Department of Anesthesiology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, No. 134, Dongjie, Fuzhou, 350001, Fujian, China.
Fujian Provincial Key Laboratory of Critical Care Medicine, Fuzhou, Fujian, China.
Inflamm Res. 2023 Jun;72(6):1161-1173. doi: 10.1007/s00011-023-01738-8. Epub 2023 May 15.
Postoperative cognitive dysfunction (POCD) is a common complication following surgery among elderly patients. Emerging evidence demonstrates that neuroinflammation plays a pivotal role in the pathogenesis of POCD. This study tested the hypothesis that fluoxetine can protect against POCD by suppressing hippocampal neuroinflammation through attenuating TLR4/MyD88/NF-κB signaling pathway activation.
Aged C57BL/6 J male mice (18 months old) were studied.
Aged mice were intraperitoneally injected with fluoxetine (10 mg/kg) or saline for seven days before splenectomy. In addition, aged mice received an intracerebroventricular injection of a TLR4 agonist or saline seven days before splenectomy in the rescue experiment.
On postoperative days 1, 3, and 7, we assessed hippocampus-dependent memory, microglial activation status, proinflammatory cytokine levels, protein levels related to the TLR4/MyD88/NF-κB signaling pathway, and hippocampal neural apoptosis in our aged mouse model.
Splenectomy induced a decline in spatial cognition, paralleled by parameters indicating exacerbation of hippocampal neuroinflammation. Fluoxetine pretreatment partially restored the deteriorated cognitive function, downregulated proinflammatory cytokine levels, restrained microglial activation, alleviated neural apoptosis, and suppressed the increase in TLR4, MyD88, and p-NF-κB p65 in microglia. Intracerebroventricular injection of LPS (1 μg, 0.5 μg/μL) before surgery weakened the effect of fluoxetine.
Fluoxetine pretreatment suppressed hippocampal neuroinflammation and mitigated POCD by inhibiting microglial TLR4/MyD88/NF-κB pathway activation in aged mice.
术后认知功能障碍（POCD）是老年患者手术后常见的并发症。新出现的证据表明，神经炎症在 POCD 的发病机制中起着关键作用。本研究通过抑制 TLR4/MyD88/NF-κB 信号通路的激活，检测了氟西汀通过抑制海马神经炎症来预防 POCD 的假说。
研究了年龄在 18 个月的 C57BL/6J 雄性小鼠。
在脾切除术前 7 天，老年小鼠通过腹腔注射氟西汀（10mg/kg）或生理盐水。此外，在脾切除术前 7 天，在抢救实验中，老年小鼠接受了脑室内注射 TLR4 激动剂或生理盐水。
在术后第 1、3 和 7 天，我们评估了老年小鼠模型的海马依赖性记忆、小胶质细胞激活状态、促炎细胞因子水平、TLR4/MyD88/NF-κB 信号通路相关蛋白水平以及海马神经凋亡。
脾切除术导致空间认知能力下降，同时伴有海马神经炎症加重的参数。氟西汀预处理部分恢复了认知功能的恶化，下调了促炎细胞因子水平，抑制了小胶质细胞的激活，减轻了神经凋亡，并抑制了小胶质细胞中 TLR4、MyD88 和 p-NF-κB p65 的增加。手术前脑室内注射 LPS（1μg，0.5μg/μL）削弱了氟西汀的作用。
氟西汀预处理通过抑制老年小鼠小胶质细胞 TLR4/MyD88/NF-κB 通路的激活，抑制海马神经炎症，减轻 POCD。
