| Postoperative cognitive dysfunction(POCD)is a decline in cognitive functions after anesthesia and surgery,characterized by disordered thinking,altered mental status,personality change,and memory impairment etc.POCD is particularly common among older adults and considered to be associated with long-term dementia.The pathological mechanism of POCD is not fully clear.Whereas,it has been consistently suggested by studies that POCD may be induced by general anesthetic agents(e.g.sevoflurane)and surgical trauma that are linked with neuronal apoptosis and inflammation.The occurrence of POCD contributes to prolonged hospital stay,increased family financial pressure as well as social economic burden,and thereby becoming an important public health issue.Nonetheless,no effective approach to the prevention and treatment of POCD has been developed yet to the day.Preconditioning(PC)refers to the internal protective mechanism that is activated by exposure to harmful stimuli close to the injury threshold,aiming at inducing resistance against the subsequent fatal injury.As a significant strategy,PC has been well studied and applied in clinical trials to prevent potential disease or reduce disease severity.In recent years,normobaric hyperoxia preconditioning(NBO-PC)has raised the attention among the researchers for its feasible clinical application.As indicated by a number of studies,NBO-PC can be applied to prevent ischemia-reperfusion injury in target organs like heart,kidney and brain.Especially,NBO-PC is beneficial for protecting against cerebral ischemia and traumatic brain injury,due to its biochemical effects in anti-apoptosis and anti-inflammation.Therefore,we can hypothesize that NBO-PC may have imperative clinical impacts on ameliorating POCD by inhibiting neuronal apoptosis and inflammation.Part one Effects of normobaric hyperoxia preconditioning on cognitive dysfunction induced by sevoflurane in aged ratsObjective: To investigate the effects of NBO-PC on cognitive impairment induced by sevoflurane and its possible mechanism.Method: A total of 66 male Sprague-Dawley 20-month-old rats(450-550g)were randomly divided into 3 groups(n=22 each): control group(C group),sevoflurane anesthesia group(S group)and normobaric hyperoxia preconditioning group(HO group).Rats assigned to the HO group received 4hours of NBO treatment at 1 atmosphere absolute(ATA)in 100% oxygen each day of a 6-day duration.Rats in C and S groups received no NBO-PC.24 hours after the last preconditioning(the sixth)cycle,rats in S and HO groups were treated with 2.5% sevoflurane for 5 hours.Rats in C group remained untreated by sevoflurane.24 hours after exposing sevoflurane to S and HO groups,rats were subdivided for Morris water maze test,apoptosis detection in the hippocampus and cytosolic calcium concentration measurement of hippocampal cells.Results: Morris water maze test results revealed that S and HO groups had significantly longer escape latency and lower platform crossings compared with C group rats(P < 0.05);Additionally,HO group owned shorter escape latency(P < 0.05)but higher platform crossings(P < 0.05)in comparison to rats in S group.Compared with C group,the apoptotic rate and intracellular calcium concentration of hippocampal cells in S and HO groups were considerably higher(P < 0.05);The apoptotic rate of hippocampal cells in rats of HO group(12.44%)was remarkably lower than that of S group(20.03%)(P < 0.05),and the intracellular calcium concentration in HO group was significantly lower than that in S group(P < 0.05)as well.It was noticeable that the levels of bax and active caspase-3 in the hippocampus of S and HO groups witnessed an increase(P< 0.05)compared with C group,and the levels of bcl-2 decreased significantly(P< 0.05);Apart from that,the changes of bcl-2,bax and active caspase-3 in HO group were less than those in S group(P< 0.05).Conclusion: Normobaric hyperoxia preconditioning can alleviate spatial learning and memory impairment induced by sevoflurane,probably through inhibiting hippocampal apoptosis by reducing the intracellular calcium concentration.Part two Effects of normobaric hyperoxia preconditioning on posto- perative cognitive dysfunction in aged rats undergoing splenectomyObjective: To study the effects of NBO-PC on POCD and its possible mechanism through establishing the POCD animal model by splenectomy.Method: A total of 112 male Sprague-Dawley 20-month-old rats(450-550 g)were randomly divided into 4 groups(n=28 each): control group(Con group),sevoflurane anesthesia group(Sev group),operation group(Ope group)and normobaric hyperoxia preconditioning group(Hop group).Seven days before splenectomy,rats assigned to Hop group had been treated with NBO at 1 atmosphere absolute(ATA)in 100% oxygen 4 hours per day for 6consecutive days,while the other groups received no such NBO-PC treatment.24 hours after the last preconditioning(the sixth)cycle,rats in Ope and Hop groups were anesthetized with 2.5% sevoflurane for splenectomy,whereas rats in Sev group were only anesthetized with 2.5% sevoflurane without splenectomy,and rats in Con group received no anesthesia or surgery.24 