Neuroprotectin D1 Protects Against Postoperative Delirium-Like Behavior in Aged Mice.

Ying Zhou,Lei Chen,Mian Peng,Ke Li,Xiaofeng Li,Jiayu Wang,Zongze Zhang

doi:10.3389/fnagi.2020.582674

Abstract

Postoperative delirium (POD) is the most common postoperative complication affecting elderly patients, yet the underlying mechanism is elusive, and effective therapies are lacking. The neuroinflammation hypothesis for the pathogenesis of POD has recently emerged. Accumulating evidence is supporting the role of specialized proresolving lipid mediators (SPMs) in regulating inflammation. Neuroprotectin D1 (NPD1), a novel docosahexaenoic acid (DHA)-derived lipid mediator, has shown potent immunoresolvent and neuroprotective effects in several disease models associated with inflammation. Here, using a mouse model of POD, we investigated the role of NPD1 in postoperative cognitive impairment by assessing systemic inflammatory changes, the permeability of the blood–brain barrier (BBB), neuroinflammation, and behavior in aged mice at different time points. We report that a single dose of NPD1 prophylaxis decreased the expression of tumor necrosis factor alpha TNF-α and interleukin (IL)-6 and upregulated the expression of IL-10 in peripheral blood, the hippocampus, and the prefrontal cortex. Additionally, NPD1 limited the leakage of the BBB by increasing the expression of tight junction (TJ)-associated proteins such as ZO-1, claudin-5, and occludin. NPD1 also abolished the activation of microglia and astrocytes in the hippocampus and prefrontal cortex, which is associated with improved general and memory function after surgery. In addition, NPD1 treatment modulated the inflammatory cytokine expression profile and improved the expression of the M2 marker CD206 in lipopolysaccharide (LPS)-stimulated macrophages, which may partly explain the beneficial effects of NPD1 on inflammation. Collectively, these findings shed light on the proresolving activities of NPD1 in the pro-inflammatory milieu both in vivo and in vitro and may bring a novel therapeutic approach for POD.

Highlights

Postoperative delirium (POD), defined as delirium occurring mainly within 1 week after surgery, is a common neuropsychiatric complication characterized by fluctuating and concurrent disturbances of attention, cognition, psychomotor behavior, emotion, and sleep–wake rhythm (Auerbach et al, 2018)
We demonstrate that Neuroprotectin D1 (NPD1), a novel lipidderived mediator of specialized proresolving lipid mediators (SPMs), contributes to the postoperative recovery of POD-like behavior in aged mice through its anti-inflammatory and proresolving effects
Our results indicate that prophylaxis with NPD1 at peripheral injury sites alleviates the systemic inflammatory response and protects blood–brain barrier (BBB) integrity after laparotomy

Summary

Introduction

Postoperative delirium (POD), defined as delirium occurring mainly within 1 week after surgery, is a common neuropsychiatric complication characterized by fluctuating and concurrent disturbances of attention, cognition, psychomotor behavior, emotion, and sleep–wake rhythm (Auerbach et al, 2018). The interaction between the peripheral and central immune systems amplifies inflammation in the brain (D’Mello et al, 2009; Perry and Teeling, 2013), and the cascade of neuroinflammation induces synaptic dysfunction and neuronal apoptosis, which impairs cognitive function (Munster et al, 2011; Plaschke et al, 2016; Skvarc et al, 2018). On this basis, treatments targeting the regulation of neuroinflammation show great potential as candidate therapies for POD

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