The Role Of MMP-9 In Postoperative Cognitive Dysfunction In Aged Mice

Backgrounds:Postoperative cognitive dysfunction(POCD)is a complication of central nervous system after anesthesia and surgery,which shows a decline in cognitive function,especially in memory,attention and executive function.POCD has worse effects on the quality of patient’s life.It can increase the financial burden of family and society,increase morbidity and mortality.Although aging is regarded as the only one exact risk factor of POCD,the underlying mechanism is still unknown.Matrix metalloproteinase-9(MMP-9)is an important extracellular matrix enzyme,and can participate in many pathological processes.The increased MMP-9 after cerebral ischemia is associated with neuron injury,oxidative stress and the permeability of blood brain barrier(BBB).The integrity of BBB plays an essential role on maintaining the homeostasis of the central nervous system(CNS).Here we investigate the role of MMP-9 in the occurrence of POCD in aged mice,and try to provide new targets for the therapy of POCD in clinical setting.Methods and Results: 1.The effect of surgery on cognitive function and expression of MMP-9 in 2-month-old mice Methods: We adopted 2-month-old mice undergoing splenectomy/appendectomy after anesthesia,and cognitive function was assessed with Morris water maze on the third day after surgery.The expression of MMP-9 in hippocampus was detected following water maze test.Results: Neither splenectomy nor appendectomy damaged the spatial learning and memory ability of adult mice.The expression of MMP-9 in hippocampus had no change after surgery.2. The effect of surgery on cognitive function and expression of MMP-9 in aged mice Methods: 24 aged mice were subjected to anesthesia for appendectomy,and cognitive function was assessed with Morris water maze on the third day after surgery.The plasma and hippocampus of another 36 aged mice were harvested respectively at 6,12,24,48,72 hours after surgery.Then the levels of MMP-9 and the expression of tight junction proteins,such as ZO-1、Occludin and Claudin 5,were measured. Results: Compared with na?ve group,aged mice of surgery group showed a significant deficit in spatial learning and memory ability.The plasma MMP-9 level was increased significantly at 6 h after surgery until 72 h.Active MMP-9 levels in plasma were significantly elevated at 6 h,and peaked at 48 h.Compared with na?ve group,the expression of MMP-9 in surgery group was significantly increased,while the expression of ZO-1,Occludin and Claudin 5 were decreased at 24 h after surgery.3.The correlation between the concentration of plasma MMP-9 and POCD in elderly patients Methods:30 cases of elderly patients over 60 years old,undergoing elective total hip or knee arthroplasty/replacement surgery,were involved in this prospective study.The plasma samples were collected before and 7 days after surgery.MMP-9 levels in plasma were measured with enzyme-linked immunosorbent assay(ELISA).The cognitive function tests were performed at 1-3 days before and at 7 days and 2 months after operation.The incidence of POCD was represented by the Z-score,and patients were separated into two groups: POCD group and non-POCD group.We then analyzed the relationship between MMP-9 concentration and cognitive test scores.Results:8 of 30 patients demonstrated POCD at 7 days after surgery,the incidence of POCD was 26.67%;4 patients showed POCD at 2 months after surgery,the incidence was 13.33%.The plasma MMP-9 concentration in the POCD group was increased by 25.85±15.72 ng/ml,while the MMP-9 concentration of non-POCD group was decreased by 1.34±5.67 ng/ml.And the changed value of plasma MMP-9 concentration(△MMP-9)between two groups has significant difference.Plasma △MMP-9 levels were negatively correlated with Z score of postoperative function of digit span test at 7 days,which had no correlation with Z score of postoperative function at 2 months.Conclusions: 1.Surgery didn’t affect cognitive function and levels of MMP-9 in hippocampus in adult mice.2.Surgery can up-regulate the level of MMP-9,which can impair BBB and participate in the occurrence of POCD in aged mice.3.The incidence of POCD in aged patients who underwent total hip or knee arthroplasty/replacement surgery was 26.67% at 7 days and 13.33% at 2 months after surgery.Plasma △MMP-9 concentration was correlated with cognitive dysfunction at 7 days after operation.