创伤性脑损伤及低温脑保护机制实验研究
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摘要
创伤性脑损伤(traumatic brain injury,TBI)由于其发病率随着经济及交通的发展逐年增高已经越来越引起临床医生及科研学者的重视,多年来许多研究者致力探索促进创伤性脑损伤患者康复的途径,对创伤性脑损伤的致伤机制、临床评估、辅助诊断以及治疗方法的探索一直在以基础结合临床的模式向前延伸。他们从不同角度对颅脑损伤的发生原因、生物力学机制、病理生理学、病理形态学及分子病理学变化等方面进行了广泛而深入的研究。目前认为,颅脑创伤后的继发性因素,或称二次脑损伤因素,是造成脑损害发生、发展的重要原因。这些因素涉及:脑缺血、能量代谢障碍、钙离子超载、氧自由基堆积、兴奋性氨基酸的神经毒作用、炎性因子刺激等等。
在创伤性脑损伤中创伤性昏迷是研究中的难点,其发病机制及治疗一直困扰着广大研究者,揭示创伤昏迷机制已成为神经科学工作者面临的新课题。对创伤昏迷这一临床问题的关注是推动基础研究的原动力。颅脑伤导致的长期昏迷,与颅脑创伤导致的早期脑内病理变化密切相关,从急性创伤昏迷的动物模型着手,有可能获取与创伤打击相关性较为密切的病理机制依据。在本研究的实验一我们成功建立了正中液压冲击致创伤昏迷动物模型,在此基础上分析及探讨了钙蛋白酶Ⅱ及电压门控钠通道亚型mRNA在中脑的表达,并研究了microRNA在中脑的变化,试图从mRNA表达方面及microRNA调控方面阐释创伤性昏迷的部分发病机制。
低温疗法一直是创伤性脑损伤的治疗研究中的热点,自19世纪国外学者着手这方面研究到国内外学者的广泛基础研究及临床应用已有百余年历史,其研究成果令人满意,通过实验性研究及临床应用研究,对亚低温脑保护的机制,适用范围等都有了较深入的认识,并把低温治疗应用于临床,形成了较为完整的理论及应用体系。但其确切脑保护机制仍未完全清楚,研究亚低温脑保护机制仍然是个极具吸引力的课题,很多学者仍在致力于亚低温脑保护机制的探索。本研究的实验二应用侧方液压损伤建立中型颅脑损伤模型,从髓鞘结构、细胞骨架、炎症调节、免疫功能等方面较为细致地分析、阐述了亚低温脑保护的可能机理,旨在丰富亚低温脑保护作用的机制,并为亚低温更深入的实验研究以及临床应用提供实验依据。
在低温脑保护的实验及临床研究方面,有关超深低温脑保护的研究较少,因为其临床应用较为困难,但超深低温脑保护作为低温脑保护的研究整体的一部分是不可或缺的,否则我们就无法全方位的了解其作用机理,无法更全面的临床应用。本研究的实验三在我院与上海交通大学合作前期研究成果的基础上进一步探讨选择性脑超深低温复苏技术对恒河猴颈动脉血流阻断时限的研究,旨在发现超深低温对全脑缺血复苏的极限时间窗,并研究热缺血不同时限超深低温的脑保护作用,为今后超深低温基础研究及临床应用奠定实验及理论基础。
实验一大鼠急性创伤昏迷模型的建立及昏迷机制的实验研究
目的:1.建立稳定大鼠急性创伤昏迷模型2.研究CalpainⅡ、电压门控钠通道亚型6(Nach6)mRNA在创伤昏迷大鼠中脑的表达变化。3.分析创伤昏迷大鼠中脑microRNA变化。
方法:健康Sprague-Dawley(SD)大鼠12只,雌雄不限,随机分为两组。假手术对照组(n=6):大鼠麻醉后正中钻孔埋管而不打击。急性创伤昏迷组(n=6):麻醉,3%戊巴比妥钠腹腔注射(50mg/kg),麻醉生效后备皮消毒,固定头部于大鼠立体定向仪。头皮正中切口3am,骨膜剥离器剥离骨膜,正中矢状缝环钻钻孔,骨窗直径约4.8mm,暴露完整硬脑膜。于骨窗前后颅骨固定螺丝两枚,骨窗内置入内径2.6mm打击管(injury tube),即干胶粘合与颅骨连接处,牙科骨水泥牢固固定后缝合头部切口。麻醉清醒(翻正反射恢复)后使用液压损伤打击仪压力约1.7atm液压冲击大鼠硬脑膜,造成大鼠急性昏迷。实验组昏迷1小时后断头取脑,对照组麻醉1小时后断头取脑,取中脑组织采用Realtime PCR法测定CalpainⅡ、电压门控钠通道亚型(Nach6)mRNA的表达,microRNA芯片测定昏迷大鼠中脑microRNh变化。
结果:1.建立较稳定大鼠创伤昏迷模型,死亡率＜20%,昏迷时间＞1h。2.Realtime PCR结果:实验组与对照组比较CalpainⅡmRNA表达明显增加(p＜0.01),Nach6mRNA表达明显增加(p＜0.05)。3.昏迷大鼠中脑33个microRNA上调2倍以上,38个microRNA下调50%。
结论:1.急性创伤昏迷大鼠中脑中钙蛋白酶起到了损害性因素的作用,溶解神经组织及髓鞘。电压门控钠通道亚型在急性创伤昏迷大鼠中脑中表达增加,钠离子内流,导致神经细胞及神经胶质细胞损伤。两者亦可能相互影响,加速钠钙离子内流,影响中脑网状激活系统,可能和创伤昏迷发病机制有关。2.创伤昏迷大鼠中脑33个microRNh上调2倍以上,38个microRNA下调50%以上。microRNA在创伤昏迷大鼠的发生机制中可能参与了中脑细胞骨架、细胞黏附、细胞凋亡、代谢相关、缺血相关等多环节,可能参与了创伤昏迷相关基因的表达调控。
实验二侧方液压脑损伤及亚低温脑保护机制研究
第一部分大鼠侧方液压脑损伤模型的建立
目的:建立稳定大鼠侧方液压脑损伤动物模型。
方法:麻醉,3%戊巴比妥钠腹腔注射(50mg/kg),麻醉生效后备皮消毒,固定头部于大鼠立体定向仪。头皮正中切口3cm,矢状缝右侧4mm环钻钻孔,暴露完整硬脑膜。于骨窗前后颅骨固定螺丝两枚,骨窗内置入内径2.6mm打击管(injury tube),即干胶粘合与颅骨连接处,牙科骨水泥牢固固定。使用液压损伤打击仪压力约1.4atm造成中度颅脑损伤,建立稳定侧方液压脑损伤动物模型。
结果:本次实验使用国际认可的侧方液压冲击建立脑损伤动物模型,压力为1.4atm,模型稳定性好,死亡率低,仅一只死亡(约为5.6%),重复性强,可信度高。
结论:本模型显著特点为:(1)致伤力定量准确,重复性好;(2)根据打击能量划分伤情,可复制出轻、中、重型脑损伤模型,打击能量越大,伤情越重,预后越差;(3)可以观察各种治疗方法对颅脑伤后死亡率和神经功能障碍的影响。
第二部分侧方液压脑损伤大鼠海马CalpainⅡ及MBP、MAP2 mRNA的表达
目的:研究CalpainⅡ及MBP、MAP2 mRNA在侧方液压脑损伤海马的表达。
方法:健康Sprague-Dawley(SD)大鼠18只,雌雄不限,假手术对照组(n=6):钻孔埋管而不打击。侧方液压脑损伤组(n=6):在打击后即刻予呼吸机辅助通气,使用电热毯维持体温,监测各项生理指标。亚低温组(n=6):在侧方液压损伤后待生理指标稳定后使用冰屑降温法将大鼠肛温降至33℃并维持亚低温不致波动,肛温计监测肛温,亚低温维持3小时。伤后3小时断头取脑,海马组织做RT-PCR实验分别检测CalpainⅡ及MBP、MAP2 mRNA在海马的表达。
结果:钙蛋白酶Ⅱ常温创伤组和对照组比较,CalpainⅡmRNA表达明显增高(P＜0.01):亚低温组和常温创伤组比较,CalpainⅡmRNA表达明显降低(P＜0.01)。MBP常温创伤组和对照组比较,MBP mRNA表达明显降低(P＜0.01);亚低温组和常温创伤组比较,MBP mRNA表达表达明显增高(P＜0.01)。MAP2常温创伤组和对照组比较,MAP2 mRNA表达明显降低(P＜0.01):亚低温组和常温创伤组比较,MAP2 mRNA表达表达明显增高(P＜0.01)。
结论:1.亚低温可通过抑制海马CalpainⅡ表达而发挥脑保护作用。2.亚低温能通过增加海马MBP表达而减轻MBP降解及脱髓鞘,从而起到神经保护作用。3.亚低温能够通过维持海马MAP2的稳定而起到脑保护作用。4.亚低温可能通过抑制CalpainⅡ表达减轻钙离子对神经细胞及神经胶质细胞髓鞘及细胞骨架的溶解破坏而减轻MBP降解及脱髓鞘,维持MAP2的稳定而起到脑保护作用。但维持髓鞘及细胞骨架正常结构的因素很多,具体机制有待以后实验中进一步研究。
第三部分侧方液压脑损伤大鼠皮层PPAR-γ、NF-κBmRNA的表达
目的:研究PPAR-γ、NF-κB在侧方液压脑损伤大鼠皮层的表达。
方法:健康Sprague-Dawley(SD)大鼠18只,雌雄不限,假手术对照组(n=6):钻孔埋管而不打击。侧方液压脑损伤组(n=6):在打击后即刻予呼吸机辅助通气,使用电热毯维持体温,监测各项生理指标。亚低温组(n=6):在侧方液压损伤后待生理指标稳定后使用冰屑降温法将大鼠肛温降至33℃并维持亚低温不致波动,肛温计监测肛温,亚低温维持3小时。伤后3小时断头取脑,皮层组织做RT-PCR实验分别检测PPAR-γ、NF-κB在液压脑损伤大鼠皮层的表达。
