猴脑常温不同缺血时限下选择性超深低温对脑细胞骨架蛋白影响的研究
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摘要
【目的】观察猴脑常温缺血0分钟、10分钟、15分钟、20分钟后进行选择性脑超深低温复苏对脑细胞骨架蛋白β-tubulin、MAP-2、Vimentin和GFAP表达的变化,以了解脑缺血后选择性超深低温复苏对猴神经元及神经胶质细胞的骨架的影响,探讨猴脑常温缺血复苏的极限时间。
【方法】健康成年恒河猴15只,雄性,随机分为四组,0分钟组(双侧颈动脉阻断立即超深低温灌注组,简称0分钟组,n=4),10分钟组(双侧颈动脉常温阻断10分钟超深低温灌注组,简称10分钟组,n=4),15分钟组(双侧颈动脉常温阻断15分钟超深低温灌注组,简称15分钟组,n=4),20分钟组(双侧颈动脉常温阻断20分钟超深低温灌注组,简称20分钟组,n=3)。右侧颈内动脉远心端插管连接冷灌注系统,右侧颈内静脉远心端及双侧股静脉近心端插管连接超滤复温装置,建立脑局部体外循环。夹闭双侧颈外动静脉、在侧颈内动静脉常温缺血后向右侧颈内动脉内注入4℃林格氏液,维持脑温≤16℃60分钟。手术前后行头颅MRI检查,术后行神经功能缺失评分。实验猴灌注或复苏死亡后立即开颅取脑,长期存活猴饲养到术后4周处死开颅取脑。免疫组纵化学法检测神经细胞β-tubulin、MAP-2及神经胶质细胞Vimentin和GFAP蛋白的表达水平。
【结果】0分钟组(n=4)、10分钟组(n=4)安全复苏并长期存活,术中、术后血流动力学稳定,术后头颅MRI检查未见异常,术后神经功能评分无异常。15分钟组(n=4)长期存活2只,重残1只,死亡1只。20分钟组于灌注后未能安全复苏,全部死亡。免疫组化结果表明,20分钟组及15分钟组与0分钟组比较和20分钟组及15分钟组与10分钟组比较,神经元微管蛋白的β-tubulin、MAP-2表达下降P＜0.01,神经胶质细胞的Vimentin和GFAP表达明显升高P＜0.01。10分钟组与0分钟组比较和20分钟组与15分钟组比较则差异没有统计学意义。
【结j沦】(1)灵长类动物恒河猴可以在单侧颈内动脉冷灌注的条件下迅速达到脑选择性超深低温(14.3-16℃)。(2)常温下阻断猴双侧颈内动脉血流0分钟、10分钟行脑选择性超深低温灌注60分钟后可安全复苏并长期存活,对血流动力学、脑组织及神经功能无明显影响,超深低温具有明显脑保护作用。(3)常温下缺血15分钟行选择性超深低温复苏是可能的,但实验猴死残率高。20分钟常温脑缺血后低温灌注,实验猴无法复苏。脑缺血对神经元破坏,出现不可逆性脑损伤,神经元微管蛋白β-tublin,Map-2崩解增加,神经胶质细胞增生及肥大,胶质细胞标记性蛋白GFAP及Vimentin表达明显增强。(4)脑常温缺血后低温复苏的黄金时间可能就为10分钟。15分钟缺血后低温复苏虽有可能挽救生命,但神经功能缺失及死残率均较高,存在较大复苏风险。
[Objective]To understand the influence to the cytoskeleton of neuron and glia cell by studying the expression of cytoskeletons proteinβ-tubulin,MAP-2,Vimentin and GFAP in experimental monkeys with occluding bilateral internal carotid arteries for 60 min under selective cerebral ultra-profound hypothermia after occlusion of cerebral blood flow under different time limits(0,10,15 and 20min),determine the limit time of monkey brain ischemia resuscitation under common temperature.
