Department of Anesthesiology, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China.
School of Public Health, Jining Medical University, Jining, Shandong 272067, P.R. China.
Mol Med Rep. 2019 May;19(5):3815-3822. doi: 10.3892/mmr.2019.10052. Epub 2019 Mar 18.
Post‑operative cognitive dysfunction is a common complication after anesthesia and surgery. Sevoflurane (SEV), a widely used inhalational anesthetic, can exaggerate neuroinflammation and cause cognitive dysfunction under chronic intermittent hypoxia (CIH) conditions by downregulating hippocampal peroxisome proliferator‑activated receptor‑γ (PPAR‑γ). In the present study, it was examined whether treatment with PPAR‑γ agonist pioglitazone (PIO) is beneficial in counteracting SEV‑induced neuroinflammation and cognitive decline in a rat model of CIH. Rats were exposed to CIH for 4 weeks. After 2 weeks of CIH, these animals underwent either 2.6% SEV or control (CON) exposure for 4 h. PIO (60 mg/kg) or vehicle (VEH) was administered orally twice daily for 2 weeks, starting one day prior to SEV or CON exposure. Compared with CIH‑CON+VEH rats, CIH‑SEV+VEH rats exhibited significant cognitive decline as indicated by increased latency to locate the hidden platform and shorter dwell‑time in the goal quadrant in the Morris Water Maze task. Molecular studies revealed that CIH‑SEV+VEH rats had increased proinflammatory cytokine expression and microglial activation in the hippocampus, which were associated with decreased PPAR‑γ activity. Notably, SEV‑induced cognitive decline and increases in proinflammatory cytokine expression and microglial activation were prevented by PIO, which increased hippocampal PPAR‑γ activity. PIO also increased hippocampal PPAR‑γ activity in CIH‑CON rats but did not alter proinflammatory cytokine expression and microglial activation as well as cognitive function. Additionally, expression of hippocampal PPAR‑α and PPAR‑β, two other PPAR isotypes, were comparable among the groups. These data suggest that PIO prevents SEV‑induced exaggeration of neuroinflammation and cognitive decline under CIH conditions by upregulating hippocampal PPAR‑γ. PIO may have the potential to prevent anesthetic SEV‑induced cognitive decline in surgical patients with obstructive sleep apnea.
术后认知功能障碍是麻醉和手术后的常见并发症。七氟醚（SEV）是一种广泛使用的吸入性麻醉剂，在慢性间歇性低氧（CIH）条件下，通过下调海马过氧化物酶体增殖物激活受体-γ（PPAR-γ），可加重神经炎症并导致认知功能障碍。在本研究中，研究人员探讨了 PPAR-γ 激动剂吡格列酮（PIO）治疗是否有益于对抗 CIH 大鼠模型中 SEV 诱导的神经炎症和认知下降。大鼠接受 CIH 4 周。在 CIH 2 周后，这些动物接受 2.6% SEV 或对照（CON）暴露 4 小时。PIO（60mg/kg）或载体（VEH）每天口服两次，共 2 周，在 SEV 或 CON 暴露前一天开始。与 CIH-CON+VEH 大鼠相比，CIH-SEV+VEH 大鼠在 Morris 水迷宫任务中表现出明显的认知下降，表现为找到隐藏平台的潜伏期增加和目标象限的停留时间缩短。分子研究表明，CIH-SEV+VEH 大鼠海马内促炎细胞因子表达增加和小胶质细胞激活，与 PPAR-γ 活性降低有关。值得注意的是，PIO 可预防 SEV 诱导的认知下降以及促炎细胞因子表达和小胶质细胞激活的增加，从而增加海马 PPAR-γ 活性。PIO 还增加了 CIH-CON 大鼠海马中的 PPAR-γ 活性，但未改变促炎细胞因子表达和小胶质细胞激活以及认知功能。此外，各组海马中 PPAR-α 和 PPAR-β 的表达（两种其他 PPAR 同型物）相当。这些数据表明，PIO 通过上调海马 PPAR-γ 可预防 CIH 条件下 SEV 诱导的神经炎症和认知下降加重。PIO 可能有潜力预防阻塞性睡眠呼吸暂停手术患者麻醉 SEV 引起的认知下降。