结果:PPAR-γmRNA在大鼠皮层的相对表达量,侧方液压打击组(n=6)与对照组(n=6)比较明显降低(P＜0.05);亚低温组(n=6)与侧方液压打击组比较(n=6)明显升高(P＜0.05):对照组(n=6)与亚低温组(n=6)比较,差异无显著性(P＞0.05)。NF-κB mRNA在大鼠皮层的相对表达量,侧方液压打击组(n=6)与对照组(n=6)比较明显增加(P＜0.05);亚低温组(n=6)与侧方液压打击组(n=6)比较明显降低(P＜0.05)。
结论:亚低温可能通过增加PPAR-γ表达,与NF-κB的亚基P65/P50结合增加,降低了NF-κB与DNA结合活性,抑制NF-κB DNA合成,达到抑制NF-κB表达的作用,或通过竞争结合协同活化因子P300和CBP增强来抑制NF-κB的转录。通过调节PPAR-γ和NF-κB的协同或单独发挥作用多途径减轻脑损伤,达到脑保护作用。
第四部分亚低温对侧方液压脑损伤大鼠免疫功能的影响
目的:研究侧方液压脑损伤大鼠亚低温治疗后血清CD4~+T细胞、CD8~+ T细胞、IL-2、TNF-α、IL-6、IL-10的变化。
方法:将大鼠随机分为正常对照组(n=6)、液压脑损伤第1到3组(n=6),亚低温第1到3组(n=6)。时相点分别为3h、1d、3d。动物模型完成后于不同时点分别经下腔静脉抽血,流式细胞仪检测血清CD4~+T细胞、CD8~+T细胞相对含量,酶联免疫吸附实验(ELISA)检测血清IL-2、TNF-α、IL-6、IL-10水平。
结果:1.CD4~+T细胞T1组、T2组、T3组与正常对照组比较相对含量明显降低(P＜0.05),同一时间段H1组与T1组比较、H2组与T2组比较、H3组与T3组比较CD4~+T细胞相对含量明显上升(P＜0.01);CD8~T细胞T1组、T2组、T3组与正常对照组比较相对含量明显升高(P＜0.05),同一时间段H1组与T1组比较、H2组与T2组比较、H3组与T3组比较CD8~+T细胞相对含量明显降低(P＜0.01)。2.血清IL-2含量T1组、T2组、T3组与正常对照组比较相对含量明显降低(P＜0.05),同一时间段H1组与T1组比较、H2组与T2组比较、H3组与T3组比较血清IL-2含量明显上升(P＜0.05);血清TNF-α含量T1组、T2组、T3组与正常对照组比较相对含量明显升高(P＜0.05),同一时间段H1组与T1组比较、H2组与T2组比较、H3组与T3组比较血清TNF-α含量明显降低(P＜0.05);血清IL-6含量T1组、T2组、T3组与正常对照组比较相对含量明显升高(P＜0.05),同一时间段H1组与T1组比较、H2组与T2组比较、H3组与T3组比较血清IL-6含量明显升高(P＜0.05);血清IL-10含量T1组、T2组、T3组与正常对照组比较相对含量明显升高(P＜0.05),同一时间段H1组与T1组比较、H2组与T2组比较、H3组与T3组比较血清IL-10含量明显升高(P＜0.05)。
结论:1.亚低温可增加创伤性脑损伤大鼠血清CD4~+T细胞相对含量,降低CD8~+T细胞相对含量。2.创伤性脑损伤后大鼠血清IL-2水平明显降低;创伤性脑损伤后大鼠血清TNF-α水平明显升高;创伤性脑损伤后大鼠血清IL-6水平明显升高:创伤性脑损伤后大鼠血清IL-10水平明显升高。3.亚低温可增加创伤性脑损伤后大鼠血清IL-2水平;亚低温可降低创伤性脑损伤后大鼠血清TNF-α水平;亚低温可提高创伤性脑损伤后大鼠血清IL-6水平;亚低温可提高创伤性脑损伤后大鼠血清IL-10水平。4.创伤性脑损伤后亚低温治疗可能通过多种途径改善机体免疫状态,抑制创伤后炎症反应来达到脑保护作用。
实验三恒河猴脑常温极限缺血时间窗下选择性超深低温对其保护作用的研究
目的:研究不同缺血时间窗下选择性超深低温复苏的脑保护作用,探讨脑缺血复苏的极限时间。
方法:健康成年恒河猴15只(由中国科学院昆明动物研究所提供),雄性,反应灵敏,神经功能正常,年龄4-10岁,平均年龄7.90±1.82岁,体重4.2-14kg,平均8.22±2.15 kg,随机分为四组,双侧颈总动脉阻断立即超深低温灌注组(n=4),双侧颈动脉阻断10分钟超深低温灌注组(n=4),双侧颈动脉阻断15分钟超深低温灌注组(n=4),双侧颈动脉阻断20分钟超深低温灌注组(n=3),建立超深低温复苏模型。
结果:双侧颈总动脉阻断立即超深低温灌注组(n=4),双侧颈动脉阻断10分钟超深低温灌注组(n=4)安全复苏,全部长期存活;双侧颈动脉阻断15分钟深低温灌注组(n=4)长期存活2只,重残1只,死亡1只;双侧颈动脉阻断20分钟深低温灌注组(n=3)复苏困难,生命体征分别维持3、7、20小时后全部死亡;双侧颈总动脉阻断立即超深低温灌注组(n=4)、双侧颈动脉阻断10分钟超深低温灌注组(n=4)、15分钟阻断复苏组磁共振(MRI、MRA、DWI、ADC)均未见明显缺血改变。微细结构观察双侧颈总动脉阻断立即超深低温灌注组、双侧颈动脉阻断10分钟超深低温灌注组脑及全身器官未见异常改变;15分钟阻断复苏组存活3只猴病理检查散在神经细胞坏死;20分钟阻断复苏组及15分钟阻断复苏组死亡1只猴见大量神经细胞死亡,全身各器官明显异常改变。
结论:(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)脑选择性超深低温灌注是安全、可靠及有效的,既具有明显的脑保护作用、延长断血流的安全时限,又可避免全身超深低温带来的各器官并发症。可作为脑缺血的有效复苏手段。(3)10分钟常温缺血时间窗下复苏是安全的,复苏后脑及全身各器官正常,无并发症。(4)15分钟常温脑缺血超深低温复苏是可能的,但但疗效不确切,可能存留不同程度神经功能障碍,且死残率较高。(5)20分钟常温脑缺血时间窗下复苏由于不可逆性损害已经出现,导致复苏无效。(6)脑缺血复苏的黄金时间为10分钟,在10分钟内采取超深低温复苏可完全恢复大脑功能而无器官并发症;在10分钟-15分钟时间窗内进行超深低温复苏可在大脑短暂完全缺血情况下提高缺血耐受,虽有可能挽救生命,但神经功能缺失及死残率均较高。
The research of traumatic brain injury(TBI)has been attracted by clinician and scientific researchers owing to its increased morbidity with the development of economy and transportation,many years wilderness researcher devote themselves to search for the rehabilitative method of TBI,the exploration for vulnerate mechanism,clinical evaluation, auxiliary diagnosis,and treatment of TBI go extends ahead with the mode of foundation binding clinic constantly.They have performed extensive and penetrating investigation from different point of view for the occurrence reasons,biomechanics mechanisms,pathophysiology, pathomorphology,molecular pathology and other aspects of brain trauma. At present,we presume that the secondly brain injured factors be the important reasons for the brain damage.These lectors involve in cerebral ischemia,energy dysmetabolism,overload of ca~(2+),accretion of oxygen-derived free radicals,neurotoxic action of excitatory amino acids, stimulus by inflammatory factor,and so on.
