Electroacupuncture improves postoperative cognitive dysfunction by inhibiting ferroptosis via TFR1-DMT1-FPN pathway

Abstract

Objective Postoperative cognitive dysfunction is a common complication of anesthesia and postoperative surgery, which seriously affects the quality of life of patients, and its treatment mechanism is not completely clear. Ferroptosis is a recently discovered form of non-apoptotic cell death.[1, 2] Iron metabolic imbalance is the main mechanism of ferroptosis. Recent reports suggest that ferroptosis is a new mechanism contributing to postoperative cognitive dysfunction. Currently, there is no completely effective treatment for postoperative cognitive dysfunction, however, electroacupuncture has been extensively used in clinical practice. By inhibiting neuroinflammation and microbial cell activation, electroacupuncture has shown potential in addressing postoperative cognitive dysfunction. Nevertheless, it remains unclear whether electroacupuncture can effectively inhibit ferroptosis through the TFR1-DMT1-FPN pathway. Therefore, the purpose of this study is to investigate the role of ferroptosis in the occurrence of postoperative cognitive dysfunction, and to elucidate whether electroacupuncture can improve postoperative cognitive dysfunction by suppressing ferroptosis via the TFR1-DMT1-FPN pathway. Methods The experiment involved three groups: the control group, the POCD group, and the POCD + electroacupuncture group. The POCD animal model was established using sevoflurane anesthesia and tibial fracture. Cognitive behavioral changes in mice were assessed using the novel object recognition test, one day and three days after the operation. Hematoxylin eosin staining was performed to observe changes in the tissue structure of the hippocampus. The enzyme-linked immunosorbent assay was conducted to determine the levels of glutathione (GSH) and iron ions (Fe) concentration. Western blot analysis was used to measure the expression of transferrin receptor 1 protein (TFR1), divalent metal transporter 1 protein (DMT1), and iron pump protein (FPN). Moreover, quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was employed to detect the mRNA levels of DMT1 and FPN. Results Compared with the control group, the POCD group, which underwent sevoflurane anesthesia and tibial fractures, exhibited a decrease in the cognitive index as measured by the novel object recognition experiment in mice. Moreover, sevoflurane anesthesia and tibial fractures were found to decrease the levels of glutathione (GSH) and iron pump protein (FPN), while increasing the expression of divalent metal transporter 1 protein (DMT1) and transferrin receptor 1 protein (TFR1). This led to an elevated concentration of iron ions and subsequent induction of ferroptosis in mice. In contrast, the POCD + electroacupuncture group showed improved cognitive index in the novel object recognition experiment compared to the POCD group. Additionally, the POCD + electroacupuncture group exhibited increased levels of glutathione (GSH) and iron pump protein (FPN), as well as decreased expression of DMT1 and TFR1, resulting in a reduction in the concentration of iron ions. These results indicate that sevoflurane anesthesia and tibial fractures contribute to the occurrence of postoperative cognitive dysfunction through the induction of ferroptosis, whereas electroacupuncture can ameliorate postoperative cognitive dysfunction by inhibiting the occurrence of ferroptosis induced by sevoflurane anesthesia and tibial fractures. Conclusion This study reveals that sevoflurane and tibial fractures cause cognitive damage through the mechanism of ferroptosis, while electroacupuncture can inhibit ferroptosis through the TFR1-DMT1-FPN pathway, thus improving postoperative cognitive dysfunction induced by sevoflurane and tibial fractures.