基于cAMP/CREB信号通路探究芬太尼联合右美托咪定对七氟醚诱导新生模型远期认知功能的作用机制  

Based on cAMP/CREB signaling pathway,the mechanism of fentanyl combined with dexmedetomidine on the long-term cognitive function of sevoflurane induced neonatal model was explored

作　　者：王景蕴 王洋 Wang Jingyun;Wang Yang(Department of Anesthesiology,the Fourth People's Hospital of Hengshui,Hebei 053000,China)

机构地区：[1]衡水市第四人民医院麻醉科,河北053000

出　　处：《脑与神经疾病杂志》2025年第4期199-205,共7页Journal of Brain and Nervous Diseases

基　　金：衡水市重点研发计划项目(2021014071Z);河北省重点研发计划项目(22004328816D)。

摘　　要：目的探究芬太尼联合右美托咪定(DEx)对七氟醚诱导新生大鼠远期认知功能的作用及机制。方法新生大鼠在出生后第7天(P7)暴露于七氟醚(0.75%,6 h)。大鼠分组:对照组、七氟醚组、芬太尼组、DEx组、芬太尼联合DEx组。用TUNEL法和氟玉B染色法检测七氟醚暴露后神经元凋亡。蛋白印迹法检测凋亡相关蛋白的表达。qRT-PCR分析脑源性神经营养因子(BDNF)和酪氨酸蛋白激酶B(TrkB)mRNA水平。ELISA检测cAMP活性。恐惧条件化测试评估学习能力。Morris水迷宫实验评估大鼠的学习和记忆能力。结果与对照组相比,七氟醚暴露后,B淋巴细胞瘤-2基因相关启动子(Bad)、裂解的半胱天冬蛋白酶-3(cleaved caspase-3)和BCL2相关X蛋白(Bax)水平增加,B淋巴细胞瘤-2基因(Bcl-2)和B淋巴细胞瘤-2基因相关启动子(Bcl-xL)水平明显降低。然而,单独芬太尼组、DEx组和芬太尼联合DEx组的Bad、cleaved caspase-3和Bax水平明显降低,Bcl-2和Bcl-xL水平明显升高。qRT-PCR和蛋白印迹分析显示,与对照组相比,七氟醚组BDNF和TrkB mRNA和蛋白水平显著降低,而单独芬太尼组、DEx组和芬太尼联合DEx组BDNF和TrkB mRNA和蛋白水平升高。此外,与七氟醚组相比,单独芬太尼组、DEx组和芬太尼联合DEx组cAMP水平和CREB和TrkB的磷酸化明显上调。芬太尼联合DEx改善大鼠一般行为,增强学习记忆能力。结论这些观察结果表明芬太尼联合DEx通过抑制七氟醚诱导的神经元凋亡和激活cAMP/CREB/BDNF/TrkB信号传导发挥神经保护作用。Objective To explore the effect and mechanism of fentanyl combined with dexmedetomidine(DEx)on sevoflurane-induced long-term cognitive function in neonatal rats.Methods Neonatal rats were exposed to isoflurane(0.75%,6 h)on postnatal day 7(P7).Rats were divided into control group,sevoflurane group,fentanyl group,DEx group,fentanyl combined with DEx group.Neuronal apoptosis after sevoflurane exposure was detected by TUNEL and fluorochrome B staining.The expression of apoptosis-related proteins was detected by Western blotting.The mRNA levels of brain-derived neurotrophic factor(BDNF)and tyrosine receptor Kinase B(TrkB)were analyzed by qRT-PCR.The activity of cAMP was detected by ELISA.Fear conditioning test was used to evaluate learning ability.Morris water maze test was used to evaluate the learning and memory ability of rats.Results Compared with the control group,the levels of Bcl2-associcated agonist of cell death(Bad),cleaved caspase-3 and BCL2-Associated X(Bax)increased,and the levels of B-cell lymphoma-2(Bcl-2)and B-cell lymphoma-extra large(Bcl-xL)decreased significantly after sevoflurane exposure.However,the levels of Bad,cleaved caspase-3 and Bax were significantly decreased,and the levels of Bcl-2 and Bcl-xL were significantly increased in the fentanyl group,DEx group and fentanyl combined with DEx group.Compared with the control group,the mRNA and protein levels of BDNF and TrkB were significantly decreased in the sevoflurane group,while the mRNA and protein levels of BDNF and TrkB were increased in the fentanyl group,DEx group and fentanyl combined with DEx group.In addition,compared with the sevoflurane group,the level of cAMP and the phosphorylation of CREB and TrkB were significantly up-regulated in the fentanyl group,the DEx group and the fentanyl combined with DEx group.Fentanyl combined with DEx improved the general behavior of rats and enhanced learning and memory ability.Conclusion These observations suggest that fentanyl combined with DEx exerts neuroprotective effects by inhibiting sevofluran

关 键 词：芬太尼 右美托咪定 cAMP/CREB信号通路 七氟醚 认知功能 

分 类 号：R741[医药卫生—神经病学与精神病学]