异氟醚与手术对老龄大鼠海马Cyt.C和ChAT表达及认知功能的影响研究
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摘要
背景与目的
术后认知功能障碍(postoperative cognitive dysfunction,POCD)是指术前无精神障碍的病人,受多种因素的影响,在麻醉及手术后数天至数周出现认知能力减退、焦虑、记忆受损、语言理解能力和社会融合能力减退为临床特点的并发症,易发生于老年人。近年来尽管医疗技术水平的提高使围术期的死亡率和并发症大大降低,但POCD的发生率却居高不下,引起了临床上的广泛关注,然相关因素的确切影响及其分子机制仍未知。以往的研究认为老龄是POCD发生的确定危险因素,同时,越来越多的研究表明,麻醉药和手术成为POCD发生最密切关联的两大因素。而目前的研究认为海马胆碱能神经元的损伤是认知功能受损害的形态学基础,ChAT是生成乙酰胆碱的限速酶,常作为研究胆碱能神经元的特殊标志。在中枢神经系统损伤的研究中,细胞凋亡导致的神经元数量减少已作为包括阿尔兹海默病(Alzheimer’s disease,AD)在内的多种神经退行性疾病认知功能减退的可能基础,作为细胞凋亡的研究,近年来,人们逐渐认识到线粒体可能是调控细胞凋亡的中心,线粒体Cyt.C释放到胞浆是线粒体凋亡途径的主要特征。基于上述理由,我们推测在老龄后中枢胆碱能神经系统退行性变的基础上,异氟醚或手术通过经典的线粒体凋亡信号通路诱导海马神经细胞凋亡,损伤中枢胆碱能神经系统,进而引发POCD,这正是本研究立题的目的所在。本研究采用Morris水迷宫实验、免疫组化、反转录聚合酶链式反应(reverse transcriptase polymerase chain reactio,RT-PCR)、蛋白质印记(Western blot)等技术和方法,通过检测海马神经元胆碱乙酰转移酶(Choline acetyltransferase,ChAT)和胞浆内细胞色素C(Cytochrome C,Cyt.C)的表达水平变化、大鼠空间学习记忆能力的改变,探讨POCD发生的确切原因和可能机制。
方法
实验分三部分:
健康雄性老龄SD大鼠103只,年龄20月龄,体重500g～600g,随机分为4组,对照组(C组)、0.75%异氟醚麻醉组(I1组)、1.5%异氟醚麻醉组(I2组)和手术组(O组)。C组吸入30%氧气2 h(n=16); I1组吸入0.75%异氟醚和30%氧气2 h(n=29);I2组吸入1.5%异氟醚和30%氧气2 h(n=29); O组吸入1.5%异氟醚和30%氧气2 h,并实施腹部手术(n=29)。在麻醉和手术中,维持动脉血氧饱和度≥95%,体温37.8℃～38.7℃,各组随机抽取5只大鼠在0.5、1、1.5 h时间点取动脉血样0.3ml,采用ABL700血气分析仪行血气分析,其后脱离实验。
1、异氟醚与手术对老龄大鼠认知功能的影响
麻醉结束后或术后24 h进行Morris水迷宫实验,测定认知功能。
2、异氟醚与手术对老龄大鼠海马ChAT表达的影响
麻醉结束后或术后24 h 10%水合氯醛腹腔麻醉成功后,取脑并分离海马,免疫组化法和RT-PCR法检测ChAT的表达。
3、异氟醚与手术对老龄大鼠海马胞浆内Cyt.C表达的影响
麻醉结束后或术后24 h 10%水合氯醛腹腔麻醉成功后,取脑并分离海马,免疫组化法和Western blot法检测Cyt.C的表达。
结果
1、实验动物的一般情况
异氟醚麻醉或手术中生命体征平稳,大鼠口唇及肢端部位红润,无体动、低血压、呼吸抑制和缺氧征象出现,说明麻醉效果满意。同时,各组大鼠间天龄、体重、游泳速度、麻醉或手术中血氧饱和度和血气分析各项指标差异无统计学性意义(P>0.05),排除了相关因素对认知功能改变的干扰。
2、老龄大鼠认知功能的改变
2.1定位航行试验结果显示,各组大鼠随着训练天数的增加,逃避潜伏期缩短,说明逐渐产生学习记忆;与C组比较,I1组、I2组和O组老龄大鼠2d～5d逃避潜伏期延长(p<0.05),学习曲线后移,至第四天渐趋稳定,而C组第3天趋于稳定;与I2组比较,O组4d～5d逃避潜伏期延长(P<0.05);I1组和I2组之间差异无统计学意义(P>0.05)。
2.2空间探索试验结果显示,与C组比较,I1组、I2组和O组老龄大鼠停留原平台象限时间和穿越原平台次数减少(p<0.05);与I2组比较,O组4d～5d停留原平台象限时间减少(P<0.05);I1组和I2组之间差异无统计学意义(P>0.05)。
3、海马ChAT表达水平的改变
与C组比较,I1组、I2组和O组海马ChAT的转录水平降低(p<0.05),蛋白的表达水平也降低(p<0.05);I1组和I2组之间无显著性差异(P>0.05);与I2组比较,O组海马ChAT表达水平降低(p<0.05)。
4、海马胞浆Cyt.C表达水平的改变
与C组比较,I1组、I2组和O组海马胞浆Cyt.C蛋白的表达水平增多(p<0.05);与I1组比较,I2组海马胞浆Cyt.C蛋白的表达水平增多(p<0.05);与I2组比较,O组海马胞浆Cyt.C蛋白的表达水平增多(p<0.05)。
结论
1、通过Morris水迷宫实验,证实异氟醚麻醉可导致老龄大鼠的早期认知功能减退,但无本研究范围内浓度差异,联合手术操作可加重此种损伤。