Traumatic coma is the difficult spot in the research of TBI,the pathogenesis and treatment always perplex many researchers,how to reveal the mechanism of traumatic coma has already become the new topic that neuroscience worker faced,pay close attention to the clinic issue of traumatic coma is the motive power for foundation research.Long term coma make close correlation with the earlier period in brain induced by brain trauma,initiate with the animal model of acute traumatic coma,we may obtain the pathomechanism correlated with trauma.In test 1 of our research,we established the traumatic coma animal model successfully by midline fluid percussion(MFP),and analysised the expression of calpainⅡ, Voltage-gated sodium channel-6(Nach6)and the variation of microRNA in midbrain,try to interpret the section of pathogenesis of traumatic coma on the expression of mRNA and regulation of microRNA.
Hypothermia treatment always to be the hot spot in the research of treatment about TBI,it has been hundreds of years from the 19 century overseas scholar initiate to extensive elementary investigation and clinical application,the outcome is satisfactory,the fairly penetrating recognition on mechanisms applicability of mild hypothermia neuroprotection has been achieved by experiment and clinical application study.But it is not clearly about the neuroprotective mechanisms,the study on neuroprotective mechanisms of mild hypothermia still to be the extremely attractive topic,many scholars still dedicate to explore this topic.In test 2 of our research,we established the moderate brain injury animal model,detailed analyze and explain the neuroprotective mechanisms of mild hypothermia on myelin sheath constitution,cytoskeleton, inflammatory regulation,immune function,and so on,in order to supplement the neuroprotective mechanisms of mild hypothermia,and provide experimental evidence for further empirical study and clinical application.
The research of ultraprofound hypothermia is less than that of mild hypothermia in experimental and clinical study,for the reason of it is difficult to applicated in clinical.But as the whole integrity of the research of hypothermia,ultraprofound hypothermia should not de neglected,otherwise we could not understand the mechanism of hypothermia omnibearing and full-scale clinical application.In test 3 of our research, we research the duration time limit of selective cerebral ultraprofound hypothermia following both carotid arteries clip in monkey based on the research achievement that made by our college cooperation with Shanghai jiaotong university,in order to find the duration time limit of selective cerebral ultraprofound hypothermia following both carotid arteries clip,establish experimental and theory foundation for the further research and clinical application of ultraprofound hypothermia.
Test 1.The establishment of animal model of acute traumatic coma in rat and research of the mechanism of it
Objective:1.Establish safe animal model of acute traumatic coma in rat.2.Research the expression of calpainⅡand Voltage-gated sodiumchannel-6(Nach-6)mRNA in midbrain.3.study the variation of microRNA in mindbrain.
Methods:12 Sprague-Dawley(SD)rats were subjected to 2 groups randomly,sham operated group(n=6):rats were anesthetized,the placement of injury tube inside the craniectomy,but not accepted fluid injury. acute traumatic coma group(n=6):rats under anesthesia with amobarbital(50mg/kg),Fixed Head with rat stereotaxic apparatus,a 4.8mm craniectomy centered over the midline parietal bone,exposured cerebral dura mater,the placement of injury tube(2.6mm)inside the craniectomy, dental bone cement fixed the tube,1.7atm fluid pressure impacted cerebral dura mater after conscious(righting reflex recovered).The brain were removed in experimental group 1h after coma,and in control group1h after operation,midbrain tissue were analyzed by RT-PCR to determine the expression of calpainⅡand Voltage-gated sodium channel-6(Nach-6)mRNA, and were studied by microRNA chip.
Results:1.Established corresponding stable animal model of acute traumatic coma in rat.mortality<20%,coma time>1h.2.Results of RT-PCR: experimental group compared with control group,the relative amount of the expression of calpainⅡmRNA increased significantly(p＜0.01),the relative amount of the expression of Nach6 mRNA increased significantly (p＜0.05).3.33microRNA up-regulation above 2 fold,38 microRNA down regulation 50%.
Conclusion:1.CalpainⅡacted as damage factor to dissolve nerve and myelin sheath.The expression of Nach6 increased in midbrain in traumatic coma rats,sodium ion inflow,resulted in nerve cell and glial cell injuried.They may influence each other,accelerated sodium and calcium ion inflow,effected reticular activating system in midbrain,it may concerned with the pathogenesis of traumatic coma.2.33microRNA up-regulation above 2 fold,38 microRNA down regulation 50%.microRNA may involved in cytoskeleton,cell adhesion,apoptosis,metabolism,ischemia, and involved in the regulation of expression in related gene in the mechanism of traumatic coma.
Test 2.
study on mechanism of the lateral fluid percussion brain injury and mild hypothermic neuroprotection
Part 1 the establishment of animal model of the lateral fluid percussion brain injury in rat
Objective:Established stable animal model of the lateral fluid percussion brain injury.
Methods:12 Sprague-Dawley(SD)rats were subjected to 2 groups randomly. sham operated group(n=6):rats were anesthetized,the placement of injury tube inside the craniectomy,but not accepted fluid injury,acute traumatic coma group(n=6):rats under anesthesia with amobarbital (50mg/kg),Fixed Head with rat stereotaxic apparatus,a 4.8mm craniectomy centered over the the left parietal bone,4.0mm lateral to the sagittal suture,the placement of injury tube(2.6mm)inside the craniectomy, dental bone cement fixed the tube,1.7atm fluid pressure impacted cerebral dura mater to establish moderate brain injury,established stable animal model of the lateral fluid percussion brain injury.
Results:We use international approved fluid percussion brain injury device to establish animal model of brain injury,pressure is 1.4atm,it appears better stability,better repeatability,low mortality,high degree of confidenceonly one rat was dead(about5.6%).
Conclusions:This animal model significant characteristic is:1. accurate quantitation of pressure,better repeatability,2.traumatic condition can be divided according to quantitation of energy,it can replicate mild,moderate,severe brain injury animal model.3.we can observe various kinds of treatment effect on mortality,dysfunction of nervous system after brain injury.
Part 2 the expression of calpainⅡ,MBP,MAP2 mRNA in hippocampus
objective:Study the expression of calpainⅡ,MBP,MAP2 mRNA in hippocampus.
Methods:18 Sprague-Dawley(SD)rats were subjected to 3 groups randomly,sham operated group(n=6):rats were anesthetized,the placement of injury tube inside the craniectomy,but not accepted fluid injury.LFP brain injury group(n=6):rats were assisted ventilation by respirator after injury,maintained body temperature by electrically heated blanket. Mild hypothermia group(n=6):rats'rectal temperature were dropped to 33℃and been maintained in this lever by ice after injury,rectal temperature were monitored by meter,it takes 3 hours for mild hypothermia. hippocampus tissue were analyzed by RT-PCR to determine the expression of calpainⅡ,MBP,MAP2 mRNA.
