脑微透析/深部电极技术研究及其在脑缺血康复中的应用
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摘要
缺血性脑中风是目前人类死亡和残疾的主要原因之一,该疾病的发生主要与短暂性或永久性缺血缺氧引起的胞外谷氨酸过度释放,进而产生兴奋性毒性有关。目前研究表明包括脑缺血,癫痫和帕金森病在内的多种神经系统疾病均与中枢神经系统内神经递质失衡密切相关。此外脑内神经递质的紊乱还造成了电活动生理基础的破坏,神经电信号在病理条件下表现出异常的活动特征和模式。因此本研究旨在结合脑微透析技术和深部脑电极技术,在不同生理和病理条件下,研究局部脑组织中神经电信号和生化信号的动态变化过程及其相互联系。
本研究首先通过一系列的体内、体外实验,探讨了结构、温度、材料和透析时间等多个因素对于微透析探针性能的影响,自行设计和制作了脑微透析探针并进行了优化,深入研究和探讨了体内、体外多种微透析常用的回收率校正和标定方法,建立了脑微透析探针设计、制作和标定的系统平台。该脑微透析探针同国际现有产品的性能进行了比较,在稳定性、可靠性和准确性方面均满足在体实验要求。
本研究应用自制的脑微透析探针,结合高效液相色谱技术,建立了在体动物的脑内氨基酸类神经递质、单胺类神经递质及其代谢产物的检测方法,实现了两类递质的同时检测,并利用自制“三通”收集器简化了单胺类递质的收集和保存方法。同时,建立了在体动物深部脑刺激器和深部脑记录的实验平台,结合基于自回归模型参数的功率谱估计,基于符号动力学参数和近似熵的复杂度分析方法,可用于局部脑损伤区神经电信号的检测和参数分析。
应用以上神经生化和电信号检测技术,本研究通过建立急性局灶性脑缺血/再灌注大鼠模型,获取了缺血/再灌注病理条件下大脑缺血中心区(纹状体)和缺血敏感区(海马)内神经递质和电信号的动态变化过程,实验结果显示,包括谷氨酸在内多种神经递质在缺血过程中均显著上升,局部场电位信号幅度减弱,相对功率谱上Delta频段成分显著升高,复杂度下降。
基于上述模型和方法,研究了药物干预下脑缺血大鼠脑内神经递质水平的动态变化,结果表明葛根素和天麻素可有效地抑制缺血损伤引起的兴奋性毒性,用药组谷氨酸的峰值比对照组下降了24～48%,而Glu/GABA的变化率仅为对照组44～49%。在分子水平上证明两种中药成分对于脑缺血急性损伤有一定的保护作用,显示了上述技术在中药药物研究和开发中的应用潜力。
本研究还进一步研究了中风模型动物在接受功能性电刺激和运动康复时脑内氨基酸类神经递质的变化,结果表明电刺激和运动能上调脑内谷氨酸水平,并显著干预了脑内的牛磺酸和γ-氨基丁酸,同类结果国内外未见报道。从神经生化的角度提示运动康复和大脑可塑性有着一定的相关性,以及物理康复在中风后康复治疗环节中的积极作用。
在神经生化和神经电生理检测技术研究的基础上,本研究整合脑微透析技术与深部脑记录/刺激技术,构建了脑微透析/深部电极复合装置,实现了脑微透析探针和深部电极在体、原位的双向(记录/刺激)功能,进行了相关的实验研究:(1)微透析结合深部脑记录技术,在动物缺血损伤病理条件下,实现了对神经生化参数和电生理参数的同步和原位记录;(2)反向微透析结合深部脑记录技术,在动物海马区记录了外源性谷氨酸引起深部场电位信号的变化,探讨了该方法在兴奋性毒性和药物研究中的作用;(3)微透析结合深部脑刺激技术,记录了动物颅内自刺激过程中,氨基酸类和单胺类神经递质水平的变化过程,探讨了相关神经递质的变化在程序性记忆中作用,为深部脑刺激机制和奖赏性学习机制研究提供了客观的数据和新的研究手段。
以上的研究表明,脑微透析及深部电极技术及其复合装置同步、定量、神经生化结合神经电生理多参数的检测方法,在研究脑缺血等神经系统性疾病的发病机制、相关药物的作用机理,以及药物的疗效评价中具有重要的意义和潜在的应用价值。
Ischemic stroke is a leading cause of death and disability worldwide, and it is related to extreme release of glutamate resulting from a transient or permanent reduction in cerebral blood flow,which leading to excitotoxicity. The current researches show that a lot of neuronal diseases including cerebral ischemia,epilepsy and Parkinson's Disease are related to the imbalance of neurotransmitters.The neuroelectrical signals show different patterns or characters of activity duing to the destruction to physilogical basis results from neurotransmission disorder.So the main task of this research is to investigate the changes and relationship between neuroelectrical and neurochemical signals under different physilogical and pathological conditions by combinating the brain microdialysis and deep brain electrode techniques.
