| ObjectivePostoperative cognitive dysfunction (POCD) is a central nervous system complications which seriously affecting the quality of life of patients and a heavy burden on family and society caused by surgery, anesthesia and other factors.Because of the pathogenesis of POCD is not only very complex, but its mechanism is also different opinions.There are many unknown areas in the epidemiology, etiology, pathogenesis, prevention and treatment, etc.Therefore, the study of POCD has important medical and social significance.Isoflurane is a very popular clinical application of inhaled anesthetics.A study reported that isoflurane anesthesia on postoperative cognitive dysfunction was obvious.As with other diseases, the mitogen-activated protein kinases signal transduction pathway also plays an essential role in the process of cognitive dysfunction.p38MAPK is an important member of the MAPKs family, which was involved in cell proliferation, apoptosis and differentiation, plays an important role in apoptosis of neuronal cells.Recent studies have also found that p38MAPK signaling pathway plays an important role in the process of the learning and memory downing induced by the IL-1β, and it can be activated by many pro-inflammatory cytokines such as TNFα, IL-1 and other factors.The objective of this study was to evaluate cognitive function caused by isoflurane in neonatal rats,,and the expression of p38 protein and IL-1βmRNA in hippocampus tissue, which is possible in future clinical prevention and providing theoretical guidance by discussing the relationship between cognitive impairment and p38 pathway and its possible mechanism.Methods Use of homemade anesthetic gas inhalation cases to SD rats inhaled 1.2%(0.8MAC) and 1.8%(1.3MAC) of isoflurane inhalation for 4h.Select 112 normal activities male SD rats of SPF level randomly divide into 7 groups 7 days after birth(n=16), add liquid (intraperitoneal injection of glucose saline 0.5ml/time, usually 1-2 times can be) during anesthesia as the case,to observe whether hypoxia and vital signs are normal:①Group A, control group (n=16):do not do special handling;②Group B,1.2% isoflurane group (n=16):Using homemade box inhalation anesthetic isoflurane 1.2%;③Group C:1.8% isoflurane group (n=16):Using homemade box inhalation anesthetic isoflurane 1.8%;④Group D:1.2% Isoflurane+inhibitor (SB203580) group (n=16):intraperitoneal injection inhibitor SB203580 10mg/ml 30min before anesthesia, using homemade box inhalation anesthetic isoflurane 1.2%;⑤Group E:1.8% Isoflurane+inhibitor (SB203580) group (n=16):intraperitoneal injection inhibitor SB203580 10mg/ml 30min before anesthesia, using homemade box inhalation anesthetic isoflurane 1.8%;⑥Group F:1.2% isoflurane+IL-1βgroup (n= 16):intraperitoneal injection IL-1βcytokine lOug/ml 30min before anesthesia, using homemade box inhalation anesthetic isoflurane 1.2%;⑦Group G:1.8% isoflurane+IL-1βgroup (n= 16):intraperitoneal injection IL-1βcytokine 10ug/ml 30min before anesthesia, using homemade box inhalation anesthetic isoflurane 1.8%.Return to the breeding boxes and cages for 6 weeks after anesthesia. Observed rats for the activity, eating, breathing, vertical hair, diarrhea, sunken eyes, urine, etc. at different time points, the dead animals were excluded and re-making model to add. Implement Morris water maze test after 6 weeks,analysis of data for assessmenting the cognitive level;rats were killed within 24h after the Morris water maze test, stripped hippocampus for testing the expression of p38 protein and IL-1βmRNA in hippocampal tissue.Results1.The time of isoflurane groups in the navigation test finding the platform the escape latency (T1) within 2 min is significantly longer than the control group (P<0.05), while experiments in space exploration, the exploration time (T2)within 30s staying the original time of the quadrant platform is significantly shorter than the control group (P<0.05);For different concentrations of isoflurane group, T1 of the high concentration (1.8%) group was significantly longer than that of the low concentration (1.2%) group (P<0.05); T2 of the high concentration (1.8%) group was significantly shorter than that of the low concentration of (1.2%) group (P<0.05);p38 protein and IL-1βmRNA expression of isofiurane groups is significantly higher (P<0.05).2.Inhibitor groups in the navigation test, the escape latency (Tl) was significantly shorter than the groups for same concentration of isoflurane (P<0.05), while experiments in space exploration, the exploration time (T2) was significantly longer than the group for same concentration of isoflurane (P<0.05); Of the different concentrations of inhibitor groups,(P> 0.05), not statistically significant; Comparing Tl and T2 of two inhibitor groups with control (P> 0.05), not statistically significant;p38 protein expression of inhibitor groups was significantly lower than the groups for same concentration of isoflurane (P<0.05);Comparing the expression of p38 protein for two Inhibitor groups and control group,(P>0.05), was not statistically significant, Comparing the expression of p38 protein for two Inhibitor groups, (P> 0.05), was not statistically significant;Comparing the expression of IL-1βmRNA of two inhibitor groups and the groups for same concentration of isoflurane,(P>0.05), was not statistically significant,Respectively comparing the expression of IL-1βmRNA of two inhibitor groups and the control group, (P<0.05);Of IL-1βmRNA of two inhibitor groups,(P> 0.05),was not statistically significant;3.Isoflurane groups in the navigation test,the escape latency (Tl) was significantly shorter than the groups for same concentration of IL-1β(P<0.05), while experiments in space exploration, the exploration time (T2)is significantly longer than the group for same concentration of IL-1β(P<0.05); Of the different IL-1βgroups,(P> 0.05), not statistically significant; IL-1βgroups in the navigation test,the escape latency (Tl) was significantly longer than the control group(P<0.05), while experiments in space exploration, the exploration time (T2)is significantly shorter than the control group (P<0.05);p38 protein expression of IL-1βgroups is significantly higher than that of the same concentration of isoflurane groups(P<0.05);Respectively comparing p38 protein expression of IL-1βgroups with control group(P<0.05);Of the p38 protein expression of two IL-1βgroups (P> 0.05), was not statistically significant;Comparing the IL-1βmRNA expression of IL-1βgroups with the same concentration of isoflurane groups, (P<0.05);Of the IL-1βmRNA expression of two IL-1βgroups (P> 0.05), Respectively comparing IL-1βmRNA expression of IL-1βgroups with control group(P<0.05),not statistically significant.Conclusion1. Isoflurane inhalation can cause cognitive dysfunction in neonatal rats, and lasted for 6 weeks or even longer.2. Cognitive impairment caused by isoflurane inhalation in neonatal rats is possible positive correlation for the concentration.3.The expression levels of p38 protein and IL-1βmRNA for the rats is rised after inhalation of isoflurane.4.1ntraperitoneal injection of p38 pathway inhibitor SB203580, can effectively inhibit the p38 pathway and reduce cognitive impairment. This may provide valuable theoretical reference to the clinical control of POCD.5.1ntraperitoneal injection of IL-1βcytokines, may enhance the p38 pathway activation in rats, increasing the degree of cognitive impairment.6.The possible mechanism of cognitive impairment induced by isoflurane in neonatal rats are:to promote the expression of IL-1βmRNA and p38 protein in hippocampus, activate the p38MAPK pathway through abnormal expression of IL-1β, and play a role in further to cognitive impairment.In summary, p38 pathway is closely related to cognitive dysfunction induced by isoflurane in neonatal rats, playing an important role in this process;Cognitive dysfunction induced by isoflurane in neonatal rats is possible realized by the activation of p38 pathway implementation. IL-1β, as an activator of p38 pathway,plays an important role in the development of cognitive dysfunction, but not the exclusion the impact of other inflammatory factors such as TNF-a and IL-6.
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