17β-Estradiol Ameliorates Postoperative Cognitive Dysfunction in Aged Mice via miR-138-5p/SIRT1/HMGB1 Pathway.

Background: Postoperative cognitive dysfunction (POCD) is a common neurological complication in older patients and correlated with adverse outcomes. 17β-estradiol treatment was reported to provide neuroprotective protection in various neurologic disorders, but whether it attenuated POCD was unknown. The purpose of this study was to explore the effects of 17β-estradiol treatment on POCD and its mechanisms.

Methods: We generated a POCD model in 15-month-old mice via laparotomy, followed by subcutaneous injection of 17β-estradiol, intraperitoneal injection of EX527 (a Sirtuin 1 [SIRT1] inhibitor), or bilateral hippocampal injection of miR-138-5p-agomir. Morris water maze test and open field test were applied to evaluate the cognitive function. The neuronal apoptosis in the hippocampus was detected using the terminal transferase dUTP nick end labeling assay. Meanwhile, the levels of interleukin-1β (IL-1β) and microglia activation were measured by enzymelinked immunosorbent assay and immunofluorescence, respectively. Western blot was utilized to assess the expression of SIRT1 and high mobility group box 1 (HMGB1) protein, and gene expression of miR-138-5p was determined through quantitative real-time polymerase chain reaction.

Results: Behavioral tests showed that 17β-estradiol treatment improved cognitive function in aged POCD mice. In addition, 17β-estradiol attenuated neuronal apoptosis and microglia activation as well as IL-1β expression in the hippocampus. Nonetheless, injection with EX527 abolished the beneficial impacts of 17β-estradiol against POCD. Furthermore, miR-138-5p was verified to bind with SIRT1, which regulated the expression of HMGB1. After treatment with 17β-estradiol, miR-138-5p expression was reduced in the hippocampus, and the neuroprotective influence of 17β-estradiol on aged POCD mice was reversed after administration of miR-138-5p-agomir.

Conclusions: 17β-estradiol treatment exerted neuroprotection effects on POCD in aged mice, which might be relevant to alleviating neuroinflammation via miR-138-5p/SIRT1/HMGB1 pathway.