Results:Brain injury group compared with control group,the relative amount of the expression of calpainⅡmRNA increased significantly(p＜0.01);mild hypothermia group compared with brain injury group,the relative amount of the expression of calpainⅡmRNA decreased significantly(p＜0.01).brain injury group compared with control group, the relative amount of the expression of MBP mRNA decreased significantly (p＜0.01);mild hypothermia group compared with brain injury group, the relative amount of the expression of MBP mRNA increased significantly (p＜0.01).brain injury group compared with control group,the relative amount of the expression of MAP2 mRNA decreased significantly(p＜0.01); mild hypothermia group compared with brain injury group,the relative amount of the expression of MAP2mRNA increased significantly(p＜0.01).
Conclutions:1.Mild hypothermia may provide neuroprotection by inhibit the expression of calpainⅡ.2.Mild hypothermia may provide neuroprotection by promote the expression of MBP,reduce degradation of MBP and demyelination.3.Mild hypothermia may provide neuroprotection by maintain tabilization of MAP2.4.Mild hypothermia may provide neuroprotection by inhibit the expression of calpainⅡand reduce solution and damage of myelin sheath and cytoskeleton in nerve cell and glial cell, reduce degradation of MBP and demyelination,tabilization of MAP2.But there are many factors that maintain normal structure of cytoskeleton, specific mechanisms will be studied in afterwards tests.
Part 3 The expression of PPAR-γ、NF-κBmRNA in cortex
Objective:Study the expression of PPAR-γ、NF-κBmRNA in cortex.
Methods:18 Sprague-Dawley(SD)rats were subjected to 3 groups randomly,sham operated group(n=6):rats were anesthetized,the placement of injury tube inside the craniectomy,but not accepted fluid injury.LFP brain injury group(n=6):rats were assisted ventilation by respirator after injury,maintained body temperature by electrically heated blanket. Mild hypothermia group(n=6):rats' rectal temperature were dropped to 33℃and been maintained in this lever by ice after injury,rectal temperature were monitored by meter,it takes 3 hours for mild hypothermia,cortex tissue were analyzed by RT-PCR to determine the expression of PPAR-γ、NF-κB mRNA in cortex.
Results:Brain injury group compared with control group,the relative amount of the expression of PPAR-γmRNA decreased significantly(p＜ 0.01);mild hypothermia group compared with brain injury group,the relative amount of the expression of PPAR-γmRNA increased significantly (p＜0.01).brain injury group compared with control group,the relative amount of the expression of NF-κB mRNA increased significantly(p＜0.01); mild hypothermia group compared with brain injury group,the relative amount of the expression of NF-κB mRNA decreased significantly(p＜0.01).
conclusion:Mild hypothermia probably increase the expression of PPAR-γ,it makes the number of PPAR-γcombine with P65/P50 subunit of NF-κB increased,then makes combine activity depressed,inhibit synthesis of NF-κB DNA,at last inhibit the expression of NF-κB,or inhibit NF-κB transcription by reinforce competitive binding cooperation activating factor P300 and CBP.mild hypothermia provide neuroprotection probably through PPAR-γin coordination with NF-κB or act alone make multi-pathway to relieve brain damage.
Part 4 The effect of mild hypothermia on immune function in LFP brain injuried rats
objective:Study the change of CD4~+,CD8~+antigen,IL-2、TNF-α、IL-6、IL-10 levels in serum after mild hypothermia treatment for LFP brain injuried rats.
Methods:Rats were subjected to 3 groups randomly.Control group(n=6), LFP brain injuried 1-3 group(n=6),mild hypothermia 1-3 group(n=6),time points is:3h、1d、3d.blood was drew from inferior caval vein in different time points after the animal model accomplished,CD4~+,CD8~+ levels in serum were determined by using flow cytometry,IL-2、TNF-α、IL-6、IL-10levels in serum were determined though enzyme-linked immunosorbent assay (ELISA).
Results:1.T1 group,T2 group,T3group compared with control group, relative amount of CD4~+T cell decreased significantly(P＜0.05),H1 group compared with T1 group,H2 group compared with T2 group,H3 group compared with T3 group in the same time point,relative amount of CD4~+T cell increased significantly(P＜0.01);T1 group,T2 group,T3group compared with control group,relative amount of CD8~+T cell increased significantly (P＜0.05),H1 group compared with T1 group,H2 group compared with T2 group,H3 group compared with T3 group in the same time point,relative amount of CD8~+T cell decreased significantly(P＜0.01).2.T1 group,T2 group,T3group compared with control group,IL-2 levels in serum decreased significantly(P＜0.05),H1 group compared with T1 group,H2 group compared with T2 group,H3 group compared with T3 group in the same time point,IL-2 levels in serum increased significantly(P＜0.05);T1 group, T2 group,T3group compared with control group,TNF-αlevels in serum increased significantly(P＜0.05),H1 group compared with T1 group,H2 group compared with T2 group,H3 group compared with T3 group in the same time point,TNF-αlevels in serum decreased significantly(P＜0.05); T1 group,T2 group,T3group compared with control group,IL-6 levels in serum increased significantly(P＜0.05),H1 group compared with T1 group, H2 group compared with T2 group,H3 group compared with T3 group in the same time point,IL-6 levels in serum increased significantly(P＜0.05); T1 group,T2 group,T3group compared with control group,IL-10 levels in serum increased significantly(P＜0.05),H1 group compared with T1 group, H2 group compared with T2 group,H3 group compared with T3 group in the same time point,IL-10 levels in serum increased significantly(P＜0.05).
Conclusions:1.Mild hypothermia can increase relative amount of CD4~+T cell and decrease CD8~+T cell in serum in brain injuried rats.2.IL-2 levels in serum decreased,TNF-α,IL-6,IL-10 levels in serum increased in brain injuried rats.3.Mild hypothermia can increase IL-2,IL-6,IL-10 levels in serum,decrease TNF-αlevels in serum in brain injuried rats.4.Mild hypothermia treatment after brain injury can provide neuroprotection probably by improving body immune state through multi-pathway and inhibit traumatic inflammatory reaction.
Test3 Neuroprotection of selective ultro-pround hypothermia in time limit of common temperature brain ischemia in rhesus monkey
Objective:Study the Neuroprotection of selective ultro-pround hypothermia in different time limit of common temperature brain ischemia,approach the limit time of brain ischemia resuscitation.
Methods:15 healthy adult rhesus monkey,male,normal nervous function, 4-10 years old,average old 7.90±1.82 years old,4.2-14kg,average weight 8.22±2.15kg,randomly divided into 4 groups:resuscitation of Omin of 2 carotid artery blockage group(n=4),resuscitation of 10min of 2 carotid artery blockage group(n=4),resuscitation of 15min of 2 carotid artery blockage group(n=4),resuscitation of 20min of 2 carotid artery blockage group(n=3),establish animal models of ultro-pround hypothermia resuscitation.
Results:All of the monkey in esuscitation of 0min of 2 carotid artery blockage group(n=4)and resuscitation of 10min of 2 carotid artery blockage group(n=4)were survived;2 long-term surviving,1 severe disable, 1 died in 15min of 2 carotid artery blockage group(n=4);it is difficult to resus the monkey in 20min of 2 carotid artery blockage group(n=3), vital sign were sustained 3、7、20 hours then died.Image of obviously ischemia were not found in 0min,10min,15min of 2 carotid artery blockage group in MRI、MRA、DWI、ADC.In fine structure observation,generous nerve cell and organ structure were normal in 0min,10min and survived monkey in 10min group.Minority of nerve cell were died in 15min of 2 carotid artery blockage group.Generous nerve cell were died in 20min of 2 carotid artery blockage group and died monkey in 10 min group.
Conclutions:(1)Selective brain ultro-pround hypothermia(14.3-16℃) may achieved by half internal carotid artery cold irritating in mayrhesus monkey.(2)Selective brain ultro-pround hypothermia is safe,reliability and effective,not only act as neuroprotection and prolonged the time limit of ischemia but also avoid organ complication in system,it can be used as a tool of resuscitation.(3)It is safety for resuscitation in 10 min brain ischemia.(4)It is possible for resuscitation in 15 min brain ischemia,but may result in different degree the nerve nerve disfunction and organ complication and high disability and death rate.(5) resuscitation of 20min of 2 carotid artery blockage was invalid due to irreversibility damage.(6)We presume:the gold time of resuscitation for brain ischemia is in 10min,cerebral function will be full recovered without organ complication by ultro-pround hypothermia in 10min;life can be saved in 15min,but may result in different degree nerve disfunction and high disability and death rate.
