Si Yanna, Zhang Yuan, Han Liu, Chen Lihai, Xu Yajie, Sun Fan, Ji Muhuo, Yang Jianjun, Bao Hongguang
Department of Anesthesiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.
Department of Anesthesiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, China; Jiangsu Province Key Laboratory of Anesthesiology, College of Anesthesiology, Xuzhou Medical College, Xuzhou, Jiangsu, China.
PLoS One. 2016 Oct 21;11(10):e0164763. doi: 10.1371/journal.pone.0164763. eCollection 2016.
Previous studies showed that isoflurane-induced cognitive deficits could be alleviated by dexmedetomidine in young animal subjects. In the current study, we examine whether dexmedetomidine could also alleviate isoflurane-induced cognitive deficits in senile animals.
Senile male C57BL/6 mice (20 months) received dexmedetomidine (50 μg/kg, i.p.) or vehicle 30 minutes prior to isoflurane exposure (1.3% for 4 h). Cognitive function was assessed 19 days later using a 5-day testing regimen with Morris water maze. Some subjects also received pretreatment with α2 adrenoreceptor antagonist atipamezole (250 μg/kg, i.p.), JAK2 inhibitor AG490 (15 mg/kg i.p.) or STAT3 inhibitor WP1066 (40 mg/kg i.p.) 30 minutes prior to dexmedetomidine.
Isoflurane exposure increased and reduced the time spent in the quadrant containing the target platform in training sessions. The number of crossings over the original target quadrant was also decreased. Dexmedotomidine attenuated such effects. Effects of dexmedotomidine were reduced by pretreatment with atipamezole, AG490 and WP1066. Increased phosphorylation of JAK2 and STAT3 in the hippocampus induced by isoflurane was augmented by dexmedetomidine. Effects of dexmedetomidine on JAK2/STAT3 phosphorylation were attenuated by atipamezole, AG490 and WP1066. Isoflurane promoted neuronal apoptosis and increased the expression of cleaved caspase-3 and BAD, and reduced Bcl-2 expression. Attenuation of such effects by dexmedotomidine was partially blocked by atipamezole, AG490 and WP1066.
Dexmedetomidine could protect against isoflurane-induced spatial learning and memory impairment in senile mice by stimulating the JAK2/STAT3 signaling pathway. Such findings encourage the use of dexmedetomidine in geriatric patients receiving isoflurane anesthesia.
先前的研究表明，右美托咪定可减轻幼龄动物异氟烷诱导的认知缺陷。在本研究中，我们探究右美托咪定是否也能减轻老年动物异氟烷诱导的认知缺陷。
老年雄性C57BL/6小鼠（20个月）在异氟烷暴露（1.3%，持续4小时）前30分钟接受右美托咪定（50μg/kg，腹腔注射）或溶剂。19天后使用莫里斯水迷宫的5天测试方案评估认知功能。一些实验对象在右美托咪定前30分钟还接受了α2肾上腺素能受体拮抗剂阿替美唑（250μg/kg，腹腔注射）、JAK2抑制剂AG490（15mg/kg腹腔注射）或STAT3抑制剂WP1066（40mg/kg腹腔注射）预处理。
异氟烷暴露增加并减少了训练过程中在包含目标平台象限所花费的时间。原目标象限的穿越次数也减少。右美托咪定减轻了这些影响。阿替美唑、AG490和WP1066预处理减弱了右美托咪定的作用。异氟烷诱导的海马中JAK2和STAT3磷酸化增加被右美托咪定增强。右美托咪定对JAK2/STAT3磷酸化的作用被阿替美唑、AG490和WP1066减弱。异氟烷促进神经元凋亡并增加裂解的caspase-3和BAD的表达，降低Bcl-2表达。右美托咪定对这些影响的减轻被阿替美唑、AG490和WP1066部分阻断。
右美托咪定可通过刺激JAK2/STAT3信号通路预防老年小鼠异氟烷诱导的空间学习和记忆损伤。这些发现鼓励在接受异氟烷麻醉的老年患者中使用右美托咪定。