hours after the operation,Morris water maze test was used to examine the cognitive function of the subjec;HE staining was used to visualize the pathological changes of the hippocampus of the rats;Enzyme-linked immunosorbent assay was used for detecting the levels of IL-1?,IL-6 and TNF-? in blood plasma and hippocampus;Flow cytometry was used to detect the apoptotic rate of hippocampal cells;Weston blot was used to detect the expression of apoptosis factors(bcl-2,bax and active caspase-3)in the hippocampus.Results: Morris water maze test showed that the escape latency were remarkably longer and the platform crossings were lower in Ope and Hop group rats compared with Con group(P< 0.05),and nevertheless no significant variations in the escape latency and the platform crossings between Sev group and Con group(P> 0.05)were observed;Meanwhile,compared with Ope group,the escape latency of rats in Hop group was significantly shorter,and the platform crossings increased with significant difference(P<0.05).The HE staining showed that the arrangement of hippocampal cells in Ope group was disturbed,that some cells experienced shape change with stained nucleus appeared to be darker,and that intercellular space increased.Compared with Ope group,the pathological damage in Hop group was alleviated.Also,compared with Con group,the levels of IL-1?,IL-6 and TNF-? in blood plasma and hippocampus of rats in Ope and Hop groups climbed(P< 0.05).However,there was no significant difference in the levels of inflammatory factors in Sev group(P> 0.05);Compared with Ope group,the levels of IL-1?,IL-6 and TNF-? in blood plasma and hippocampus of rats in Hop group decreased significantly(P< 0.05).As for the flow cytometry,the apoptosis rate of hippocampal cells in Ope and Hop groups considerably increased compared with Con group(P< 0.05),while there was no great difference between Con group and Sev group(P> 0.05);The apoptosis rate in Hop group was lower than that in Ope group(P< 0.05).Based on the Western Blot,compared with Con group,the expression of bcl-2 decreased and the expressions of bax and active caspase-3 increased in Ope and Hop groups(P< 0.05).There was no difference between Con and Sev groups(P>0.05).The changes of bcl-2,bax and active caspase-3 in Hop group were less than those in Ope group(P< 0.05).Conclusion: Normobaric hyperoxia preconditioning can lighten POCD in aged rats after splenectomy to some extent,and the behind mechanism is related to the inhibition of inflammatory response and apoptosis of hippocampal neurons.Part Three Effects of normobaric hyperoxia preconditioning on postop-erative delirium in elderly patients undergoing off-pump coronary artery bypass graftingObjective: To study the influence of NBO-PC on postoperative delirium in elderly patients undergoing off-pump coronary artery bypass grafting by observing the occurrence of postoperative delirium,the levels of inflammatory factors and brain injury markers in blood plasma.Method: Eighty patients of both sexes,aged 65-75 yr,scheduled for elective off-pump coronary artery bypass grafting,were randomly divided into two groups(n=40): control group(C group)and normobaric hyperoxia preconditioning group(NBO group).Patients in NBO group started to receive NBO-PC seven days prior to the operation day,and the NBO-PC regimen was100% oxygen inhalation by mask for 4 hours a day for 6 consecutive days.Patients in C group received no special treatment.Enzyme-linked immunosorbent assay was used for detecting the levels of TNF-?,IL-1?,IL-6,s100? and brain-derived neurotrophic factor(BDNF)of the blood samples taken from the radial artery of the subject at five distinctive time points: before anesthesia induction(T0),immediately after surgery(T1),1 day(T2),3 days(T3)and 7 days(T4)after surgery.Confusion assessment method for the ICU(CAM-ICU)was used to assess the occurrence of postoperative delirium,and the postoperative recovery of the patients were recorded.Results: Thirty-eight patients were enrolled in C group and 39 patients in NBO group.Compared with T0,the levels of TNF-?,IL-1? and IL-6 in two groups significantly increased at T1-4(P<0.05);Compared with C group,the levels of TNF-?,IL-1? and IL-6 in NBO group were generally lower at T1-4(P< 0.05).Compared with T0,the levels of s100? in two groups both increased at T1-4(P<0.05),while the levels of BDNF significantly decreased(P<0.05).Compared with C group,the levels of s100? in NBO group dramatically decreased at T1-4(P<0.05),while the levels of BDNF significantly increased(P<0.05).Compared with C group,the incidence of postoperative delirium in NBO group experienced a reduction(P<0.05),with corresponding shortened extraction time of endotracheal tube,ICU time and postoperative hospital time(P<0.05).Conclusion: Normobaric hyperoxia preconditioning can reduce the the probability of postoperative delirium and promote postoperative recovery in aging patients undergoing off-pump coronary artery bypass surgery,and the mechanism of which may be contributed from the inhibition of inflammatory response and reduction of brain injury. |
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