在创伤性脑损伤中创伤性昏迷是研究中的难点,其发病机制及治疗一直困扰着广大研究者,揭示创伤昏迷机制已成为神经科学工作者面临的新课题。对创伤昏迷这一临床问题的关注是推动基础研究的原动力。颅脑伤导致的长期昏迷,与颅脑创伤导致的早期脑内病理变化密切相关,从急性创伤昏迷的动物模型着手,有可能获取与创伤打击相关性较为密切的病理机制依据。在本研究的实验一我们成功建立了正中液压冲击致创伤昏迷动物模型,在此基础上分析及探讨了钙蛋白酶Ⅱ及电压门控钠通道亚型mRNA在中脑的表达,并研究了microRNA在中脑的变化,试图从mRNA表达方面及microRNA调控方面阐释创伤性昏迷的部分发病机制。
低温疗法一直是创伤性脑损伤的治疗研究中的热点,自19世纪国外学者着手这方面研究到国内外学者的广泛基础研究及临床应用已有百余年历史,其研究成果令人满意,通过实验性研究及临床应用研究,对亚低温脑保护的机制,适用范围等都有了较深入的认识,并把低温治疗应用于临床,形成了较为完整的理论及应用体系。但其确切脑保护机制仍未完全清楚,研究亚低温脑保护机制仍然是个极具吸引力的课题,很多学者仍在致力于亚低温脑保护机制的探索。本研究的实验二应用侧方液压损伤建立中型颅脑损伤模型,从髓鞘结构、细胞骨架、炎症调节、免疫功能等方面较为细致地分析、阐述了亚低温脑保护的可能机理,旨在丰富亚低温脑保护作用的机制,并为亚低温更深入的实验研究以及临床应用提供实验依据。
在低温脑保护的实验及临床研究方面,有关超深低温脑保护的研究较少,因为其临床应用较为困难,但超深低温脑保护作为低温脑保护的研究整体的一部分是不可或缺的,否则我们就无法全方位的了解其作用机理,无法更全面的临床应用。本研究的实验三在我院与上海交通大学合作前期研究成果的基础上进一步探讨选择性脑超深低温复苏技术对恒河猴颈动脉血流阻断时限的研究,旨在发现超深低温对全脑缺血复苏的极限时间窗,并研究热缺血不同时限超深低温的脑保护作用,为今后超深低温基础研究及临床应用奠定实验及理论基础。
实验一大鼠急性创伤昏迷模型的建立及昏迷机制的实验研究
目的:1.建立稳定大鼠急性创伤昏迷模型2.研究CalpainⅡ、电压门控钠通道亚型6(Nach6)mRNA在创伤昏迷大鼠中脑的表达变化。3.分析创伤昏迷大鼠中脑microRNA变化。
方法:健康Sprague-Dawley(SD)大鼠12只,雌雄不限,随机分为两组。假手术对照组(n=6):大鼠麻醉后正中钻孔埋管而不打击。急性创伤昏迷组(n=6):麻醉,3%戊巴比妥钠腹腔注射(50mg/kg),麻醉生效后备皮消毒,固定头部于大鼠立体定向仪。头皮正中切口3am,骨膜剥离器剥离骨膜,正中矢状缝环钻钻孔,骨窗直径约4.8mm,暴露完整硬脑膜。于骨窗前后颅骨固定螺丝两枚,骨窗内置入内径2.6mm打击管(injury tube),即干胶粘合与颅骨连接处,牙科骨水泥牢固固定后缝合头部切口。麻醉清醒(翻正反射恢复)后使用液压损伤打击仪压力约1.7atm液压冲击大鼠硬脑膜,造成大鼠急性昏迷。实验组昏迷1小时后断头取脑,对照组麻醉1小时后断头取脑,取中脑组织采用Realtime PCR法测定CalpainⅡ、电压门控钠通道亚型(Nach6)mRNA的表达,microRNA芯片测定昏迷大鼠中脑microRNh变化。
结果:1.建立较稳定大鼠创伤昏迷模型,死亡率＜20%,昏迷时间＞1h。2.Realtime PCR结果:实验组与对照组比较CalpainⅡmRNA表达明显增加(p＜0.01),Nach6mRNA表达明显增加(p＜0.05)。3.昏迷大鼠中脑33个microRNA上调2倍以上,38个microRNA下调50%。
结论:1.急性创伤昏迷大鼠中脑中钙蛋白酶起到了损害性因素的作用,溶解神经组织及髓鞘。电压门控钠通道亚型在急性创伤昏迷大鼠中脑中表达增加,钠离子内流,导致神经细胞及神经胶质细胞损伤。两者亦可能相互影响,加速钠钙离子内流,影响中脑网状激活系统,可能和创伤昏迷发病机制有关。2.创伤昏迷大鼠中脑33个microRNh上调2倍以上,38个microRNA下调50%以上。microRNA在创伤昏迷大鼠的发生机制中可能参与了中脑细胞骨架、细胞黏附、细胞凋亡、代谢相关、缺血相关等多环节,可能参与了创伤昏迷相关基因的表达调控。
实验二侧方液压脑损伤及亚低温脑保护机制研究
第一部分大鼠侧方液压脑损伤模型的建立
目的:建立稳定大鼠侧方液压脑损伤动物模型。
方法:麻醉,3%戊巴比妥钠腹腔注射(50mg/kg),麻醉生效后备皮消毒,固定头部于大鼠立体定向仪。头皮正中切口3cm,矢状缝右侧4mm环钻钻孔,暴露完整硬脑膜。于骨窗前后颅骨固定螺丝两枚,骨窗内置入内径2.6mm打击管(injury tube),即干胶粘合与颅骨连接处,牙科骨水泥牢固固定。使用液压损伤打击仪压力约1.4atm造成中度颅脑损伤,建立稳定侧方液压脑损伤动物模型。
结果:本次实验使用国际认可的侧方液压冲击建立脑损伤动物模型,压力为1.4atm,模型稳定性好,死亡率低,仅一只死亡(约为5.6%),重复性强,可信度高。
结论:本模型显著特点为:(1)致伤力定量准确,重复性好;(2)根据打击能量划分伤情,可复制出轻、中、重型脑损伤模型,打击能量越大,伤情越重,预后越差;(3)可以观察各种治疗方法对颅脑伤后死亡率和神经功能障碍的影响。
第二部分侧方液压脑损伤大鼠海马CalpainⅡ及MBP、MAP2 mRNA的表达
目的:研究CalpainⅡ及MBP、MAP2 mRNA在侧方液压脑损伤海马的表达。
方法:健康Sprague-Dawley(SD)大鼠18只,雌雄不限,假手术对照组(n=6):钻孔埋管而不打击。侧方液压脑损伤组(n=6):在打击后即刻予呼吸机辅助通气,使用电热毯维持体温,监测各项生理指标。亚低温组(n=6):在侧方液压损伤后待生理指标稳定后使用冰屑降温法将大鼠肛温降至33℃并维持亚低温不致波动,肛温计监测肛温,亚低温维持3小时。伤后3小时断头取脑,海马组织做RT-PCR实验分别检测CalpainⅡ及MBP、MAP2 mRNA在海马的表达。
结果:钙蛋白酶Ⅱ常温创伤组和对照组比较,CalpainⅡmRNA表达明显增高(P＜0.01):亚低温组和常温创伤组比较,CalpainⅡmRNA表达明显降低(P＜0.01)。MBP常温创伤组和对照组比较,MBP mRNA表达明显降低(P＜0.01);亚低温组和常温创伤组比较,MBP mRNA表达表达明显增高(P＜0.01)。MAP2常温创伤组和对照组比较,MAP2 mRNA表达明显降低(P＜0.01):亚低温组和常温创伤组比较,MAP2 mRNA表达表达明显增高(P＜0.01)。
结论:1.亚低温可通过抑制海马CalpainⅡ表达而发挥脑保护作用。2.亚低温能通过增加海马MBP表达而减轻MBP降解及脱髓鞘,从而起到神经保护作用。3.亚低温能够通过维持海马MAP2的稳定而起到脑保护作用。4.亚低温可能通过抑制CalpainⅡ表达减轻钙离子对神经细胞及神经胶质细胞髓鞘及细胞骨架的溶解破坏而减轻MBP降解及脱髓鞘,维持MAP2的稳定而起到脑保护作用。但维持髓鞘及细胞骨架正常结构的因素很多,具体机制有待以后实验中进一步研究。
第三部分侧方液压脑损伤大鼠皮层PPAR-γ、NF-κBmRNA的表达
目的:研究PPAR-γ、NF-κB在侧方液压脑损伤大鼠皮层的表达。
方法:健康Sprague-Dawley(SD)大鼠18只,雌雄不限,假手术对照组(n=6):钻孔埋管而不打击。侧方液压脑损伤组(n=6):在打击后即刻予呼吸机辅助通气,使用电热毯维持体温,监测各项生理指标。亚低温组(n=6):在侧方液压损伤后待生理指标稳定后使用冰屑降温法将大鼠肛温降至33℃并维持亚低温不致波动,肛温计监测肛温,亚低温维持3小时。伤后3小时断头取脑,皮层组织做RT-PCR实验分别检测PPAR-γ、NF-κB在液压脑损伤大鼠皮层的表达。
结果:PPAR-γmRNA在大鼠皮层的相对表达量,侧方液压打击组(n=6)与对照组(n=6)比较明显降低(P＜0.05);亚低温组(n=6)与侧方液压打击组比较(n=6)明显升高(P＜0.05):对照组(n=6)与亚低温组(n=6)比较,差异无显著性(P＞0.05)。NF-κB mRNA在大鼠皮层的相对表达量,侧方液压打击组(n=6)与对照组(n=6)比较明显增加(P＜0.05);亚低温组(n=6)与侧方液压打击组(n=6)比较明显降低(P＜0.05)。
