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

Aging 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.

Appendectomy 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.

The 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.

These findings suggest that peripheral neutrophils-derived MMP-9 could lead to POCD of aged mice through increasing the BBB permeability.