2、异氟醚与手术可引起海马神经元ChAT表达减少和胞浆内Cyt.C表达增多,并且这种表达水平变化与老龄大鼠早期认知能力减退形成规律一致,提示麻醉与手术在老龄大鼠中枢胆碱能神经系统发生退行性改变的基础上,可能诱导海马神经元凋亡的发生,损伤海马胆碱能神经系统,进而引发老龄大鼠认知功能减退。
Background and purpose
Postoperative cognitive dysfunction (POCD) defined as patients without mental disorders before operation suffered cognitive decline, impaired memory, declined language comprehension and social integration ability a few days or several weeks after anesthesia and operation. This phenomenon usually occurres in the old people.In recent years, the high incidence of POCD attracts widespread attention, but the exact factors and mechanisms are still unknown. Previous studies showed that aging was the exact risk factors of POCD, At the same time, increasing evidences indicated that anesthetics and operation were closely correlated with the occurrence of POCD. The previous study suggested that the damage of hippocampal cholinergic neurons was the morphological basis of the decline of cognitive function. Choline acetyltransferase (ChAT), a rate-limiting enzyme, is always regarded as the special symbol of the cholinergic neurons. Study on the central nervous system showed that the reduction in the number of neurons due to apoptosis might be the basis of cognitive decline in various neurodegenerative diseases including Alzheimer's disease (AD). With the increasing study of apoptosis, it has gradually been realized that mitochondria may be the central regulation of apoptosis and the release of mitochondrial Cytochrome C (Cyt.C) into the cytoplasm is the main feature of mitochondrial apoptosis pathway. Based on the theories mentioned above, we speculated that, on the basis of central cholinergic system degeneration, isoflurane or operation might induce neuronal apoptosis through the classical mitochondrial apoptosis pathway and caused the damage of cholinergic nervous system and then triggered POCD. this was the main content of this study. In the present study, we adopted Morris water maze test, immunohistochemistry and reverse transcription polymerase chain reaction for observation the changes of choline acetyltransferase of hippocampal neurons and Cyt.C of cytoplasm expression and cognitive function in elder rats to explore the exact factors and the possible mechanism of POCD.
