R020—1724对氯胺酮麻醉后未成年大鼠认知功能的影响

Effects of RO20-1724 on cognitive function in immature rats after ketamine anesthesia

目的探讨R020—1724对氯胺酮麻醉后未成年大鼠认知功能的影响。方法SD大鼠96只，雌雄各半，21日龄，体重45—55g，采用随机数字表法，将大鼠随机分为8组（n=12）：对照组（C组）、氯胺酮组（K组）、氯胺酮＋生理盐水组（K＋N组）、氯胺酮＋无水乙醇组（K＋A组）、氯胺酮＋不同剂量R020．1724组（K＋R1-4组）。K组、K＋N组、K＋A组和K＋R1-4组腹腔注射氯胺酮70mg／kg，30min后K＋N组、K＋A组和K＋R。组分别腹腔注射生理盐水2ml、无水乙醇8出（生理盐水稀释到2m1）和R020—17240．25、0．50、0．75、1．00mg／kg（先溶于8μl无水乙醇中，再用生理盐水稀释至2mi）。给药结束后24h时，每组取6只大鼠，进行Morris水迷宫实验测试认知功能。给药结束后48h时，每组处死6只大鼠，采用Western blot法检测海马和大脑皮层环磷酸腺苷反应元件结合蛋白（CREB）和磷酸化CREB（p-CREB）的表达。结果与c组比较，K组、K＋N组、K＋A组、K＋R，组和K＋R1组给药后2～4d时逃避潜伏期延长，穿越平台次数减少，海马和皮层CREB和p-CREB表达下调（P〈0．05）；与K组比较，K＋地组和K＋凡组给药后2～4d时逃避潜伏期缩短，穿越平台次数增多，海马和皮层CREB和p-CREB表达上调（P〈O．05）；与K＋R，组和K＋R1组比较，K＋凡组和K＋心组给药后2—4d时逃避潜伏期缩短，穿越平台次数增多，海马和皮层CREB和p-CREB表达上调（P〈0．05）；K＋R1组与K＋R组间、K＋比组与K＋凡组间上述各指标比较差异无统计学意义（P〉0．05）。结论R020—17240．75～1．00mg／kg可通过上调海马和大脑皮层CREB和p-CREB的表达，改善氯胺酮致未成年大鼠认知功能障碍。

Objective To investigate the effect of R020-1724 on the cognitive function in immature rats after ketamine anesthesia. Methods Ninety-six SD rats of both sexes, aged 21 days, weighing 45-55 kg, were randomly divided into 8 groups （n = 12 each） ： control group （group C） ; ketamine group （group K） ; ketamine ＋ normal saline group （group K ＋ N） ; ketamine ＋ anhydrous alcohol group （group K ＋ A） ; ketamine ＋ 4 different doses of R020-1724 groups （group K ＋ R1-） .The rats were anesthetized with intraperitoneal injection of ketamine 70 mg/kg in groups K, K＋ N, K＋ A and K＋ R1-. Normal saline 2 ml, anhydrous alcohol （in normal saline 2 ml）, and R020-1724 0.25, 0.50, 0.75 and 1.00 mg/kg （in anhydrous alcohol 8/LI and then in normal saline 2 ml） were injected intraperitoneally in groups K ＋ N, K ＋ A and K ＋ RI-4 respectively 30 min later. Six rats from each group were randomly selected at 24 h after administration and Morris water maze was used to test the ability of learning and memory. Six rats from each group were sacrificed at 48 h after administration and hippocampus and cerebral cortex were removed for determination of the expression of CREB and phospho-CREB （p-CREB） by Western blot. Results Compared with group C, the escape latency was significantly prolonged at 2-4 days after administration, the number of animals＇ swimming across the platform decreased, and the expression of CREB and p CREB in hippocampus and cerebral cortex down-regulated in groups K, K＋ N, K＋ E, K＋ RI and K＋ R2（P 〈 0.05）. Compared with group K, the escape latency was significantly shortened at 2-4 days after administration, the number of animals＇ swimming across the platform increased, and the expression of CREB and p-CREB in hippocampus and cerebral cortex up-regulated in groups K ＋ R3 and K ＋ tL （ P 〈 0.05）. Compared with groups K ＋ R1 and K ＋ R2, the escape latency was significantly shortened at 2-4 days after administration, the number of ani- mals＇ swimming across the platform increased, and the expression of CREB and p-CREB in hippocampus and cere- bral cortex up-regulated in groups K ＋ R3 and K ＋ IL （P 〈 0.05）. There were no significant differences in the es- cape latency, the number of animals＇ swimming across the platform, and the expression of CREB and p-CREB in hippocampus and cerebral cortex between groups K ＋ R1 and K ＋ R2, and between groups K ＋ R3 and K ＋ IL （ P 〉 0.05 ）. Conclusion RO20-1724 0.75-1.00 mg/kg can improve ketamine-induced cognitive dysfunction by up-regulating CREB and p-CREB expression in hippocampus and cerebral cortex in immature rats.