Dexemetomidine Prevents Postoperative Cognitive Dysfunction Via Downregulating Of MMP-9

Objective: With the development of aging society,the incidence of postoperative cognitive dysfunction(POCD)is increasing.Currently,POCD is considered as the result of inflammation in brain regions such as the hippocampus due to the dysfunction of the blood-brain barrier(BBB).As an important matrix enzyme,MMP-9 damages the structural integrity of BBB and is mainly released by peripheral inflammatory cells.Perioperative administration of dexmedetomidine can prevent postoperative cognitive decline in elderly patients,but the underlying mechanism remains unclear.Therefore,this study aims to investigate the effects of dexmedetomidine on postoperative cognitive function,peripheral inflammation and MMP-9 level in elderly patients after hip replacement.In addition,POCD animal model was used to explore the potential mechanisms of dexmedetomidine in preventing the occurrence of POCD.Methods: 1.A total of 200 elderly patients who underwent unilateral hip replacement surgery in Traditional Chinese Medicine Hospital Affiliated to Southwest Medical University from March 2020 to September 2022 were randomly divided into control group and dexmedetomidine group,with 100 cases in each group.Patients in dexmedetomidine group were intravenously pumped with dexmedetomidine,while patients in control group were intravenously pumped with normal saline during perioperative period.Hip replacement surgery under general anesthesia was performed in two groups.The general conditions,intraoperative indicators and MMSE scores at different time points were recorded.The number of CD4+T lymphocytes in peripheral blood was detected by flow cytometry,and the levels of IFN-γ,IL-17,TNF-α,IL-6 and MMP-9 in peripheral blood were analyzed by ELISA.2.Healthy aged male C57BL/6 mice were randomly divided into three groups as follows:control group,model group and dexmedetomidine group,with 28 mice in each group.Mice in model group and dexmedetomidine group were performed with tibial fracture internal fixation under sevoflurane anesthesia,while sham-operation was performed in control group.Additionally,mice in dexmedetomidine group were intraperitoneally administrated with dexmedetomidine(25μg/kg),while mice in control group and model group were intraperitoneally administrated with normal saline.Before operation,all mice were performed with 5 consecutive days of acquisition phase,1 day of space exploring test.On postoperative day 1,3 and 7,all mice were performed with space exploring test using water maze.On the postoperative day 7,Th1 and Th17 cells in peripheral blood were detected by flow cytometry,the levels of IFN-γ,IL-17,TNF-α,IL-6 and MMP-9 in peripheral blood and hippocampus were analyzed by ELISA,the blood-brain barrier function of hippocampus was observed by evan’s blue(EB)staining.Results: 1.There were no significant differences in age,sex,education level,BMI,ASA grade and complications between two groups(P > 0.05).In addition,there were no significant differences in anesthesia time,operation time,extubation time,intraoperative blood loss,hypotension incidences between two groups(P> 0.05),but the bradycardia incidence of dexmedetomidine group was increased in comparison to control group(P<0.05).Compared with preoperative day 1,MMSE scores in two groups were significantly decreased at after surgery(P < 0.05).At postoperative day 1,3 and 7,MMSE scores in dexmedetomidine group were significantly increased in comparison to control group(P < 0.05).The number of CD4+T cells in peripheral blood of two groups were significantly decreased after surgery(P < 0.05).Compared with the control group,the number of CD4+T cells and the levels of IL-4 and IL-10 in peripheral blood of dexmedetomidine group were significantly increased(P <0.05),while the levels of IFN-γ,IL-17 and MMP-9 in peripheral blood of dexmedetomidine group were significantly decreased(P < 0.05).2.At postoperative day 1,3 and 7,the platform-crossing times and target quadrant traveling time of model group and dexmedetomidine group were significantly decreased compared with the control group,the escape latency was increased.However,the platform-crossing times and target quadrant traveling time of dexmedetomidine group were significantly increased compared with the model group,the escape latency was decreased(P < 0.05).On the postoperative day 7,the number of Th1 and Th17 cells,levels of IFN-γ,IL-17 and MMP-9 in peripheral blood,and levels of IFN-γ,IL-17,TNF-α,IL-6 and EB in hippocampus of model group and dexmedetomidine group were significantly increased compared with the control group(P < 0.05).Compared with the model group,the above indexes peripheral blood and hippocampus in dexmedetomidine group were significantly decreased(P < 0.05).Conclusion: 1.Dexmedetomidine prevents cognitive decline and regulates the immune function and inflammation in elderly patients after hip replacement.2.Dexmedetomidine reduces the release of MMP-9 by inhibiting the proliferation and differentiation of peripheral inflammatory cells such as Th1 and Th17,further preventing the destruction of BBB and the progression of hippocampal neuroinflammation,so as to prevent the occurrence of POCD.