Maresin1 improves postoperative delirium-like behavior in mice with tibial fractures by inhibiting the TLR4/MyD88/NF-kB pathway

Background

Postoperative delirium (POD) is a common complication in elderly patients following surgery, contributing to increased morbidity and healthcare costs. Although the pathophysiological mechanisms of POD are not fully understood, it is believed to involve significant inflammatory responses, particularly the activation of astrocytes. This study investigates the neuroprotective potential of Maresin1 (MaR1), alone and in combination with the TLR4 inhibitor TAK-242, in a mouse model of POD. Our findings indicate that MaR1 reduces astrocyte activation by inhibiting the TLR4/MyD88/NF-κB signaling pathway, which mitigates inflammatory responses associated with POD. These results suggest that targeting astrocytic TLR4/MyD88/NF-κB activation could be a promising therapeutic strategy for POD prevention and treatment.

Purpose

This study aims to evaluate the effects of Maresin1 (MaR1), a bioactive molecule derived from the omega-3 fatty acid DHA, alone or in combination with TAK-242, a synthetic TLR4 inhibitor, on cognitive outcomes and inflammatory responses in a mouse model of POD induced by tibial fracture internal fixation.

Methods

Ninety C57BL/6 mice were subjected to tibial fracture surgery and divided into six groups to receive different treatments: sham, surgery only, surgery with normal saline, surgery with MaR1, surgery with TAK-242, and surgery with both MaR1 and TAK-242. Cognitive functions were assessed using the Buried Food Test, Y Maze Test and Open Field Test. Western blotting, qRT-PCR, immunofluorescence, and transmission electron microscopy were utilized to examine astrocytic activation and the integrity of the TLR4/MyD88/NF-κB pathway.

Results

Compared to the sham-operated group, mice pretreated with MaR1 exhibited significant improvements in postoperative delirium-like behavior. Furthermore, in contrast to the positive control group treated with TAK-242 alone, Combination treatment with MaR1 and TAK-242 improved the delirium-like behavior in mice, and effectively reduced the activation of astrocytes as well as the expression of associated markers (GFAP and S100β) in the mouse brain. Additionally, these treatments modulated the TLR4/MyD88/NF-κB signaling pathway, which serves as a potential neuroprotective mechanism to mitigate the impact of surgical trauma and prevent postoperative delirium.

Conclusion: MaR1, whether used alone or in combination with TAK-242, demonstrates significant anti-inflammatory and neuroprotective effects in a POD mouse model, achieved likely through the inhibition of TLR4/MyD88/NF-kB activation. These findings suggest that targeting TLR4/MyD88/NF-kB inflammatory pathway may help prevent or mitigate POD in surgical patients.