右美托咪定经RasGRF1-NR2B-ERK通路减轻发育期大鼠七氟醚神经损伤的研究
收稿日期: 2025-06-09
修回日期: 2025-10-14
录用日期: 2025-12-24
网络出版日期: 2026-01-26
基金资助
2021年度山东省自然科学基金项目（ZR2021MH016）
Study on the Alleviation of Sevoflurane Induced Nerve Injury in Developing Rats by Dexmedetomidine through the RasGRF1-NR2B-ERK Pathway
1.Department of Anesthesiology， Affiliated Hospital of
Shandong Second Medical University， Shandong Weifang 261053， China；
2.School of Anesthesiology， Shandong Second Medical
University， Shandong Weifang 261053， China；
Received date: 2025-06-09
Revised date: 2025-10-14
Accepted date: 2025-12-24
Online published: 2026-01-26
目的：探讨右美托咪定（DEX）经Ras鸟嘌呤释放因子1（RasGRF1）-N-甲基-D-天冬氨酸受体2B亚基（NR2B）-ERK信号通路减轻七氟醚致发育期神经损伤的作用机制。方法：将出生7 d雄性SD大鼠20只随机分为CTL组与SEV组各10只，对比其Morris水迷宫实验结果及海马区脑组织NR2B、ERK蛋白表达。构建AAV-RasGRF1与AAV-RasGRF1 shRNAi。另选择30只大鼠随机分为Control组、Sevo组、Sevo+NS组、Sevo+DEX25组、Sevo+DEX50组、Sevo+DEX75组（n=5），除Control组外均经脑立体定位注射AAV-RasGRF1与AAV-RasGRF1 shRNAi至大鼠双侧海马，2周后暴露于2%七氟醚，连续3 d，暴露前30 min腹腔注射DEX或氯化钠溶液，检测NR2B、ERK、磷酸化ERK（pERK）蛋白表达及ERK/pERK、神经细胞凋亡率。结果：SD大鼠暴露在七氟醚中6 h时海马区脑组织NR2B受体表达数量达峰值（P<0.05）。SEV组在平台所在象限游泳时间短于CTL组（P<0.05）；第4天 SEV组大鼠定位航行潜伏期长于CTL组（P<0.05）；第5天，SEV组定位航行潜伏期较CTL组延长，而原象限停留时间短于CTL组，神经功能评分高于CTL组（P<0.05）。第4天Sevo+DEX75组定位航行潜伏期最短（P<0.05）；第5天各七氟醚处理组中Sevo+DEX75定位航行潜伏期最短，原象限停留时间最长，神经功能评分最低（P<0.05）；Sevo+DEX75组神经细胞凋亡率、NR2B水平最低，Sevo+DEX75组p-ERK/ERK水平最高（P<0.05）。结论：DEX可能通过作用于RasGRF1-NR2B-ERK信号通路而对七氟醚所致发育期神经损伤起保护作用。
马慧洁
,
孙银贵
.
右美托咪定经RasGRF1-NR2B-ERK通路减轻发育期大鼠七氟醚神经损伤的研究
Objective： To explore the mechanism by which dexmedetomidine （DEX） alleviates sevoflurane induced nerve injury during the developmental period through the Ras guanine nucleotide releasing factor 1 （RasGRF1）-N-methyl-D-aspartate receptor 2B subunit （NR2B） -ERK signaling pathway.Methods： Twenty 7-day-old male SD rats were randomly divided into the CTL group and the SEV group， with 10 rats in each group. The results of the Morris water maze test and the protein expressions of NR2B and ERK in the brain tissue of the hippocampus were compared. The AAV-RasGRF1 and AAV-RasGRF1 shRNAi were constructed. Another 30 rats were randomly divided into the Control group， Sevo group， Sevo+NS group， Sevo+DEX25 group， Sevo+DEX50 group， and Sevo+DEX75 group （n=5）. Except for the Control group， AAV-RasGRF1 and AAV-RasGRF1 shRNAi were injected into the bilateral hippocampus of rats by stereotactic brain injection. After 2 weeks， 2% sevoflurane was exposed for 3 consecutive days. DEX or sodium chloride solution was intraperitoneally injected 30 minutes before exposure. Detect the protein expressions of NR2B， ERK and phosphorylated ERK （pERK）， as well as the rates of ERK/pERK and apoptosis of nerve cells.Results： When SD rats were exposed to sevoflurane for 6 hours， the expression quantity of NR2B receptors in the brain tissue of the hippocampus reached the peak （P<0.05）. The swimming time of the SEV group in the quadrant where the platform is located was shorter than that of the CTL group （P<0.05）. On the 4th day， the localization navigation latency of rats in the SEV group was longer than that in the CTL group （P<0.05）. On the 5th day， the localization latency in the SEV group was longer than that in the CTL group， while the residence time in the original quadrant was shorter than that in the CTL group， and the neurological function score was higher than that in the CTL group （P<0.05）. On the 4th day， the localization latency was the shortest in the Sevo+DEX75 group （P<0.05）. On the 5th day， among the sevoflurane treatment groups， the Sevo+DEX75 group had the shortest localization latency， the longest stay time in the original quadrant， and the lowest neurological function score （P<0.05）. The apoptosis rate of nerve cells and NR2B level in the Sevo+DEX75 group were the lowest， and the p-ERK/ERK was the highest in the Sevo+DEX75 group （P<0.05）.Conclusion： DEX may play a protective role against sevoflurane induced nerve injury during developmental period by acting on the RasGRF1-NR2B-ERK signaling pathway.
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