结论:亚低温可能通过增加PPAR-γ表达,与NF-κB的亚基P65/P50结合增加,降低了NF-κB与DNA结合活性,抑制NF-κB DNA合成,达到抑制NF-κB表达的作用,或通过竞争结合协同活化因子P300和CBP增强来抑制NF-κB的转录。通过调节PPAR-γ和NF-κB的协同或单独发挥作用多途径减轻脑损伤,达到脑保护作用。
第四部分亚低温对侧方液压脑损伤大鼠免疫功能的影响
目的:研究侧方液压脑损伤大鼠亚低温治疗后血清CD4~+T细胞、CD8~+ T细胞、IL-2、TNF-α、IL-6、IL-10的变化。
方法:将大鼠随机分为正常对照组(n=6)、液压脑损伤第1到3组(n=6),亚低温第1到3组(n=6)。时相点分别为3h、1d、3d。动物模型完成后于不同时点分别经下腔静脉抽血,流式细胞仪检测血清CD4~+T细胞、CD8~+T细胞相对含量,酶联免疫吸附实验(ELISA)检测血清IL-2、TNF-α、IL-6、IL-10水平。
结果:1.CD4~+T细胞T1组、T2组、T3组与正常对照组比较相对含量明显降低(P＜0.05),同一时间段H1组与T1组比较、H2组与T2组比较、H3组与T3组比较CD4~+T细胞相对含量明显上升(P＜0.01);CD8~T细胞T1组、T2组、T3组与正常对照组比较相对含量明显升高(P＜0.05),同一时间段H1组与T1组比较、H2组与T2组比较、H3组与T3组比较CD8~+T细胞相对含量明显降低(P＜0.01)。2.血清IL-2含量T1组、T2组、T3组与正常对照组比较相对含量明显降低(P＜0.05),同一时间段H1组与T1组比较、H2组与T2组比较、H3组与T3组比较血清IL-2含量明显上升(P＜0.05);血清TNF-α含量T1组、T2组、T3组与正常对照组比较相对含量明显升高(P＜0.05),同一时间段H1组与T1组比较、H2组与T2组比较、H3组与T3组比较血清TNF-α含量明显降低(P＜0.05);血清IL-6含量T1组、T2组、T3组与正常对照组比较相对含量明显升高(P＜0.05),同一时间段H1组与T1组比较、H2组与T2组比较、H3组与T3组比较血清IL-6含量明显升高(P＜0.05);血清IL-10含量T1组、T2组、T3组与正常对照组比较相对含量明显升高(P＜0.05),同一时间段H1组与T1组比较、H2组与T2组比较、H3组与T3组比较血清IL-10含量明显升高(P＜0.05)。
结论:1.亚低温可增加创伤性脑损伤大鼠血清CD4~+T细胞相对含量,降低CD8~+T细胞相对含量。2.创伤性脑损伤后大鼠血清IL-2水平明显降低;创伤性脑损伤后大鼠血清TNF-α水平明显升高;创伤性脑损伤后大鼠血清IL-6水平明显升高:创伤性脑损伤后大鼠血清IL-10水平明显升高。3.亚低温可增加创伤性脑损伤后大鼠血清IL-2水平;亚低温可降低创伤性脑损伤后大鼠血清TNF-α水平;亚低温可提高创伤性脑损伤后大鼠血清IL-6水平;亚低温可提高创伤性脑损伤后大鼠血清IL-10水平。4.创伤性脑损伤后亚低温治疗可能通过多种途径改善机体免疫状态,抑制创伤后炎症反应来达到脑保护作用。
实验三恒河猴脑常温极限缺血时间窗下选择性超深低温对其保护作用的研究
目的:研究不同缺血时间窗下选择性超深低温复苏的脑保护作用,探讨脑缺血复苏的极限时间。
方法:健康成年恒河猴15只(由中国科学院昆明动物研究所提供),雄性,反应灵敏,神经功能正常,年龄4-10岁,平均年龄7.90±1.82岁,体重4.2-14kg,平均8.22±2.15 kg,随机分为四组,双侧颈总动脉阻断立即超深低温灌注组(n=4),双侧颈动脉阻断10分钟超深低温灌注组(n=4),双侧颈动脉阻断15分钟超深低温灌注组(n=4),双侧颈动脉阻断20分钟超深低温灌注组(n=3),建立超深低温复苏模型。
结果:双侧颈总动脉阻断立即超深低温灌注组(n=4),双侧颈动脉阻断10分钟超深低温灌注组(n=4)安全复苏,全部长期存活;双侧颈动脉阻断15分钟深低温灌注组(n=4)长期存活2只,重残1只,死亡1只;双侧颈动脉阻断20分钟深低温灌注组(n=3)复苏困难,生命体征分别维持3、7、20小时后全部死亡;双侧颈总动脉阻断立即超深低温灌注组(n=4)、双侧颈动脉阻断10分钟超深低温灌注组(n=4)、15分钟阻断复苏组磁共振(MRI、MRA、DWI、ADC)均未见明显缺血改变。微细结构观察双侧颈总动脉阻断立即超深低温灌注组、双侧颈动脉阻断10分钟超深低温灌注组脑及全身器官未见异常改变;15分钟阻断复苏组存活3只猴病理检查散在神经细胞坏死;20分钟阻断复苏组及15分钟阻断复苏组死亡1只猴见大量神经细胞死亡,全身各器官明显异常改变。
结论:(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)脑选择性超深低温灌注是安全、可靠及有效的,既具有明显的脑保护作用、延长断血流的安全时限,又可避免全身超深低温带来的各器官并发症。可作为脑缺血的有效复苏手段。(3)10分钟常温缺血时间窗下复苏是安全的,复苏后脑及全身各器官正常,无并发症。(4)15分钟常温脑缺血超深低温复苏是可能的,但但疗效不确切,可能存留不同程度神经功能障碍,且死残率较高。(5)20分钟常温脑缺血时间窗下复苏由于不可逆性损害已经出现,导致复苏无效。(6)脑缺血复苏的黄金时间为10分钟,在10分钟内采取超深低温复苏可完全恢复大脑功能而无器官并发症;在10分钟-15分钟时间窗内进行超深低温复苏可在大脑短暂完全缺血情况下提高缺血耐受,虽有可能挽救生命,但神经功能缺失及死残率均较高。
The research of traumatic brain injury(TBI)has been attracted by clinician and scientific researchers owing to its increased morbidity with the development of economy and transportation,many years wilderness researcher devote themselves to search for the rehabilitative method of TBI,the exploration for vulnerate mechanism,clinical evaluation, auxiliary diagnosis,and treatment of TBI go extends ahead with the mode of foundation binding clinic constantly.They have performed extensive and penetrating investigation from different point of view for the occurrence reasons,biomechanics mechanisms,pathophysiology, pathomorphology,molecular pathology and other aspects of brain trauma. At present,we presume that the secondly brain injured factors be the important reasons for the brain damage.These lectors involve in cerebral ischemia,energy dysmetabolism,overload of ca~(2+),accretion of oxygen-derived free radicals,neurotoxic action of excitatory amino acids, stimulus by inflammatory factor,and so on.
