The Study Of Effects And Mechanism Of Propofol Toxicity On The Developing Brain In Neonatal Rats

With the fast development of the surgery and anesthesiology of pediatrics, more and more neonates and infants in the peak period of brain development, would receive sedation or general anesthesia. In view of the mechanism of the general anesthetics in the central nervous system is not totally clarified and in these period central nervous system is extraordinarily sensitive to the environment changes, so we are often perplexed in the choose of anesthetics to the neonates and infants.It has been recognized that N-methyl-Daspartate(NMDA) receptor andγ-aminobutyric acid-A(GABA) receptor are the two important target sites of general anesthetics in the CNS:(1)NMDA receptor antagonists, for example, ketamine and nitrous oxide, could block the conduction of excitement in the CNS by blocking glutamate and glycine binding to the NMDA receptor. (2)GABA receptor is a ligand-gated iron channel, which specifically bind to the propofol and midazolam, increasing the opening frequency of the Cl- channel, emerging inhibitory postsynaptic potential, suppressing the fuction of the central nevers system. Since Olney first contrived that the general anesthetics could induce the neuron apoptosis during the period of brain development, series researches have confirmed that many general anesthetics including GABA receptor agonist and NMDA receptor antagonist could trigger widespread apoptotic neurondegeneration and impair long-term cognitive function. Furthermore the period that general anesthetics prone to induce apoptotic neurodegeneration coincides to the peak time of the neural development which involving late pregnancy and early neonatal. Unfortunately, the specific mechanism of the general anesthetics induced neurodegeneration and long- term cognitive injury is not clearly acknowledged, particularly at the molecular level. Currently, scientist believe that anesthetics could active the apoptotic pathway and change the synaptic plasticity while they produce general anesthesia effect, ultimately lead to the increasing of the neurondegeneration and the cognitive function injury. If we could clarify the mechanism of the general anesthetics in the CNS, undoubtedly, it will help to providing theoretic and experiment basis for new drug development. This issue focus on different does and different injection times of propofol to the late pregnant fetal rats and neonatal rats, observe the effect of propofol on apoptotic neurodegeneration and long- term cognitive injury.1,Effects of propofol on neuron apoptosis and expression of NMDAR1 protein and Connexin 43 in fetal rats Objective To observe the effect of propofol repeated injection to pregnant rats on apoptotic neurodegeneration and NMDAR1 protein and Cx43 protein of fetal rats, and investigate the mechanism of apoptotic neurondegeneration triggered by propofol in developing brain. Methods Forty-two female rats that have gravid for 18 days were randomly divided into three groups: group C received intraperitoneal 0.9% normal saline 8ml/kg once per day for three days as control; group L received intraperitoneal propolfol 80mg·kg-1 once per day for three days; and group H received intraperitoneal propofol 120mg·kg-1 once per day for three days. Two hours after the third day injection, two pregnant rats randomly selected from each group were used to detect the blood sugar level. And decapitate all the left pregnant rats and take out fetal rats.48 fetal rats from each group were randomly used to analyze neurons apoptosis and Cx43 and NMDAR1 protein expression levels of this group. Results Compared with group C and group L , group H were founded marked increasing in neuron apoptosis and casepase-8 expression(P<0.01). The expression of NMDAR1 protein and Cx43 protein in group H were higher than those of group C and group L(P<0.05or P<0.01),furthermore, the protein expression was more higher in group H than in group L(P<0.05). Conclusion Continuous exposure of the developing brain during the period of brain growth-spurt to propofol could cause facilitation effect in apoptotic neurondegeneration, and this mechanism might be involved in propofol-induced increasing of NMDAR1 protein and Cx43 protein expression. 2,The study of the effects and mechanism of propofol on long-time cognitive function of neonatal rats Objective To discuss the effects and mechanism of propofol on long-time cognitive function of neonatal rats. Methods 72 seven-day-old male and female S-D rats were randomly divided into three groups(n=24,each): group C received intraperitoneal 0.9% normal saline 7.5ml/kg once per day for seven days as control, group P1 received 0.9% normal saline 7.5ml/kg once per day for six days and propofol 75mg·kg-1 on the seventh day, group P2 received propofol 75mg·kg-1 once per day for seven days. At the end of the 7th day anesthesia, 3 rats from each group were randomly selected to sample the arterial blood to determine the arterial blood gas from the left cardiac ventricle. At the 30th,90th and 180th day, randomly selected 7 rats from each three group to determine the cognitive function, including Morris warter maze and open field test. The animals were decapitated immediately after the tests the hippocampus from CA1 region were isolated for determination of the apoptosis rate and the morphology analysis of the pyramid cells. Results Long-term cognitive function decline were discovered in P2 group at 30th day compare to the other two groups(P<0.05), furthermore the neuron apoptosis rate was significantly higher and the surface area density and volume density of the pyramid cells was apparently decreased in P2 group at 30th day(P<0.05). At 90th and 180th day, there were no significant differences in neuron apoptosis rate and pyramid cell surface area density and volume density(P > 0.05). Conclusion Long-term cognitive function injury was discovered in neonatal rats that received multiple does of propofol, this could be attributed to propofol induced apoptotic neurondegeneration and the injury of the pyramid cells. And the cognitive function injury was disappear in adolescent period. While single does of propofol will not induce long-term cognitive function injury.