AIM:To investigate the effects of memantine(Mem),an N-methyl-D-aspartate(NMDA)recep-tor antagonist,on sevoflurane(Sev)anesthetic depth and perioperative neurocognitive disorders in mice,and to explore the possible mechanisms involved.METHODS:Mouse electroencephalogram(EEG)monitoring and cognitive disorder models were established.For EEG monitoring,male C57BL/6J mice were randomly divided into control group,Sev group,and Mem+Sev group.The EEG monitoring electrodes were implanted in the heads of the mice 7 d before anesthe-sia.On the day of anesthesia,the mice in Mem+Sev group received an intraperitoneal injection of 20 mg/kg Mem dissolved in normal saline,while those in control and Sev groups received intraperitoneal injection of an equivalent volume of normal saline based on body weight.Thirty minutes later,the mice in Sev and Mem+Sev groups were anesthetized with 400 mL/min O2+3%Sev for 5 h,while those in control group were treated with 400 mL/min O2 for 5 h.The EEG monitoring was ter-minated after the righting reflex was restored in Sev and Mem+Sev groups.The time of disappearance and recovery of the righting reflex was recorded,and changes in EEG burst suppression ratio and relative power of each frequency band were analyzed.For the cognitive disorder part,another batch of male C57BL/6J mice were selected and divided into the same groups as before.The mice underwent water maze spatial navigation training for 6 d before anesthesia.On the day of anes-thesia,the mice in Mem+Sev group received an intraperitoneal injection of 20 mg/kg Mem dissolved in normal saline,while those in control and Sev groups received intraperitoneal injection of an equivalent volume of normal saline based on body weight.Thirty minutes later,the mice in Sev and Mem+Sev groups were anesthetized with 400 mL/min O2+3%Sev for 5 h,and those in control group were treated with 400 mL/min O2 for 5 h.Spatial navigation and exploration tests were conducted 3 d after anesthesia.After the tests,the mice were sacrificed,and their hippocampal tissues were collected.The levels of interleukin-1β(IL-1β),tumor necrosis factor-α(TNF-α)and acetylcholine(ACh)in the hippocampal tis-sues were detected by ELISA.The concentration of Ca2+in the hippocampal tissues was measured using a calcium assay kit.Pathological changes in the hippocampal CA3 region were observed by HE staining,and the protein levels of NMDA receptor GluN1 subunit,GABAA receptor,amyloid β-protein(Aβ),and p-tau were detected by Western blot.RE-SULTS:Compared with control group,the mice in Sev group had increased burst suppression ratio at all time points dur-ing anesthesia and prolonged escape latency and reduced platform crossings 3 d after anesthesia(P<0.05).The levels of IL-1β and TNF-α in the hippocampal tissues increased,while the level of ACh decreased,and the concentration of Ca2+in-creased.The protein levels of GluN1 subunit,Aβ and p-tau were elevated(P<0.05).Compared with Sev group,the mice in Mem+Sev group had shortened anesthesia induction time and increased burst suppression ratio at all time points during anesthesia,with elevated relative power of slow waves and δ waves(P<0.05).The escape latency was shortened,and the platform crossings increased 3 d after anesthesia(P<0.05).The levels of IL-1β and TNF-α in the hippocampal tissues decreased,while the levels of ACh increased,and the protein levels of GluN1 subunit,Aβ and p-tau were reduced(P<0.05).There was no significant difference in anesthesia recovery time among the groups(P>0.05).CONCLU-SION:Memantine,in combination with Sev anesthesia,accelerates anesthesia induction and deepens anesthetic depth,which may be related to the increased relative power of δ EEG waves,but has no significant effect on recovery time.Me-mantine intervention alleviates Sev anesthesia-induced cognitive disorders by inhibiting the overexpression of NMDA recep-tors,Aβ and p-tau,and attenuating neuroinflammation.

