methylene dioxyamphetamine, MDA）、髓过氧化物酶（myeloperoxidase, MPO）等指标浓度，Western blot检测海马组织中HO‑1蛋白水平。 结果 与S组比较，其他4组潜伏期延长，穿越平台次数和目标象限游行距离减少（P<0.05）；与C组比较，U组潜伏期缩短，穿越平台次数和目标象限游行距离增加（P<0.05）；N组、Z组潜伏期、穿越平台次数及目标象限游行距离与C组比较差异无统计学意义（P>0.05）。H‑E染色显示：S组海马细胞结构整齐，界限清楚；C组、N组、Z组海马细胞受损严重，细胞分布稀疏，胞内见不均匀空泡；U组上述损伤有所减轻，细胞排列整齐。与S组比较，其他4组海马组织中MPO、MDA浓度升高，SOD浓度降低（P<0.05）；与C组比较，U组海马组织中MPO、MDA浓度降低，SOD浓度升高（P<0.05）；N组、Z组MPO、MDA及SOD浓度与C组比较差异无统计学意义（P>0.05）。与S组比较，其他4组海马组织中HO‑1蛋白水平升高（P<0.05）；与C组比较，U组海马组织中HO‑1蛋白水平升高（P<0.05），Z组HO‑1蛋白水平降低（P<0.05）；N组海马组织中HO‑1蛋白水平与C组比较差异无统计学意义（P>0.05）。 结论 KORs可增加HO‑1蛋白的表达，抑制氧化应激，改善CPB老年大鼠认知功能。
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Abstract: Objective To observe the influence of kappa‑opioid receptor agonists (KORs) to perioperative neurocognitive disorders (PND) after cardiopulmonary bypass (CPB). Methods A total of 60 old male Sprague‑Dawley rats, weighing 400−500 g. According to the random number table method, the rats were divided into 5 groups (n=12): Sham operation group (group S), CPB group (group C), KORs+CPB group (group U), KORs+CPB+κ‑opioid receptor antagonist (Nor‑BNI) group (group N), KORs+CPB+heme oxygenase (heme oxygenase‑1, HO‑1) antagonist ZnPP IX group (group Z). Brain samples were collected after collection of water maze test （record the latency, the times of crossing the platform and the target quardrant marching distance） at 1 d after CPB. The hippocampus tissues were fixed in formalin and stored in refrigerator (−80 ℃) . Hippocampal neurons morphological changes were quantitatively examined with hematoxylin eosin (H‑E) method. Enzyme‑linked immunosorbent assay (ELISA) was used to detect the levels of superoxide dismutase (SOD), methylene dioxyamphetamine (MDA) and myeloperoxidase (MPO) in hippocampus tissues. The expression of HO‑1 protein in hippocampus was detected by Western blot. Results Compared with group S, the latency of the other 4 groups were significantly prolonged, the times of crossing the platform and the target quadrant marching distance were significantly decreased (P<0.05). Compared with group C, the latency was significantly shortened, the times of crossing the platform and the target quadrant marching distance were significantly increased in group U (P<0.05), there was no significant difference among group N, group Z and group C (P>0.05). H‑E staining showed that the nerve cells of the group S is neat, clear boundaries. In group C, group N and group Z, hippocampus was impaired, the distribution of cells was sparse. Moreover, some nonuniform vacuole were observed in cells. In group U, the injury was reduced and the cell arrangement was more ordered than cells in rats of group C. Compared with group S, the concentration of MPO, MDA in the other 4 groups in the hippocampus were significantly increased, the concentration of SOD was significantly decreased (P<0.05). Compared with the group C, the concentration of MPO, MDA was significantly reduced and the concentration of SOD was significantly increased in the rats of group U (P<0.05). There was no significant difference among group N, group Z and group C (P>0.05). Compared with group S, the expression of the hippocampal HO‑1 protein in the rats of other four groups increased (P<0.05). Compared with group C, the expression of hippocampal HO‑1 protein in group U increased (P<0.05) whereas the expression of HO‑1 protein in group Z was decreased (P<0.05). There was no significant difference between group N and group C (P>0.05). Conclusions KORs can increase the expression of HO‑1 protein, inhibit oxidative stress, and improve the cognitive function of CPB elderly rats.
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