The Peripheral And Central Mechanism Of Neurocognitive Protection Of Dexmedetomidine

In elderly patients,perioperative neurocognitive dysfunction was related to poor function recovery,slowed down the process of recovery from surgeries,and also increased the mortality.Currently,reducing the incidence of perioperative neurocognitive dysfunction via modifying perioperative management,reasonable usage of anesthetics is a research highlight in anesthesiology and neurology.Dexmedetomidine,a commonly using sedative in clinical anesthetic practice and intensive care unit,was reported to reduce the incidence of perioperative neurocognitive dysfunction,and conferred anti-inflammation effect.Meanwhile,the anti-peripheral inflammation effect was also found in the application of propofol.However,compared to propofol,dexmedetomidine showed more advantage to the neurocognitive protection.As the inflammatory effect amplifier in central nerve system,activated microglia released multiple proinflammatory cytokines,which increased the permeability of blood-brain barrier by impairing vascular endothelial,in which manner further increased the neuroinflammation in central nerve system,and finally deteriorated the neurocognitive dysfunction.It has to be note that the sedative effect of dexmedetomidine is achieved by activating ?2 adrenoreceptor in locus ceruleus After peripheral application,this sedative could easily cross the blood-brain barrier and enter into the central nerve system.And,in vitro study confirmed that dexmedetomidine can directly modulated the function of microglia.So,we hypothesized that besides the inhibitory effect on peripheral inflammation,there existed potential central mechanism in the neurocognitive protection of dexmedetomidine.And alleviating blood-brain barrier impairment via the inhibition on activated microglia is the potential central mechanism In current study,firstly,we investigated the influence of two different sedative drugs on the perioperative neurocognition of elderly patients,and compared the different influence of dexmedetomidine and propofol on peripheral and central inflammation.Secondly,with the mice cecal ligation and puncture induced sepsis model,we observed the influence of dexmedetomidine on the neurocognition of mice after sepsis,and investigated the peripheral and central mechanism of dexmedetomidine's protective effect on neurocognitive function.Objective1.In the clinical trial,to investigate whether the advantage of dexmedetomidine on perioperative neurocognition is related to the stronger inhibition on peripheral inflammation,and clarify if there exist potential central mechanism for the neurocognitive protection of dexmedetomidine2.In animal study,to investigate the peripheral and central mechanism of neurocognitive protection of dexmedetomidine.To confirm whether dexmedetomidine confers direct modulation on inflammation in central nerve system,and investigate whether the inhibition on microglial activation and reducing the blood-brain barrier impairment are the potential central mechanism of neurocognitive protection of dexmedetomidine.Methods1.The influence of two different sedative drugs on the perioperative neurocognition of elderly patients,and compare the different influence of dexmedetomidine and propofol on peripheral and central inflammationA prospective,randomized controlled study was conducted with patients 65 years of age or older who received total knee arthroplasty.The patients were randomly assigned to receive a spinal anesthesia supplemented with propofol or dexmedetomidine for sedation.Incidence of postoperative delirium was the primary endpoint and was determined by the Confusion Assessment Method,and incidence of postoperative cognitive dysfunction was assessed by the Mini-Mental State Examination.Blood samples were collected postoperatively to test the plasma concentrations of TNF-?,IL-6 and S100-?.2.The influence of dexmedetomidine on neurocognitive function,peripheral and central inflammation,and the study on the mechanism of this effect6-8 weeks CD1 mice suffered cecal ligation and puncture induced sepsis were used in this study,and with intracerebroventricular antagonists,the related mechanism is studied There are four parts of experiments in this study.In part 1,mice are randomly assigned to 3 groups:Control,Sham surgery,and Sepsis.In part 2,mice are randomly assigned to 4 groups:Sham surgery,Sepsis,Dexmedetomidine+Sham surgery,and Dexmedetomidine+Sepsis.In part 3,mice are randomly assigned to 4 groups:Sepsis,Dexmedetomidine+Sepsis,Intracerebroventricular atipamezole(the selective ?2 adrenoreceptor antagonist)+Dexmedetomidine+Sepsis,Intracerebroventricular atipamezole+Sepsis.In part 4,mice are randomly assigned to 4 groups:Sepsis,Dexmedetomidine+Sepsis,Intracerebroventricular BRL44408(the selective ?A adrenoreceptor antagonist)+Dexmedetomidine+Sepsis,Intracerebroventricular BRL44408+SepsisBarns maze and fear conditioning test was used to determine the cognitive function of mice.The BBB permeability was tested by Evans blue(EB)dye.The immunoblot analysis was used to determine the expression of HMGBland RAGE in hippocampus Microglial activation in hippocampus was tested by the Iba-1 immunofluorescent staining The subtypes of ?2 adrenergic receptor,?2A,?2B and ?2C adrenergic receptor were also respectively co-stained with microglia by the immunofluorescent staining.Cytokines(TNF-?,IL-6 and IL-1?)determination in serum and hippocampus was achieved by ELISA.ResultsPatients received dexmedetomidine sedation had lower incidences of postoperative delirium,better postoperative cognitive function and lower plasma S100? concentration than the patients sedated with propofol.There was no difference in postoperative plasma concentrations of TNF-?,IL-6 and IL-1?.The CLP induced sepsis increased the peripheral inflammation and neuroinflammation in hippocampus,enhanced the activation of microglia hippocampus which was related to the increased BBB permeability and neurocognitive function decline.Peripheral application of dexmedetomidine inhibited the increased sepsis induced neuroinflammation and microglial activation in hippocampus,reduced the HMGB1 and RAGE expression in hippocampus,protected the integrity of BBB and improved the recovery of neurocognitive function.Besides peripheral inflammation,intracerebroventricular atipamezole inhibited above effect of dexmedetomidine.Only?2A adrenergic receptor expressed on the surface of microglia.Intracerebroventricular?2A adrenergic receptor antagonist alleviated the anti-neuroinflammation effect of dexmedetomidine,and also reversed the protection of dexmedetomidine on BBB and neurocognitive functionConclusionDexmedetomidine conferred perioperative neuroprotection.The inhibition on peripheral inflammation was not the only mechanism for neurocognitive protection of dexmedetomidine.Dexmedetomidine inhibited the neuroinflammation in central nerve system,protected the function of BBB and neurocognitive function via activating ?2 adrenergic receptor in central nerve system.The inhibition on activated microglia after activating the ?2A adrenergic receptor on the surface of microglia was the potential important central mechanism of dexmedetomidine's neurocognitive protection.