Traumatic coma is the difficult spot in the research of TBI,the pathogenesis and treatment always perplex many researchers,how to reveal the mechanism of traumatic coma has already become the new topic that neuroscience worker faced,pay close attention to the clinic issue of traumatic coma is the motive power for foundation research.Long term coma make close correlation with the earlier period in brain induced by brain trauma,initiate with the animal model of acute traumatic coma,we may obtain the pathomechanism correlated with trauma.In test 1 of our research,we established the traumatic coma animal model successfully by midline fluid percussion(MFP),and analysised the expression of calpainⅡ, Voltage-gated sodium channel-6(Nach6)and the variation of microRNA in midbrain,try to interpret the section of pathogenesis of traumatic coma on the expression of mRNA and regulation of microRNA.
Hypothermia treatment always to be the hot spot in the research of treatment about TBI,it has been hundreds of years from the 19 century overseas scholar initiate to extensive elementary investigation and clinical application,the outcome is satisfactory,the fairly penetrating recognition on mechanisms applicability of mild hypothermia neuroprotection has been achieved by experiment and clinical application study.But it is not clearly about the neuroprotective mechanisms,the study on neuroprotective mechanisms of mild hypothermia still to be the extremely attractive topic,many scholars still dedicate to explore this topic.In test 2 of our research,we established the moderate brain injury animal model,detailed analyze and explain the neuroprotective mechanisms of mild hypothermia on myelin sheath constitution,cytoskeleton, inflammatory regulation,immune function,and so on,in order to supplement the neuroprotective mechanisms of mild hypothermia,and provide experimental evidence for further empirical study and clinical application.
The research of ultraprofound hypothermia is less than that of mild hypothermia in experimental and clinical study,for the reason of it is difficult to applicated in clinical.But as the whole integrity of the research of hypothermia,ultraprofound hypothermia should not de neglected,otherwise we could not understand the mechanism of hypothermia omnibearing and full-scale clinical application.In test 3 of our research, we research the duration time limit of selective cerebral ultraprofound hypothermia following both carotid arteries clip in monkey based on the research achievement that made by our college cooperation with Shanghai jiaotong university,in order to find the duration time limit of selective cerebral ultraprofound hypothermia following both carotid arteries clip,establish experimental and theory foundation for the further research and clinical application of ultraprofound hypothermia.
Test 1.The establishment of animal model of acute traumatic coma in rat and research of the mechanism of it
Objective:1.Establish safe animal model of acute traumatic coma in rat.2.Research the expression of calpainⅡand Voltage-gated sodiumchannel-6(Nach-6)mRNA in midbrain.3.study the variation of microRNA in mindbrain.
Methods:12 Sprague-Dawley(SD)rats were subjected to 2 groups randomly,sham operated group(n=6):rats were anesthetized,the placement of injury tube inside the craniectomy,but not accepted fluid injury. acute traumatic coma group(n=6):rats under anesthesia with amobarbital(50mg/kg),Fixed Head with rat stereotaxic apparatus,a 4.8mm craniectomy centered over the midline parietal bone,exposured cerebral dura mater,the placement of injury tube(2.6mm)inside the craniectomy, dental bone cement fixed the tube,1.7atm fluid pressure impacted cerebral dura mater after conscious(righting reflex recovered).The brain were removed in experimental group 1h after coma,and in control group1h after operation,midbrain tissue were analyzed by RT-PCR to determine the expression of calpainⅡand Voltage-gated sodium channel-6(Nach-6)mRNA, and were studied by microRNA chip.
Results:1.Established corresponding stable animal model of acute traumatic coma in rat.mortality<20%,coma time>1h.2.Results of RT-PCR: experimental group compared with control group,the relative amount of the expression of calpainⅡmRNA increased significantly(p＜0.01),the relative amount of the expression of Nach6 mRNA increased significantly (p＜0.05).3.33microRNA up-regulation above 2 fold,38 microRNA down regulation 50%.
Conclusion:1.CalpainⅡacted as damage factor to dissolve nerve and myelin sheath.The expression of Nach6 increased in midbrain in traumatic coma rats,sodium ion inflow,resulted in nerve cell and glial cell injuried.They may influence each other,accelerated sodium and calcium ion inflow,effected reticular activating system in midbrain,it may concerned with the pathogenesis of traumatic coma.2.33microRNA up-regulation above 2 fold,38 microRNA down regulation 50%.microRNA may involved in cytoskeleton,cell adhesion,apoptosis,metabolism,ischemia, and involved in the regulation of expression in related gene in the mechanism of traumatic coma.
Test 2.
study on mechanism of the lateral fluid percussion brain injury and mild hypothermic neuroprotection
Part 1 the establishment of animal model of the lateral fluid percussion brain injury in rat
Objective:Established stable animal model of the lateral fluid percussion brain injury.
Methods:12 Sprague-Dawley(SD)rats were subjected to 2 groups randomly. sham operated group(n=6):rats were anesthetized,the placement of injury tube inside the craniectomy,but not accepted fluid injury,acute traumatic coma group(n=6):rats under anesthesia with amobarbital (50mg/kg),Fixed Head with rat stereotaxic apparatus,a 4.8mm craniectomy centered over the the left parietal bone,4.0mm lateral to the sagittal suture,the placement of injury tube(2.6mm)inside the craniectomy, dental bone cement fixed the tube,1.7atm fluid pressure impacted cerebral dura mater to establish moderate brain injury,established stable animal model of the lateral fluid percussion brain injury.
Results:We use international approved fluid percussion brain injury device to establish animal model of brain injury,pressure is 1.4atm,it appears better stability,better repeatability,low mortality,high degree of confidenceonly one rat was dead(about5.6%).
Conclusions:This animal model significant characteristic is:1. accurate quantitation of pressure,better repeatability,2.traumatic condition can be divided according to quantitation of energy,it can replicate mild,moderate,severe brain injury animal model.3.we can observe various kinds of treatment effect on mortality,dysfunction of nervous system after brain injury.
Part 2 the expression of calpainⅡ,MBP,MAP2 mRNA in hippocampus
objective:Study the expression of calpainⅡ,MBP,MAP2 mRNA in hippocampus.
Methods:18 Sprague-Dawley(SD)rats were subjected to 3 groups randomly,sham operated group(n=6):rats were anesthetized,the placement of injury tube inside the craniectomy,but not accepted fluid injury.LFP brain injury group(n=6):rats were assisted ventilation by respirator after injury,maintained body temperature by electrically heated blanket. Mild hypothermia group(n=6):rats'rectal temperature were dropped to 33℃and been maintained in this lever by ice after injury,rectal temperature were monitored by meter,it takes 3 hours for mild hypothermia. hippocampus tissue were analyzed by RT-PCR to determine the expression of calpainⅡ,MBP,MAP2 mRNA.
Results:Brain injury group compared with control group,the relative amount of the expression of calpainⅡmRNA increased significantly(p＜0.01);mild hypothermia group compared with brain injury group,the relative amount of the expression of calpainⅡmRNA decreased significantly(p＜0.01).brain injury group compared with control group, the relative amount of the expression of MBP mRNA decreased significantly (p＜0.01);mild hypothermia group compared with brain injury group, the relative amount of the expression of MBP mRNA increased significantly (p＜0.01).brain injury group compared with control group,the relative amount of the expression of MAP2 mRNA decreased significantly(p＜0.01); mild hypothermia group compared with brain injury group,the relative amount of the expression of MAP2mRNA increased significantly(p＜0.01).