We first discuss several factors which influence the performance of probe such as construct,temperature,materials and dialysis time by using a serials of in vivo/vitro experiments.With the opmized probe,the usual methods for calibration and validation are investigated and discussed.We also establish a system platform for probe design,manufacture and validation.The self-made probe meets the requirement for in vivo experiment after comparition with international commercial products.
Combining the high performance liquid chromatography technique,we set up a highly sensitive method for simulatneous detect the amino acids neurotransmitters and monoamine neurotransmitters and their metabolites. The method for sampling and storing monoanime was simplified with the self-made sampler.We also establish an experimental platform for deep brain stimulation(DBS)and deep brain record(DBR).Combinated with spectral evaluation method based on autoregressive model parameters, complexity analysis methods based on symbofic dynamics and approximate entropy,the signals from the injuried brain regions can recorded and analyzied.
Using above neurochemical and neuroelectrical techniques,we acquire the changes of neurtransmitter and electrical signals from striatum and hippocampus in the model rat of middle cerebral artery occlusion(MCAo). The results show that during the ischemic periods the concentration of a few neurotransmitters and percentage of Delta components significantly increased the amplitude of local field potential and complexity of signals decreases.
Based on above models and methods,we study the dynamic profile of neurotransmitter intervened by drugs on MCAo rats.The results show that puerarin and gastradin effectively inhibit the excitotoxity induced by cerebral ischemia.The peak value of glutamate in drugs group lower 24～48%than that of control group,the ratoi of glutamate and GABA is abouthe 44～4%. It demostrates the protective effects of both traditional chinese medicine on acute brain injuries in molecular way and the huge potentials of these techniques in research and development in medicine.
The changes of amino acids neurotransmitters of stroke model animal were studied in this work when they recept the physical tremedies,such as functional electrical stimulation(FES)and exercises.Both FES and exercises upregulate the level of Glu in brain and intervene taurine and GABA.The similar results have never been reported.It shows that the physical rehabilitation is related to the plasticity of brain and that it plays a key role in chronic post-stroke rehabilitation.
On the base of above works,we combine the brain microdialysis and DBR together to create a microdialysis/electrode combined apparatus to realize the bi-direction function of microdialysis and deep brain dectrode in the same site.We use it in there animal experiments for primary exploration for its application(1)microdialysis and deep brain recordings-to simultaneously detect the neurochemical and neurodectrical signal from the same region during cerebral ischemia period;(2)retro-microdialysis and deep brain recordings-to measure the basic levd of glutamate and local intervention of extrinsic glutamate in hippocampus;(3)microdialysis and deep brain stimulation-to investigate the changes of amino acids and monoamine neurotransmitters invoked by stimulation in VTA and provide a new tools for researches in mechanism underlying rewards and DBS.
All above results show that the brain microdialysis,deep brain electrodes and combinated apparutus with synchronous,quantitative and neurochemical-neurodectrical multi-parameters analysis methods can play a key role in investiagting the pathological mechanism underlying neural system diseases,evaluation the effects of drugs.
本研究首先通过一系列的体内、体外实验,探讨了结构、温度、材料和透析时间等多个因素对于微透析探针性能的影响,自行设计和制作了脑微透析探针并进行了优化,深入研究和探讨了体内、体外多种微透析常用的回收率校正和标定方法,建立了脑微透析探针设计、制作和标定的系统平台。该脑微透析探针同国际现有产品的性能进行了比较,在稳定性、可靠性和准确性方面均满足在体实验要求。
本研究应用自制的脑微透析探针,结合高效液相色谱技术,建立了在体动物的脑内氨基酸类神经递质、单胺类神经递质及其代谢产物的检测方法,实现了两类递质的同时检测,并利用自制“三通”收集器简化了单胺类递质的收集和保存方法。同时,建立了在体动物深部脑刺激器和深部脑记录的实验平台,结合基于自回归模型参数的功率谱估计,基于符号动力学参数和近似熵的复杂度分析方法,可用于局部脑损伤区神经电信号的检测和参数分析。
应用以上神经生化和电信号检测技术,本研究通过建立急性局灶性脑缺血/再灌注大鼠模型,获取了缺血/再灌注病理条件下大脑缺血中心区(纹状体)和缺血敏感区(海马)内神经递质和电信号的动态变化过程,实验结果显示,包括谷氨酸在内多种神经递质在缺血过程中均显著上升,局部场电位信号幅度减弱,相对功率谱上Delta频段成分显著升高,复杂度下降。
基于上述模型和方法,研究了药物干预下脑缺血大鼠脑内神经递质水平的动态变化,结果表明葛根素和天麻素可有效地抑制缺血损伤引起的兴奋性毒性,用药组谷氨酸的峰值比对照组下降了24～48%,而Glu/GABA的变化率仅为对照组44～49%。在分子水平上证明两种中药成分对于脑缺血急性损伤有一定的保护作用,显示了上述技术在中药药物研究和开发中的应用潜力。
本研究还进一步研究了中风模型动物在接受功能性电刺激和运动康复时脑内氨基酸类神经递质的变化,结果表明电刺激和运动能上调脑内谷氨酸水平,并显著干预了脑内的牛磺酸和γ-氨基丁酸,同类结果国内外未见报道。从神经生化的角度提示运动康复和大脑可塑性有着一定的相关性,以及物理康复在中风后康复治疗环节中的积极作用。
在神经生化和神经电生理检测技术研究的基础上,本研究整合脑微透析技术与深部脑记录/刺激技术,构建了脑微透析/深部电极复合装置,实现了脑微透析探针和深部电极在体、原位的双向(记录/刺激)功能,进行了相关的实验研究:(1)微透析结合深部脑记录技术,在动物缺血损伤病理条件下,实现了对神经生化参数和电生理参数的同步和原位记录;(2)反向微透析结合深部脑记录技术,在动物海马区记录了外源性谷氨酸引起深部场电位信号的变化,探讨了该方法在兴奋性毒性和药物研究中的作用;(3)微透析结合深部脑刺激技术,记录了动物颅内自刺激过程中,氨基酸类和单胺类神经递质水平的变化过程,探讨了相关神经递质的变化在程序性记忆中作用,为深部脑刺激机制和奖赏性学习机制研究提供了客观的数据和新的研究手段。