Methods
One hundred and three aged (20 months old) male Sprague-Dawley(SD) rats weighing 500-600g were randomly divided into 4 groups: group C inhaled 30% O2 for 2 h(control,n=16); group I1 was anesthetized with 0.75% isoflurane in 30% O2 for 2 h(0.75% isoflurane,n=29); group I2 was anesthetized with 1.5% isoflurane in 30% O2 for 2 h(1.5% isoflurane,n=29); operation group O underwent abodominal operation under 1.5% isoflurane (in 30% O2) for 2 h(operation,n=29). In the course of anesthesia and surgery, arterial oxygen saturation was maintained between 95% and 100% and body temperature was kept 37.8℃～38.7℃.Five rats were randomly selected from each group and arterial blood samples (0.3ml) were obtained at 0.5,1 and 2 h for blood gas analysis by ABL700 blood gas analyzer.
1. Effects of isoflurane and surgical operation on cognitive function in aged rats. Cognitive function was assessed by Morris water maze test at 24 h after anesthesia or operation.
2. Effects of isoflurane and surgical operation on the expression of ChAT in hippocampus in aged rats
24 h after anesthesia or operation, the animals were anesthetized with 10% chloral hydrate intraperitoneally. Then the animals were killed and their brains were immediately removed for the detection of the expression of ChAT in hippocampus by RT-PCR and immunohistochemistry.
3. Effects of isoflurane and surgical operation on the expression of Cyt.C in hippocampus cytoplasm in aged rats
24 h after anesthesia or operation, the animals were anesthetized with 10% chloral hydrate intraperitoneally. Then the animals were killed and their brains were immediately removed for the detection of the expression of Cyt.C in hippocampus cytoplasm by Western blot and immunohistochemistry.
Result
1. General state of experimental animals
During the period of anesthesia and operation, the vital signs of rats were stable; Lips were rosy, as well as the end part of the body; No limb movement, hypotension, respiratory depression and hypoxia signs were found. There weren’t significant difference between the groups in age, body weight, swimming speed, blood oxygen saturation and blood gas analysis (P>0.05).
2. Change of cognitive function in aged rat
2.1 The results of place navigation test showed that the escape latency of rats became shorter with the increase of the training days, which showed that the learning and memory were gaining gradually. Learning and memory curve was shift right in group I1, group I2 and group O, and turned to be stable at the 4th day but at the 3rd day in group C. At day 2, 3, 4 and 5 after treatment, the escape latency in group I1, group I2 and group O were observed significantly longer compared with group C(P<0.05). The escape latency at day 4 and 5 was significantly longer in group O than that in group I2(P<0.05).No significant differences was found between group I1 and group I2(P>0.05).
2.2 The results of spatial probe test showed that the frequency of crossing the original platform and the time consumption of staying at the original platform quadrant was lower in group I1, group I2 and group C compared with those in group C(P<0.05). The time consumption of staying at the original platform quadrant at day 4 and 5 was significantly lower in group O than that in group I2(P<0.05).There weren’t significant differences between group I1 and group I2.
3. Change of ChAT expressions in hippocampus
Compared with group C, the mRNA and protein expression levels of ChAT in hippocampus in aged rats was significantly lower in group I1, group I2 and group O(P<0.05). No significant difference was found between group I1 and group I2(P>0.05). The mRNA and protein expressions of ChAT was significantly lower in group O than group I2(P<0.05).
4. Change of Cyt.C expressions in hippocampal cytoplasm
Compared with group C, the protein expression levels of Cyt.C were significantly increased in group I1, group I2 and group O(P<0.05). At the same time, The protein expression level of Cyt.C was lower in group I1 compared with group I2(P<0.05). The protein expression level of Cyt.C was higher in group O than that in group I2(P<0.05).
Conclusion
1. Isoflurane reduced cognitive function in aged rats in the early period after anesthesia and operation, and operation further increased this damage.
2. Isoflurane or operation resulted in the reduced expression of ChAT and the increased expression of cytosolic Cyt.C in neurons in hippocampal. Operation aggravated these changes in the expressions of ChAT and Cyt.C. This abnormal change of the expression levels of ChAT and Cyt.C was consistent with the cognitive decline in rats. This suggests that anesthesia or operation based on degeneration of the central cholinergic system induced apoptosis in hippocampal neurons and damaged hippocampal cholinergic nervous system, and in turn leaded to cognitive dysfunction in aged rats. This was the possible mechanisms of POCD.