Conclutions:1.Mild hypothermia may provide neuroprotection by inhibit the expression of calpainⅡ.2.Mild hypothermia may provide neuroprotection by promote the expression of MBP,reduce degradation of MBP and demyelination.3.Mild hypothermia may provide neuroprotection by maintain tabilization of MAP2.4.Mild hypothermia may provide neuroprotection by inhibit the expression of calpainⅡand reduce solution and damage of myelin sheath and cytoskeleton in nerve cell and glial cell, reduce degradation of MBP and demyelination,tabilization of MAP2.But there are many factors that maintain normal structure of cytoskeleton, specific mechanisms will be studied in afterwards tests.
Part 3 The expression of PPAR-γ、NF-κBmRNA in cortex
Objective:Study the expression of PPAR-γ、NF-κBmRNA in cortex.
Methods:18 Sprague-Dawley(SD)rats were subjected to 3 groups randomly,sham operated group(n=6):rats were anesthetized,the placement of injury tube inside the craniectomy,but not accepted fluid injury.LFP brain injury group(n=6):rats were assisted ventilation by respirator after injury,maintained body temperature by electrically heated blanket. Mild hypothermia group(n=6):rats' rectal temperature were dropped to 33℃and been maintained in this lever by ice after injury,rectal temperature were monitored by meter,it takes 3 hours for mild hypothermia,cortex tissue were analyzed by RT-PCR to determine the expression of PPAR-γ、NF-κB mRNA in cortex.
Results:Brain injury group compared with control group,the relative amount of the expression of PPAR-γmRNA decreased significantly(p＜ 0.01);mild hypothermia group compared with brain injury group,the relative amount of the expression of PPAR-γmRNA increased significantly (p＜0.01).brain injury group compared with control group,the relative amount of the expression of NF-κB mRNA increased significantly(p＜0.01); mild hypothermia group compared with brain injury group,the relative amount of the expression of NF-κB mRNA decreased significantly(p＜0.01).
conclusion:Mild hypothermia probably increase the expression of PPAR-γ,it makes the number of PPAR-γcombine with P65/P50 subunit of NF-κB increased,then makes combine activity depressed,inhibit synthesis of NF-κB DNA,at last inhibit the expression of NF-κB,or inhibit NF-κB transcription by reinforce competitive binding cooperation activating factor P300 and CBP.mild hypothermia provide neuroprotection probably through PPAR-γin coordination with NF-κB or act alone make multi-pathway to relieve brain damage.
Part 4 The effect of mild hypothermia on immune function in LFP brain injuried rats
objective:Study the change of CD4~+,CD8~+antigen,IL-2、TNF-α、IL-6、IL-10 levels in serum after mild hypothermia treatment for LFP brain injuried rats.
Methods:Rats were subjected to 3 groups randomly.Control group(n=6), LFP brain injuried 1-3 group(n=6),mild hypothermia 1-3 group(n=6),time points is:3h、1d、3d.blood was drew from inferior caval vein in different time points after the animal model accomplished,CD4~+,CD8~+ levels in serum were determined by using flow cytometry,IL-2、TNF-α、IL-6、IL-10levels in serum were determined though enzyme-linked immunosorbent assay (ELISA).
Results:1.T1 group,T2 group,T3group compared with control group, relative amount of CD4~+T cell decreased significantly(P＜0.05),H1 group compared with T1 group,H2 group compared with T2 group,H3 group compared with T3 group in the same time point,relative amount of CD4~+T cell increased significantly(P＜0.01);T1 group,T2 group,T3group compared with control group,relative amount of CD8~+T cell increased significantly (P＜0.05),H1 group compared with T1 group,H2 group compared with T2 group,H3 group compared with T3 group in the same time point,relative amount of CD8~+T cell decreased significantly(P＜0.01).2.T1 group,T2 group,T3group compared with control group,IL-2 levels in serum decreased significantly(P＜0.05),H1 group compared with T1 group,H2 group compared with T2 group,H3 group compared with T3 group in the same time point,IL-2 levels in serum increased significantly(P＜0.05);T1 group, T2 group,T3group compared with control group,TNF-αlevels in serum increased significantly(P＜0.05),H1 group compared with T1 group,H2 group compared with T2 group,H3 group compared with T3 group in the same time point,TNF-αlevels in serum decreased significantly(P＜0.05); T1 group,T2 group,T3group compared with control group,IL-6 levels in serum increased significantly(P＜0.05),H1 group compared with T1 group, H2 group compared with T2 group,H3 group compared with T3 group in the same time point,IL-6 levels in serum increased significantly(P＜0.05); T1 group,T2 group,T3group compared with control group,IL-10 levels in serum increased significantly(P＜0.05),H1 group compared with T1 group, H2 group compared with T2 group,H3 group compared with T3 group in the same time point,IL-10 levels in serum increased significantly(P＜0.05).
Conclusions:1.Mild hypothermia can increase relative amount of CD4~+T cell and decrease CD8~+T cell in serum in brain injuried rats.2.IL-2 levels in serum decreased,TNF-α,IL-6,IL-10 levels in serum increased in brain injuried rats.3.Mild hypothermia can increase IL-2,IL-6,IL-10 levels in serum,decrease TNF-αlevels in serum in brain injuried rats.4.Mild hypothermia treatment after brain injury can provide neuroprotection probably by improving body immune state through multi-pathway and inhibit traumatic inflammatory reaction.
Test3 Neuroprotection of selective ultro-pround hypothermia in time limit of common temperature brain ischemia in rhesus monkey
Objective:Study the Neuroprotection of selective ultro-pround hypothermia in different time limit of common temperature brain ischemia,approach the limit time of brain ischemia resuscitation.
Methods:15 healthy adult rhesus monkey,male,normal nervous function, 4-10 years old,average old 7.90±1.82 years old,4.2-14kg,average weight 8.22±2.15kg,randomly divided into 4 groups:resuscitation of Omin of 2 carotid artery blockage group(n=4),resuscitation of 10min of 2 carotid artery blockage group(n=4),resuscitation of 15min of 2 carotid artery blockage group(n=4),resuscitation of 20min of 2 carotid artery blockage group(n=3),establish animal models of ultro-pround hypothermia resuscitation.
Results:All of the monkey in esuscitation of 0min of 2 carotid artery blockage group(n=4)and resuscitation of 10min of 2 carotid artery blockage group(n=4)were survived;2 long-term surviving,1 severe disable, 1 died in 15min of 2 carotid artery blockage group(n=4);it is difficult to resus the monkey in 20min of 2 carotid artery blockage group(n=3), vital sign were sustained 3、7、20 hours then died.Image of obviously ischemia were not found in 0min,10min,15min of 2 carotid artery blockage group in MRI、MRA、DWI、ADC.In fine structure observation,generous nerve cell and organ structure were normal in 0min,10min and survived monkey in 10min group.Minority of nerve cell were died in 15min of 2 carotid artery blockage group.Generous nerve cell were died in 20min of 2 carotid artery blockage group and died monkey in 10 min group.
Conclutions:(1)Selective brain ultro-pround hypothermia(14.3-16℃) may achieved by half internal carotid artery cold irritating in mayrhesus monkey.(2)Selective brain ultro-pround hypothermia is safe,reliability and effective,not only act as neuroprotection and prolonged the time limit of ischemia but also avoid organ complication in system,it can be used as a tool of resuscitation.(3)It is safety for resuscitation in 10 min brain ischemia.(4)It is possible for resuscitation in 15 min brain ischemia,but may result in different degree the nerve nerve disfunction and organ complication and high disability and death rate.(5) resuscitation of 20min of 2 carotid artery blockage was invalid due to irreversibility damage.(6)We presume:the gold time of resuscitation for brain ischemia is in 10min,cerebral function will be full recovered without organ complication by ultro-pround hypothermia in 10min;life can be saved in 15min,but may result in different degree nerve disfunction and high disability and death rate.
引文
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