[Methods]15 healthy adult rhesus monkeys,male,randomly were divided into 4 groups:0min group(resuscitation of 0min of bilateral internal carotid arteries blockage group,n=4),10min group(resuscitation of 10min of bilateral internal carotid arteries blockage group,n=4),15min group(resuscitation of 15min of bilateral internal carotid arteries blockage group,n=4),20min group(resuscitation of 20min of bilateral internal carotid arteries blockage group,n=3).A catheter was inserted into right internal carotid artery(ICA) to infuse 4℃cooling Ringer's liquid,two catheters were distally and proximally inserted into internal jugular vein (IJV) to extract the hypothermic diluted blood for ultrafiltration and then perfuse the warm blood into the right venae cava inferior after rewarming.Then left ICA and IJV was clamped,4℃cooling Ringer's liquid was perfused into the right ICA after ischemia at common temperature to induce the brain to cool less 16℃.After 60 minutes,Perfusion was stopped.MRI scans were obtained during preoperative and postoperative course and changes of hemodynamics were measured.The monkeys' brain was immediately removed soon after death in operation,and so did it in Long-term survival monkeys after we executed the monkeys 4 weeks after operation. Immunohistochemical technique was used to detect the level ofβ-tubulin、MAP-2、Vimentin and GFAP protein expression in the 0 min group,the 10 min group,15 min group and the 20 min group,respectively.
[Results]All of the monkeys in resuscitation of 0min、10min of bilateral internal carotid arteries blockage group(n=8)lived up till they were executed.Pre and post the operation the hemodynamical parameters were steady,MRI scans were normal after operation and the function of neurological deficient scale was normal.2 long-term surviving,1 severe disable,1 died in 15min of bilateral carotid artery blockage group (n=4).All monkeys of 20 min hypothermia group were not resuscitation after perfusion and died.The level ofβ-tubulin and MAP-2 protein expression was significantly lower in 15min group and 20min group than other groups But Vimentin and GFAP on the contrary.
[Conclusions](1)Selective brain ultra-profound hypothermia(14.3-16℃) may achieved by half internal carotid artery cold irritating in rhesus monkey.(2)It is safe for resuscitation in 0min,10 min brain ischemia and it is normal to the hemodynamical parameters,brain and nervous function.Ultra-profound hypothermia has obvious neuroprotection.(3)It is possible for resuscitation in 15 min brain ischemia,but result in high death and disability.Resuscitation of 20min of bilateral carotid artery blockage was invalid.Due to irreversibility brain-damage,Tubulin and MAP-2 were disaggregated;glia cell was hyperplastic and hypertrophied and increase the expression of GFAP and Vimentin protein.(4)The gold time of resuscitation for brain ischemia is probably in 10min.Life can be saved in 15min hypothermia group, but may result in different degree neurological deficits and high disability and death rate,so resuscitation is at comparative stake.
【方法】健康成年恒河猴15只,雄性,随机分为四组,0分钟组(双侧颈动脉阻断立即超深低温灌注组,简称0分钟组,n=4),10分钟组(双侧颈动脉常温阻断10分钟超深低温灌注组,简称10分钟组,n=4),15分钟组(双侧颈动脉常温阻断15分钟超深低温灌注组,简称15分钟组,n=4),20分钟组(双侧颈动脉常温阻断20分钟超深低温灌注组,简称20分钟组,n=3)。右侧颈内动脉远心端插管连接冷灌注系统,右侧颈内静脉远心端及双侧股静脉近心端插管连接超滤复温装置,建立脑局部体外循环。夹闭双侧颈外动静脉、在侧颈内动静脉常温缺血后向右侧颈内动脉内注入4℃林格氏液,维持脑温≤16℃60分钟。手术前后行头颅MRI检查,术后行神经功能缺失评分。实验猴灌注或复苏死亡后立即开颅取脑,长期存活猴饲养到术后4周处死开颅取脑。免疫组纵化学法检测神经细胞β-tubulin、MAP-2及神经胶质细胞Vimentin和GFAP蛋白的表达水平。
【结果】0分钟组(n=4)、10分钟组(n=4)安全复苏并长期存活,术中、术后血流动力学稳定,术后头颅MRI检查未见异常,术后神经功能评分无异常。15分钟组(n=4)长期存活2只,重残1只,死亡1只。20分钟组于灌注后未能安全复苏,全部死亡。免疫组化结果表明,20分钟组及15分钟组与0分钟组比较和20分钟组及15分钟组与10分钟组比较,神经元微管蛋白的β-tubulin、MAP-2表达下降P＜0.01,神经胶质细胞的Vimentin和GFAP表达明显升高P＜0.01。10分钟组与0分钟组比较和20分钟组与15分钟组比较则差异没有统计学意义。