术后认知功能障碍(postoperative cognitive dysfunction,POCD)是指术前无精神障碍的病人,受多种因素的影响,在麻醉及手术后数天至数周出现认知能力减退、焦虑、记忆受损、语言理解能力和社会融合能力减退为临床特点的并发症,易发生于老年人。近年来尽管医疗技术水平的提高使围术期的死亡率和并发症大大降低,但POCD的发生率却居高不下,引起了临床上的广泛关注,然相关因素的确切影响及其分子机制仍未知。以往的研究认为老龄是POCD发生的确定危险因素,同时,越来越多的研究表明,麻醉药和手术成为POCD发生最密切关联的两大因素。而目前的研究认为海马胆碱能神经元的损伤是认知功能受损害的形态学基础,ChAT是生成乙酰胆碱的限速酶,常作为研究胆碱能神经元的特殊标志。在中枢神经系统损伤的研究中,细胞凋亡导致的神经元数量减少已作为包括阿尔兹海默病(Alzheimer’s disease,AD)在内的多种神经退行性疾病认知功能减退的可能基础,作为细胞凋亡的研究,近年来,人们逐渐认识到线粒体可能是调控细胞凋亡的中心,线粒体Cyt.C释放到胞浆是线粒体凋亡途径的主要特征。基于上述理由,我们推测在老龄后中枢胆碱能神经系统退行性变的基础上,异氟醚或手术通过经典的线粒体凋亡信号通路诱导海马神经细胞凋亡,损伤中枢胆碱能神经系统,进而引发POCD,这正是本研究立题的目的所在。本研究采用Morris水迷宫实验、免疫组化、反转录聚合酶链式反应(reverse transcriptase polymerase chain reactio,RT-PCR)、蛋白质印记(Western blot)等技术和方法,通过检测海马神经元胆碱乙酰转移酶(Choline acetyltransferase,ChAT)和胞浆内细胞色素C(Cytochrome C,Cyt.C)的表达水平变化、大鼠空间学习记忆能力的改变,探讨POCD发生的确切原因和可能机制。
方法
实验分三部分:
健康雄性老龄SD大鼠103只,年龄20月龄,体重500g～600g,随机分为4组,对照组(C组)、0.75%异氟醚麻醉组(I1组)、1.5%异氟醚麻醉组(I2组)和手术组(O组)。C组吸入30%氧气2 h(n=16); I1组吸入0.75%异氟醚和30%氧气2 h(n=29);I2组吸入1.5%异氟醚和30%氧气2 h(n=29); O组吸入1.5%异氟醚和30%氧气2 h,并实施腹部手术(n=29)。在麻醉和手术中,维持动脉血氧饱和度≥95%,体温37.8℃～38.7℃,各组随机抽取5只大鼠在0.5、1、1.5 h时间点取动脉血样0.3ml,采用ABL700血气分析仪行血气分析,其后脱离实验。
1、异氟醚与手术对老龄大鼠认知功能的影响
麻醉结束后或术后24 h进行Morris水迷宫实验,测定认知功能。
2、异氟醚与手术对老龄大鼠海马ChAT表达的影响
麻醉结束后或术后24 h 10%水合氯醛腹腔麻醉成功后,取脑并分离海马,免疫组化法和RT-PCR法检测ChAT的表达。
3、异氟醚与手术对老龄大鼠海马胞浆内Cyt.C表达的影响
麻醉结束后或术后24 h 10%水合氯醛腹腔麻醉成功后,取脑并分离海马,免疫组化法和Western blot法检测Cyt.C的表达。
结果
1、实验动物的一般情况
异氟醚麻醉或手术中生命体征平稳,大鼠口唇及肢端部位红润,无体动、低血压、呼吸抑制和缺氧征象出现,说明麻醉效果满意。同时,各组大鼠间天龄、体重、游泳速度、麻醉或手术中血氧饱和度和血气分析各项指标差异无统计学性意义(P>0.05),排除了相关因素对认知功能改变的干扰。
2、老龄大鼠认知功能的改变
2.1定位航行试验结果显示,各组大鼠随着训练天数的增加,逃避潜伏期缩短,说明逐渐产生学习记忆;与C组比较,I1组、I2组和O组老龄大鼠2d～5d逃避潜伏期延长(p<0.05),学习曲线后移,至第四天渐趋稳定,而C组第3天趋于稳定;与I2组比较,O组4d～5d逃避潜伏期延长(P<0.05);I1组和I2组之间差异无统计学意义(P>0.05)。
2.2空间探索试验结果显示,与C组比较,I1组、I2组和O组老龄大鼠停留原平台象限时间和穿越原平台次数减少(p<0.05);与I2组比较,O组4d～5d停留原平台象限时间减少(P<0.05);I1组和I2组之间差异无统计学意义(P>0.05)。
3、海马ChAT表达水平的改变
与C组比较,I1组、I2组和O组海马ChAT的转录水平降低(p<0.05),蛋白的表达水平也降低(p<0.05);I1组和I2组之间无显著性差异(P>0.05);与I2组比较,O组海马ChAT表达水平降低(p<0.05)。
4、海马胞浆Cyt.C表达水平的改变
与C组比较,I1组、I2组和O组海马胞浆Cyt.C蛋白的表达水平增多(p<0.05);与I1组比较,I2组海马胞浆Cyt.C蛋白的表达水平增多(p<0.05);与I2组比较,O组海马胞浆Cyt.C蛋白的表达水平增多(p<0.05)。
结论
1、通过Morris水迷宫实验,证实异氟醚麻醉可导致老龄大鼠的早期认知功能减退,但无本研究范围内浓度差异,联合手术操作可加重此种损伤。
