Fluoxetine alleviates postoperative cognitive dysfunction by attenuating TLR4/MyD88/NF-κB signaling pathway activation in aged mice

• Published in: Inflammation research Vol. 72; no. 6; pp. 1161 - 1173
• Main Authors: Yao, Yusheng, Lin, Daoyi, Chen, Yuzhi, Liu, Linwei, Wu, Yushang, Zheng, Xiaochun
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.06.2023; Springer Nature B.V
• Subjects: Allergology; Animals; Apoptosis; Biomedical and Life Sciences; Biomedicine; Cognition; Cognitive ability; Cytokines; Cytokines - metabolism; Dermatology; Fluoxetine; Fluoxetine - metabolism; Fluoxetine - pharmacology; Fluoxetine - therapeutic use; Hippocampus; Immunology; Inflammation; Injection; Male; Mice; Mice, Inbred C57BL; Microglia; Microglia - metabolism; MyD88 protein; Myeloid Differentiation Factor 88 - metabolism; Neuroinflammatory Diseases; Neurology; NF-kappa B - metabolism; NF-κB protein; Original Research Paper; Pathogenesis; Pharmacology/Toxicology; Postoperative Cognitive Complications - metabolism; Pretreatment; Rheumatology; Signal Transduction; Signaling; Splenectomy; Surgery; TLR4 protein; Toll-Like Receptor 4 - metabolism; Toll-like receptors; Neuroinflammation; Postoperative cognitive dysfunction; Fluoxetine; Toll-like receptor 4; Microglia
• ISSN: 1023-3830; 1420-908X; 1420-908X
• DOI: 10.1007/s00011-023-01738-8

Objective and design 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. Subjects Aged C57BL/6 J male mice (18 months old) were studied. Treatment 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. Methods 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. Results 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. Conclusion Fluoxetine pretreatment suppressed hippocampal neuroinflammation and mitigated POCD by inhibiting microglial TLR4/MyD88/NF-κB pathway activation in aged mice.