AIM:To investigate the effects of memantine(Mem),an N-methyl-D-aspartate(NMDA)recep-tor antagonist,on sevoflurane(Sev)anesthetic depth and perioperative neurocognitive disorders in mice,and to explore the possible mechanisms involved.METHODS:Mouse electroencephalogram(EEG)monitoring and cognitive disorder models were established.For EEG monitoring,male C57BL/6J mice were randomly divided into control group,Sev group,and Mem+Sev group.The EEG monitoring electrodes were implanted in the heads of the mice 7 d before anesthe-sia.On the day of anesthesia,the mice in Mem+Sev group received an intraperitoneal injection of 20 mg/kg Mem dissolved in normal saline,while those in control and Sev groups received intraperitoneal injection of an equivalent volume of normal saline based on body weight.Thirty minutes later,the mice in Sev and Mem+Sev groups were anesthetized with 400 mL/min O2+3%Sev for 5 h,while those in control group were treated with 400 mL/min O2 for 5 h.The EEG monitoring was ter-minated after the righting reflex was restored in Sev and Mem+Sev groups.The time of disappearance and recovery of the righting reflex was recorded,and changes in EEG burst suppression ratio and relative power of each frequency band were analyzed.For the cognitive disorder part,another batch of male C57BL/6J mice were selected and divided into the same groups as before.The mice underwent water maze spatial navigation training for 6 d before anesthesia.On the day of anes-thesia,the mice in Mem+Sev group received an intraperitoneal injection of 20 mg/kg Mem dissolved in normal saline,while those in control and Sev groups received intraperitoneal injection of an equivalent volume of normal saline based on body weight.Thirty minutes later,the mice in Sev and Mem+Sev groups were anesthetized with 400 mL/min O2+3%Sev for 5 h,and those in control group were treated with 400 mL/min O2 for 5 h.Spatial navigation and exploration tests were conducted 3 d after anesthesia.After the tests,the mice were sacrificed,and their hippocampal tissues were collected.The levels of interleukin-1β(IL-1β),tumor necrosis factor-α(TNF-α)and acetylcholine(ACh)in the hippocampal tis-sues were detected by ELISA.The concentration of Ca2+in the hippocampal tissues was measured using a calcium assay kit.Pathological changes in the hippocampal CA3 region were observed by HE staining,and the protein levels of NMDA receptor GluN1 subunit,GABAA receptor,amyloid β-protein(Aβ),and p-tau were detected by Western blot.RE-SULTS:Compared with control group,the mice in Sev group had increased burst suppression ratio at all time points dur-ing anesthesia and prolonged escape latency and reduced platform crossings 3 d after anesthesia(P<0.05).The levels of IL-1β and TNF-α in the hippocampal tissues increased,while the level of ACh decreased,and the concentration of Ca2+in-creased.The protein levels of GluN1 subunit,Aβ and p-tau were elevated(P<0.05).Compared with Sev group,the mice in Mem+Sev group had shortened anesthesia induction time and increased burst suppression ratio at all time points during anesthesia,with elevated relative power of slow waves and δ waves(P<0.05).The escape latency was shortened,and the platform crossings increased 3 d after anesthesia(P<0.05).The levels of IL-1β and TNF-α in the hippocampal tissues decreased,while the levels of ACh increased,and the protein levels of GluN1 subunit,Aβ and p-tau were reduced(P<0.05).There was no significant difference in anesthesia recovery time among the groups(P>0.05).CONCLU-SION:Memantine,in combination with Sev anesthesia,accelerates anesthesia induction and deepens anesthetic depth,which may be related to the increased relative power of δ EEG waves,but has no significant effect on recovery time.Me-mantine intervention alleviates Sev anesthesia-induced cognitive disorders by inhibiting the overexpression of NMDA recep-tors,Aβ and p-tau,and attenuating neuroinflammation.

Objective To evaluate the effects of isoflurane anesthesia on NR1 expression and neuronal apoptosis in the hippocampus and cortex of adult rats .Methods Thirty-six adult male Sprague-Dawley rats , weighing 250-280 g ,were randomly assigned into 3 groups using a random number table :control group (group C , n=6 ) ,O2 inhalation group (group O , n=6 ) and isoflurane anesthesia group (group I , n=24 ) .The rats were exposed to 2% isoflurane (group I) ,to pure oxygen (group O) ,or to air (group C) for 2 h .At 2 h ,and 1 ,7 and 14 days after the rats were awake (T1-4 ) ,Morris water maze test was performed .The rats were then sacrificed and brains were removed for isolation of the hippocampus and cortex .NR1 expression was detected using SABC immuno-histochemical technique and neuronal apoptosis was determined using TUNEL .Results Compared with group C , the escape latency at T2 and total swimming distance at T1 ,2 were significantly prolonged , and the expression of NR1 in hippocampi was down-regulated at T1 ,2 in group I ,and the expression of NR1 in the cortex was down-regulated in O and I groups ( P<0.05) .There was no significant difference in the apoptosis index between the three groups ( P> 0.05 ) .Conclusion Isoflurane anesthesia can decrease the cognitive function transiently ,which is related to inhibition of up-regulation of NR1 expression in the hippocampi ,but not related to neuronal apoptosis in adult rats .

Objective To evaluate the effect of emulsified isoflurane on cognitive function in rats.Methods Seventy-two adult male SD rats,aged 8 weeks,weighing 250-300 g,were randomly divided into 3 groups:normal control group (group C,n =12),intralipid group(group E,n =12),and 8％ emulsified isoflurane group ( group EI,n =48).Morris water maze test was performed at 2 h after administration in group E and at 2 h,1,7,14 d after administration in 12 rats at each time point in group EI.The escape latency,staying time at the original platform quadrant,frequency of crossing the original platform and swimming speed were recorded.Orbital blood samples were taken from 6 rats in each group after water maze test for determination of the plasma corticosterone concentration,and then the animals were sacrificed and their hippocampi were removed for determination of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) contents.Brains were removed from another 6 rats in each group after water maze test for determination of the expression of BDNF and NGF in DG,CA3,CA2,CA1 of hippocampus.Results Compared with group C,in group EI the escape latency at 2 h after administration was prolonged,staying time at the original platform quadrant was shortened,the expression of BDNF in DG and CA3 of hippocampus was down-regulated and the BDNF content in hippocampus was decreased at 2 h and 1 d after administration( P ＜ 0.05 or 0.01).The escape latency was shortened and staying time at the original platform quadrant was prolonged at 7 and 14 d after administration,the content of NGF in hippocampus was increased at 1,7 and 14 d after administration and the expression of BDNF in DG and CA3 of hippocampus was up-regulated at 1d after administration as compared with those at 2 h after administration in group E1( P ＜ 0.05 or 0.01).There was no significant difference in the variables mentioned above between groups E and C( P ＞ 0.05 ).There was no significant difference in plasma corticosterone concentration among the 3 groups ( P ＞ 0.01 ).Conclusion The mechanism by which emulsified isoflurane results in transient cognitive impairment in rats is related to down-regulating the expression of BDNF in hippocampus,but not related to corticosterone and NGF.