Peripheral Neutrophils-Derived Matrix Metallopeptidase-9 Induces Postoperative Cognitive Dysfunction in Aged Mice.

Lili Huang,Jie Tian,Xuemei Chen,Diansan Su,Weifeng Yu,Weitian Tian,Huan Xu,Xiaodan Wu,Wanbing Dai,Yizhe Zhang

doi:10.3389/fnagi.2022.683295

Abstract

BackgroundAging is one of the most important risk factors of postoperative cognitive dysfunction (POCD); however, the mechanisms are still not completely understood. In this study, we explore the roles of matrix metalloproteinase-9 (MMP-9) in aged mice with POCD.MethodsAppendectomy was performed in 18-month-old C57BL/6 and MMP-9–/– mice under anesthesia to establish the POCD model. Learning and memory were assessed using the Morris water maze (MWM) or Barnes maze. Protein expression of MMP-9 was measured by Western blotting or enzyme-linked immunosorbent assay (ELISA). To explore the role of neutrophils-derived MMP-9 in POCD, we treated mice with anti-Gr-1 monoclonal antibody to deplete peripheral neutrophils. And the percentage of neutrophils and other leukocytes were detected by flow cytometry. We further used sodium fluorescein (NaFlu) to evaluate the blood–brain barrier (BBB) permeability.ResultsThe spatial learning and memory ability was injured, and expression of MMP-9 increased in both plasma and the hippocampus after anesthesia/surgery. However, cognitive dysfunction was alleviated in both MMP-9–/– and peripheral neutrophils-depleted mice. The permeability of BBB was increased after anesthesia/surgery while recused by anti-Gr-1 antibody administration.ConclusionThese findings suggest that peripheral neutrophils-derived MMP-9 could lead to POCD of aged mice through increasing the BBB permeability.

Highlights

Postoperative cognitive dysfunction (POCD) is a common central nervous system complication after anesthesia and surgery
There was an obvious decrease in the percentage of swimming time spent in the target quadrant in the anesthesia/surgery group (Figure 1C)
Their swimming ability was not affected by anesthesia/surgery, as no difference was found in the average swimming speed between each group (Figure 1D)

Summary

Introduction

Postoperative cognitive dysfunction (POCD) is a common central nervous system complication after anesthesia and surgery. It increases morbidity and mortality and results in a rise in the premature departure from the workforce (Steinmetz et al, 2009). Aging is considered the only definite risk factor of POCD (Rosczyk et al, 2008; Steinmetz and Rasmussen, 2016; Zhong et al, 2020), the reason why elderly patients are more vulnerable to memory deficits after surgery remains ambiguous. We explore the roles of matrix metalloproteinase-9 (MMP-9) in aged mice with POCD. We further used sodium fluorescein (NaFlu) to evaluate the blood–brain barrier (BBB) permeability

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Discussion

Conclusion