2、异氟醚与手术可引起海马神经元ChAT表达减少和胞浆内Cyt.C表达增多,并且这种表达水平变化与老龄大鼠早期认知能力减退形成规律一致,提示麻醉与手术在老龄大鼠中枢胆碱能神经系统发生退行性改变的基础上,可能诱导海马神经元凋亡的发生,损伤海马胆碱能神经系统,进而引发老龄大鼠认知功能减退。
Background and purpose
Postoperative cognitive dysfunction (POCD) defined as patients without mental disorders before operation suffered cognitive decline, impaired memory, declined language comprehension and social integration ability a few days or several weeks after anesthesia and operation. This phenomenon usually occurres in the old people.In recent years, the high incidence of POCD attracts widespread attention, but the exact factors and mechanisms are still unknown. Previous studies showed that aging was the exact risk factors of POCD, At the same time, increasing evidences indicated that anesthetics and operation were closely correlated with the occurrence of POCD. The previous study suggested that the damage of hippocampal cholinergic neurons was the morphological basis of the decline of cognitive function. Choline acetyltransferase (ChAT), a rate-limiting enzyme, is always regarded as the special symbol of the cholinergic neurons. Study on the central nervous system showed that the reduction in the number of neurons due to apoptosis might be the basis of cognitive decline in various neurodegenerative diseases including Alzheimer's disease (AD). With the increasing study of apoptosis, it has gradually been realized that mitochondria may be the central regulation of apoptosis and the release of mitochondrial Cytochrome C (Cyt.C) into the cytoplasm is the main feature of mitochondrial apoptosis pathway. Based on the theories mentioned above, we speculated that, on the basis of central cholinergic system degeneration, isoflurane or operation might induce neuronal apoptosis through the classical mitochondrial apoptosis pathway and caused the damage of cholinergic nervous system and then triggered POCD. this was the main content of this study. In the present study, we adopted Morris water maze test, immunohistochemistry and reverse transcription polymerase chain reaction for observation the changes of choline acetyltransferase of hippocampal neurons and Cyt.C of cytoplasm expression and cognitive function in elder rats to explore the exact factors and the possible mechanism of POCD.
