R020—1724对氯胺酮重复麻醉致未成年大鼠认知功能障碍的影响

Effects of RO20-1724 on repetitive ketamine administration-induced learning and memory impairment in immature rats

目的评价R020-1724对氯胺酮重复麻醉致未成年大鼠认知功能障碍的影响。方法健康SD大鼠48只，21日龄，雌雄不拘，体重45～55g，采用随机数字表法，将其分为4组（n=12）：对照组（c组）、氯胺酮组（K组）、氯胺酮＋R020—1724组（K＋R组）和氯胺酮＋无水乙醇组（K＋A组）。K组腹腔注射氯胺酮70mg／kg，1次／d，连续7d；K＋R组和K＋A组腹腔注射氯胺酮70mg／kg，30min后分别腹腔注射R020-17240．5mg／kg或等容量无水乙醇，1次，d，连续7d。C组腹腔注射等容量生理盐水，1次／d，连续7d。采用Morris水迷宫实验测定认知功能，记录逃避潜伏期和穿越原平台次数。Morris水迷宫实验结束当日，每组处死6只大鼠，取海马组织，电镜下观察超微结构。Morris水迷宫实验结束当日，每组处死6只大鼠，取海马组织，测定海马磷酸化环腺苷酸应答元件结合蛋白（p-CREB）表达。结果与C组比较，K组和K＋A组第3天和第4天时逃避潜伏期延长，穿越原平台次数减少，海马组织p-CREB表达下调（P〈0．05），K＋R组逃避潜伏期、穿越原平台次数和p-CREB表达差异无统计学意义（P〉0．05）；与K组比较，K＋R组第3天和第4天时逃避潜伏期缩短，穿越原平台次数增多，海马组织p-CREB表达上调（P〈0．05），病理学损伤减轻，K＋A组逃避潜伏期、穿越原平台次数和p-CREB表达差异无统计学意义（P〉0．05）。结论R020-1724可改善氯胺酮重复麻醉致未成年大鼠认知功能障碍，其机制与上调海马p-CREB的表达。

Objective To investigate the effects of R020-1724 on repetitive ketamine administration-in- duced learning and memory impairment in immature rats. Methods Forty-eight 21-day-old SD rats of both sexes weighing 45-55 g were randomly divided into 4 groups （ n = 12 each） ： control group（group C） ; ketamine group （group K）; ketamine ＋ R020-1724 group （group K ＋ R） and ketamine ＋ vehicle （ethanol） group （group K ＋ A）. Ketamine 70 mg/kg was injected intraperitoneally （IP） once a day for 7 consecutive days in groups K, K ＋ R and K ＋ A. R020-1724 0.5 mg/kg and equal volume of ethanol were injected IP at 30 min after IP ketamine once a day for 7 consecutive day in groups K ＋ R and K ＋ A respectively. Morris water maze test was used to assess learning and memory ability. The escape latency and the number of times of passing the safe zone were recorded. The animals were killed after water maze test and their brains removed for microscopic examination of hippoeampus and determination of p-CREB protein expression in hippocampus （by Western blot）. Results Repetitive ketamine administration significantly prolonged the escape latency, decreased the number of times of passing the safe zone and down-regulated the expression of p-CREB protein in hippocampus on the 3rd and 4th day in group K as compared with group C. RO20-1724 significantly attenuated the above changes induced by repetitive ketamine administration in group K ＋ R as compared with group K. Electron microscopic examination showed that RO20-1724 signif- icantly ameliorated repetitive ketamine administration-induced hippocampal neuronal damage. Conclusion RO20- 1724 can ameliorate cognitive dysfunction induced by repetitive ketamine administration. Up-regulation of cAMP / CREB signaling pathway is involved in the mechanism.