以上的研究表明,脑微透析及深部电极技术及其复合装置同步、定量、神经生化结合神经电生理多参数的检测方法,在研究脑缺血等神经系统性疾病的发病机制、相关药物的作用机理,以及药物的疗效评价中具有重要的意义和潜在的应用价值。
Ischemic stroke is a leading cause of death and disability worldwide, and it is related to extreme release of glutamate resulting from a transient or permanent reduction in cerebral blood flow,which leading to excitotoxicity. The current researches show that a lot of neuronal diseases including cerebral ischemia,epilepsy and Parkinson's Disease are related to the imbalance of neurotransmitters.The neuroelectrical signals show different patterns or characters of activity duing to the destruction to physilogical basis results from neurotransmission disorder.So the main task of this research is to investigate the changes and relationship between neuroelectrical and neurochemical signals under different physilogical and pathological conditions by combinating the brain microdialysis and deep brain electrode techniques.
We first discuss several factors which influence the performance of probe such as construct,temperature,materials and dialysis time by using a serials of in vivo/vitro experiments.With the opmized probe,the usual methods for calibration and validation are investigated and discussed.We also establish a system platform for probe design,manufacture and validation.The self-made probe meets the requirement for in vivo experiment after comparition with international commercial products.
Combining the high performance liquid chromatography technique,we set up a highly sensitive method for simulatneous detect the amino acids neurotransmitters and monoamine neurotransmitters and their metabolites. The method for sampling and storing monoanime was simplified with the self-made sampler.We also establish an experimental platform for deep brain stimulation(DBS)and deep brain record(DBR).Combinated with spectral evaluation method based on autoregressive model parameters, complexity analysis methods based on symbofic dynamics and approximate entropy,the signals from the injuried brain regions can recorded and analyzied.
Using above neurochemical and neuroelectrical techniques,we acquire the changes of neurtransmitter and electrical signals from striatum and hippocampus in the model rat of middle cerebral artery occlusion(MCAo). The results show that during the ischemic periods the concentration of a few neurotransmitters and percentage of Delta components significantly increased the amplitude of local field potential and complexity of signals decreases.
Based on above models and methods,we study the dynamic profile of neurotransmitter intervened by drugs on MCAo rats.The results show that puerarin and gastradin effectively inhibit the excitotoxity induced by cerebral ischemia.The peak value of glutamate in drugs group lower 24～48%than that of control group,the ratoi of glutamate and GABA is abouthe 44～4%. It demostrates the protective effects of both traditional chinese medicine on acute brain injuries in molecular way and the huge potentials of these techniques in research and development in medicine.
The changes of amino acids neurotransmitters of stroke model animal were studied in this work when they recept the physical tremedies,such as functional electrical stimulation(FES)and exercises.Both FES and exercises upregulate the level of Glu in brain and intervene taurine and GABA.The similar results have never been reported.It shows that the physical rehabilitation is related to the plasticity of brain and that it plays a key role in chronic post-stroke rehabilitation.
On the base of above works,we combine the brain microdialysis and DBR together to create a microdialysis/electrode combined apparatus to realize the bi-direction function of microdialysis and deep brain dectrode in the same site.We use it in there animal experiments for primary exploration for its application(1)microdialysis and deep brain recordings-to simultaneously detect the neurochemical and neurodectrical signal from the same region during cerebral ischemia period;(2)retro-microdialysis and deep brain recordings-to measure the basic levd of glutamate and local intervention of extrinsic glutamate in hippocampus;(3)microdialysis and deep brain stimulation-to investigate the changes of amino acids and monoamine neurotransmitters invoked by stimulation in VTA and provide a new tools for researches in mechanism underlying rewards and DBS.
All above results show that the brain microdialysis,deep brain electrodes and combinated apparutus with synchronous,quantitative and neurochemical-neurodectrical multi-parameters analysis methods can play a key role in investiagting the pathological mechanism underlying neural system diseases,evaluation the effects of drugs.
引文
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