右美托咪定对阻塞性睡眠呼吸暂停综合征大鼠海马神经元凋亡的影响及其机制研究

Effect of dexmedetomidine on apoptosis of hippocampal neurons in rats with obstructive sleep apnea syndrome and its mechanism

摘要:

目的 探究右美托咪定（Dex）对阻塞性睡眠呼吸暂停综合征（OSAS）大鼠海马神经元凋亡的影响，并分析其作用机制。方法 45只SD雄鼠随机选取10只作为对照组，其余大鼠复制OSAS模型，5只大鼠窒息死亡，剩余30只大鼠成功复制OSAS模型并随机分为OSAS组及Dex高、低剂量组，每组10只。Dex高、低剂量组分别腹腔注射Dex 2.5、0.5 μg/（kg·d），对照组与OSAS组给予等剂量的生理盐水。连续干预4周后，采用神经监测仪监测大鼠呼吸暂停情况、平均及最低血氧饱和度，苏木精-伊红染色观察海马组织CA1区病理学改变，流式细胞术检测大鼠海马组织神经元凋亡，Western blotting检测核因子E2相关因子2（Nrf2）/血红素氧合酶1（HO-1）通路相关蛋白的表达。结果 与对照组比较，OSAS组呼吸暂停次数增多（P <0.05），平均及最低血氧饱和度降低（P <0.05），细胞凋亡率升高（P <0.05），Nrf2、缺氧诱导因子1α（HIF-1α）及HO-1蛋白相对表达量升高（P <0.05）；与OSAS组比较，Dex高、低剂量组呼吸暂停次数减少（P <0.05），平均及最低血氧饱和度升高（P <0.05），细胞凋亡率降低（P <0.05），Nrf2、HIF-1α及HO-1蛋白相对表达量降低（P <0.05）；与Dex低剂量组比较，Dex高剂量组呼吸暂停次数减少（P <0.05），平均及最低血氧饱和度升高（P <0.05），细胞凋亡率降低（P <0.05），Nrf2、HIF-1α及HO-1蛋白相对表达量降低（P <0.05）。结论 Dex能够改善OSAS大鼠呼吸暂停及血氧饱和度，抑制海马神经元凋亡，其机制可能与Nrf2/HO-1通路有关。

Abstract:

Objective To investigate the effect of dexmedetomidine (Dex) on the apoptosis of hippocampal neurons in rats with obstructive sleep apnea syndrome (OSAS), and to analyze its mechanism.Methods Ten of 45 male SD rats were randomly selected as the control group, and the rest of the rats were used to establish the OSAS models. Five rats died of asphyxiation, and the remaining 30 rats were successfully established as OSAS models and were randomly divided into OSAS group, and high-dose and low-dose Dex groups, with 10 rats in each group. Rats in high-dose and low-dose Dex groups were intraperitoneally injected with Dex at a dose of 2.5 μg/(kg·d) and 0.5 μg/(kg·d), respectively, while those in the control group and OSAS group were given the same dose of normal saline. After 4 weeks of continuous intervention, the rats were monitored for apnea, and average and minimum blood oxygen saturation with a neuromonitor. HE staining was used to observe the pathological changes in the CA1 region of the hippocampus. Flow cytometry was used to detect the apoptosis of neurons in the hippocampus of the rats. Western blotting was used to detect the expressions of proteins associated with the nuclear factor erythroid 2-related factor 2 (Nrf2) / heme oxygenase-1 (HO-1) pathway.Results Compared with the control group, the number of apnea in the OSAS group increased (P < 0.05), the average and minimum blood oxygen saturation decreased (P < 0.05), the neuronal apoptosis rate increased (P < 0.05), and the protein expressions of Nrf2, hypoxia-inducible factor 1-alpha (HIF-1α) and HO-1 were up-regulated (P < 0.05). Compared with the OSAS group, the number of apnea decreased (P < 0.05), the average and minimum blood oxygen saturation increased (P < 0.05), the neuronal apoptosis rate decreased (P < 0.05), and the protein expressions of Nrf2, HIF-1α and HO-1 were down-regulated in the high-dose and low-dose Dex groups (P < 0.05). Compared with the low-dose Dex group, the number of apnea decreased (P < 0.05), the average and minimum blood oxygen saturation increased (P < 0.05), the neuronal apoptosis rate decreased (P < 0.05), and the protein expressions of Nrf2, HIF-1α and HO-1 were down-regulated in the high-dose Dex groups (P < 0.05).Conclusions Dex can improve apnea and blood oxygen saturation in OSAS rats, and inhibit the apoptosis of hippocampal neurons. The mechanism may be related to the intervention on Nrf2/HO-1 pathway.