Objective To investigate the effect of RO20-1724 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 RO20-1724 groups (group K + R1-4 ).The rats were anesthetized with intraperitoneal injection of kctamine 70 mg/kg in groups K,K+N,K+A and K+.R1-4.Normal saline 2 ml,anhydrous alcohol (in normal saline 2 ml),and RO20-1724 0.25,0.50,0.75 and 1.00 mg/kg (in anhydrous alcohol 8 μl and then in normal saline 2 ml) were injected intraperitoneally in groups K + N,K + A and K + R1-4 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.Ressults 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 pCREB in hippocampus and cerebral cortex down-regulated in groups K,K+ N,K+ E,K+ R1 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 + R4 ( 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 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+ P4(P ＜ 0.05).There were no significant differences in the escape 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 + R4 ( 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.%目的 探讨RO20-1724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45～55 g,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RO20-1724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70 mg/kg,30 min后K+N组、K+A组和K+R1～4组分别腹腔注射生理盐水2 ml、无水乙醇8 μl(生理盐水稀释到2 ml)和RO20-1724 0.25、0.50、0.75、1.00 mg/kg(先溶于8μl无水乙醇中,再用生理盐水稀释至2ml).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48 h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+R1组和K+R2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+R3组和K+R4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)；与K+R1组和K+R组比较,K+R3组和K+R4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+R2组间、K+R3组与K+R4组间上述各指标比较差异无统计学意义(P＞0.05).结论 RO20-1724 0.75 ～ 1.00 mg/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.
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