【结j沦】(1)灵长类动物恒河猴可以在单侧颈内动脉冷灌注的条件下迅速达到脑选择性超深低温(14.3-16℃)。(2)常温下阻断猴双侧颈内动脉血流0分钟、10分钟行脑选择性超深低温灌注60分钟后可安全复苏并长期存活,对血流动力学、脑组织及神经功能无明显影响,超深低温具有明显脑保护作用。(3)常温下缺血15分钟行选择性超深低温复苏是可能的,但实验猴死残率高。20分钟常温脑缺血后低温灌注,实验猴无法复苏。脑缺血对神经元破坏,出现不可逆性脑损伤,神经元微管蛋白β-tublin,Map-2崩解增加,神经胶质细胞增生及肥大,胶质细胞标记性蛋白GFAP及Vimentin表达明显增强。(4)脑常温缺血后低温复苏的黄金时间可能就为10分钟。15分钟缺血后低温复苏虽有可能挽救生命,但神经功能缺失及死残率均较高,存在较大复苏风险。
[Objective]To understand the influence to the cytoskeleton of neuron and glia cell by studying the expression of cytoskeletons proteinβ-tubulin,MAP-2,Vimentin and GFAP in experimental monkeys with occluding bilateral internal carotid arteries for 60 min under selective cerebral ultra-profound hypothermia after occlusion of cerebral blood flow under different time limits(0,10,15 and 20min),determine the limit time of monkey brain ischemia resuscitation under common temperature.
[Methods]15 healthy adult rhesus monkeys,male,randomly were divided into 4 groups:0min group(resuscitation of 0min of bilateral internal carotid arteries blockage group,n=4),10min group(resuscitation of 10min of bilateral internal carotid arteries blockage group,n=4),15min group(resuscitation of 15min of bilateral internal carotid arteries blockage group,n=4),20min group(resuscitation of 20min of bilateral internal carotid arteries blockage group,n=3).A catheter was inserted into right internal carotid artery(ICA) to infuse 4℃cooling Ringer's liquid,two catheters were distally and proximally inserted into internal jugular vein (IJV) to extract the hypothermic diluted blood for ultrafiltration and then perfuse the warm blood into the right venae cava inferior after rewarming.Then left ICA and IJV was clamped,4℃cooling Ringer's liquid was perfused into the right ICA after ischemia at common temperature to induce the brain to cool less 16℃.After 60 minutes,Perfusion was stopped.MRI scans were obtained during preoperative and postoperative course and changes of hemodynamics were measured.The monkeys' brain was immediately removed soon after death in operation,and so did it in Long-term survival monkeys after we executed the monkeys 4 weeks after operation. Immunohistochemical technique was used to detect the level ofβ-tubulin、MAP-2、Vimentin and GFAP protein expression in the 0 min group,the 10 min group,15 min group and the 20 min group,respectively.
[Results]All of the monkeys in resuscitation of 0min、10min of bilateral internal carotid arteries blockage group(n=8)lived up till they were executed.Pre and post the operation the hemodynamical parameters were steady,MRI scans were normal after operation and the function of neurological deficient scale was normal.2 long-term surviving,1 severe disable,1 died in 15min of bilateral carotid artery blockage group (n=4).All monkeys of 20 min hypothermia group were not resuscitation after perfusion and died.The level ofβ-tubulin and MAP-2 protein expression was significantly lower in 15min group and 20min group than other groups But Vimentin and GFAP on the contrary.
[Conclusions](1)Selective brain ultra-profound hypothermia(14.3-16℃) may achieved by half internal carotid artery cold irritating in rhesus monkey.(2)It is safe for resuscitation in 0min,10 min brain ischemia and it is normal to the hemodynamical parameters,brain and nervous function.Ultra-profound hypothermia has obvious neuroprotection.(3)It is possible for resuscitation in 15 min brain ischemia,but result in high death and disability.Resuscitation of 20min of bilateral carotid artery blockage was invalid.Due to irreversibility brain-damage,Tubulin and MAP-2 were disaggregated;glia cell was hyperplastic and hypertrophied and increase the expression of GFAP and Vimentin protein.(4)The gold time of resuscitation for brain ischemia is probably in 10min.Life can be saved in 15min hypothermia group, but may result in different degree neurological deficits and high disability and death rate,so resuscitation is at comparative stake.
引文
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