Methods
One hundred and three aged (20 months old) male Sprague-Dawley(SD) rats weighing 500-600g were randomly divided into 4 groups: group C inhaled 30% O2 for 2 h(control,n=16); group I1 was anesthetized with 0.75% isoflurane in 30% O2 for 2 h(0.75% isoflurane,n=29); group I2 was anesthetized with 1.5% isoflurane in 30% O2 for 2 h(1.5% isoflurane,n=29); operation group O underwent abodominal operation under 1.5% isoflurane (in 30% O2) for 2 h(operation,n=29). In the course of anesthesia and surgery, arterial oxygen saturation was maintained between 95% and 100% and body temperature was kept 37.8℃～38.7℃.Five rats were randomly selected from each group and arterial blood samples (0.3ml) were obtained at 0.5,1 and 2 h for blood gas analysis by ABL700 blood gas analyzer.
1. Effects of isoflurane and surgical operation on cognitive function in aged rats. Cognitive function was assessed by Morris water maze test at 24 h after anesthesia or operation.
2. Effects of isoflurane and surgical operation on the expression of ChAT in hippocampus in aged rats
24 h after anesthesia or operation, the animals were anesthetized with 10% chloral hydrate intraperitoneally. Then the animals were killed and their brains were immediately removed for the detection of the expression of ChAT in hippocampus by RT-PCR and immunohistochemistry.
3. Effects of isoflurane and surgical operation on the expression of Cyt.C in hippocampus cytoplasm in aged rats
24 h after anesthesia or operation, the animals were anesthetized with 10% chloral hydrate intraperitoneally. Then the animals were killed and their brains were immediately removed for the detection of the expression of Cyt.C in hippocampus cytoplasm by Western blot and immunohistochemistry.
Result
1. General state of experimental animals
During the period of anesthesia and operation, the vital signs of rats were stable; Lips were rosy, as well as the end part of the body; No limb movement, hypotension, respiratory depression and hypoxia signs were found. There weren’t significant difference between the groups in age, body weight, swimming speed, blood oxygen saturation and blood gas analysis (P>0.05).
2. Change of cognitive function in aged rat
2.1 The results of place navigation test showed that the escape latency of rats became shorter with the increase of the training days, which showed that the learning and memory were gaining gradually. Learning and memory curve was shift right in group I1, group I2 and group O, and turned to be stable at the 4th day but at the 3rd day in group C. At day 2, 3, 4 and 5 after treatment, the escape latency in group I1, group I2 and group O were observed significantly longer compared with group C(P<0.05). The escape latency at day 4 and 5 was significantly longer in group O than that in group I2(P<0.05).No significant differences was found between group I1 and group I2(P>0.05).
2.2 The results of spatial probe test showed that the frequency of crossing the original platform and the time consumption of staying at the original platform quadrant was lower in group I1, group I2 and group C compared with those in group C(P<0.05). The time consumption of staying at the original platform quadrant at day 4 and 5 was significantly lower in group O than that in group I2(P<0.05).There weren’t significant differences between group I1 and group I2.
3. Change of ChAT expressions in hippocampus
Compared with group C, the mRNA and protein expression levels of ChAT in hippocampus in aged rats was significantly lower in group I1, group I2 and group O(P<0.05). No significant difference was found between group I1 and group I2(P>0.05). The mRNA and protein expressions of ChAT was significantly lower in group O than group I2(P<0.05).
4. Change of Cyt.C expressions in hippocampal cytoplasm
Compared with group C, the protein expression levels of Cyt.C were significantly increased in group I1, group I2 and group O(P<0.05). At the same time, The protein expression level of Cyt.C was lower in group I1 compared with group I2(P<0.05). The protein expression level of Cyt.C was higher in group O than that in group I2(P<0.05).
Conclusion
1. Isoflurane reduced cognitive function in aged rats in the early period after anesthesia and operation, and operation further increased this damage.
2. Isoflurane or operation resulted in the reduced expression of ChAT and the increased expression of cytosolic Cyt.C in neurons in hippocampal. Operation aggravated these changes in the expressions of ChAT and Cyt.C. This abnormal change of the expression levels of ChAT and Cyt.C was consistent with the cognitive decline in rats. This suggests that anesthesia or operation based on degeneration of the central cholinergic system induced apoptosis in hippocampal neurons and damaged hippocampal cholinergic nervous system, and in turn leaded to cognitive dysfunction in aged rats. This was the possible mechanisms of POCD.
引文
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