Abstract: ［Abstract］ Objective To investigate the effects of LY354740 pretreatment on the learning and memory impairment induced by chronic ketamine exposure in juvenile mice. Methods Forty?eight healthy male C57BL/6 mice（weighed 22?32 g）were randomized into three groups：normal saline group （group NS）, ketamine group（group Ket）, LY354740 pretreatment group（group LY）. In group Ket and group LY, ketamine（per 30 mg/kg）was injected intraperitoneally three times a day at 30?minute intervals for 5 consecutive days, while in Group LY, LY354740 was injected intraperitoneally（per 15 mg/kg）30 minutes before the first injection of ketamine every day. While in group NS inject same normal saline. Cognitive test including Morris water maze and Openfield test was carried out 24 hours after the last administration of ketamine. Mice in each group were sacrificed immediately after the test and hippocampi were harvested to determine the expression of inflammatory cytokines including IL?6, IL?1 and TNF?α using ELISA. Results Compared to group NS, the escape latency was prolonged；the time in the original platform and central area in Openfield were decreased, the frequency of crossing the original platform was decreased；the levels of hippocampal IL?1, IL?6, TNF?α were increased in group Ket（P<0.05）. While in group LY, there were no significant differences of above indexes（P>0.05）. Compared to group Ket, in group LY the escape latency was significantly shortened；the time in the original platform and central area in Openfield were prolonged；the frequency of crossing the original platform was increased；the levels of hippocampal IL?1, IL?6, TNF?α were decreased（P<0.05）. Conclusion Cognitive dysfunction induced by chronic ketamine exposure can be reversed by LY354740 pretreatment in juvenile mice, which may be associated with the down?regulation of the excessive release of hippocampal cytokines.

Key words: cognitive function, inflammatory cytokines, LY354740, immature mice, ketamine

摘要： ［摘要］目的 探讨LY354740预先给药减轻氯胺酮麻醉致幼鼠认知功能障碍及海马炎性反应的影响。方法 清洁级雄性C57BL/6小鼠48只，21日龄，重约22~32 g，按照随机数字表法分为3组（每组16只）；生理盐水组（NS组）、氯胺酮组（Ket组）、LY354740预给药组（LY组）。LY组于每天第1次注射氯胺酮前30 min腹腔注射LY35474015 mg/kg余同Ket组；Ket组和LY组每天腹腔注射氯胺酮30 mg/kg共3次、间隔30 min，连续5天；NS组每次注射等量生理盐水。生理盐水组（NS组）、氯胺酮组30 mg/kg（Ket组）、LY354740预处理组（LY组）。LY组于每天首次腹腔注射氯胺酮前30 min注入LY35474015 mg/kg，余同另两组。Ket组和LY组于每天同一时间点腹腔注射氯胺酮30 mg/kg、间隔30min注射一次，共3次，连续5d。所有小鼠均在末次给药结束后24 h进行认知功能测试（水迷宫和旷场实验），测试完毕后立即处死大鼠，取海马组织，以酶联免疫吸附（ELISA）法，测定海马IL?1、IL?6、TNF?α的含量。结果 与NS组比较，Ket组逃避潜伏期时间明显延长，平台象限停留时间和旷场中心区停留时间缩短，平台穿越次数减少；海马IL?1、IL?6、TNF?α含量升高（P<0.05），LY组上述指标差异无统计学意义（P>0.05）。与Ket组比较，LY组逃避潜伏期明显缩短，原平台停留时间和旷场中心区停留时间延长，穿越原平台次数增多；海马IL?1、IL?6、TNF?α含量降低（P<0.05）。结论 LY354740预先给药可改善氯胺酮麻醉所致幼鼠认知功能障碍，其机制可能与抑制海马炎性反应有关。

关键词: 幼鼠, 氯胺酮, LY354740, 认知功能, 促炎因子