脑缺血及再灌注过程中大鼠海马区一氧化氮动态变化的在体研究
|
摘要
缺血性脑损伤是一个复杂的病理生理过程，其主要病理变化是缺血性神经元损伤。以往对缺血性脑损伤的研究认为，脑血流中断后，脑细胞能量供应不足而导致脑细胞死亡。近年来研究发现脑血流中断和再灌注使脑组织细胞产生损伤级联反应，至少涉及4个不同的机制：能量障碍和兴奋性氨基酸毒性、梗死周围去极化、炎症及程序性细胞死亡。大量动物实验及临床研究表明，脑缺血及再灌注期间发生着复杂的病理生理变化。一方面，脑缺血再灌注既可以挽救濒临梗死的细胞，另一方面加重细胞损伤，导致细胞死亡。
而在这个复杂的过程中，一氧化氮(Nitric Oxide，NO)起着十分重要的作用。其作为一种新型信使分子，同时具有神经介质和神经毒性作用。尤其在脑部的组织中的双重作用更是近年来研究的重点。一方面它能够增加皮层供血量，缩小梗死面积；另一方面它能够与缺血产生的氧自由基协同造成神经细胞损伤。
本论文通过在体检测脑缺血及再灌注过程中大鼠脑海马内NO的释放情况，真实反应了该过程中NO的释放变化情况，为进一步研究NO的神经介质作用和神经毒性作用奠定基础。并以培养的大鼠海马神经细胞的缺氧缺糖(OGD)为离体脑缺血／再灌注模型(即对培养的海马神经细胞进行缺氧缺糖复氧复糖)，利用荧光标记和激光共聚焦实时扫描技术，对海马神经细胞内释放的NO变化进行了检测，从而完成了对脑缺血／再灌注过程中NO的动态变化过程的整体与细胞两个层面的研究。
最新的关于脑缺血及再灌注损伤的治疗方法的研究是通过对再灌注过程的干预(post-conditioning)来减少脑部梗死面积，但该过程中NO的变化情况、具体的作用机理及究竟哪种干预方法更有效均未见报道。通过使用本论文中的在体检测NO方法，实时、连续地记录了该干预过程中NO的变化情况，从而阐明了NO确实参与了缺血后处理，提示NO通路有可能是该方法对脑缺血／再灌注损伤保护作用的一条途径。同时，利用TTC染色与流式细胞技术对比了不同后处理方法对于大脑的保护作用，为进一步优化该干预方法提供了一定的理论基础。
所得结果如下：
1．海马内NO释放减少，对血管的舒张作用降低，继而大鼠血压上升。这与理论“内皮依赖性舒张因子(endothelium-derived relaxing factor，EDRF)和一氧化氮同质”相符，进而验证了该在体检测NO技术的真实性和稳定性。同时得出结论，静脉注射一氧化氮合酶(nitric oxide synthase，NOS)抑制剂L-NAME 20μL-30μL后，NO的释放量减少了4．5 nM-6nM。
2．大鼠脑缺血／再灌注初期中，海马内NO的变化经历了四个阶段：在脑缺血的最初10min，由于大脑供血的迅速减少，NO的释放量也迅速下降，并达到最低点；之后稳定维持在一个低水平；在再灌注初期，由于血液的恢复，NO释放量迅速升高，并在10．15min内达到最高点；之后维持在一个稳定的高水平。同时通过拟合定标曲线，计算得出：在脑缺血过程中海马内NO释放的减少浓度为0．806±0．221μM，在再灌注初期NO释放量增加浓度为0．768±0．029μM。
3．在不同的时间点分别静脉注射内皮型NOS (eNOS)／神经元型NOS(nNOS)和诱生型NOS(iNOS)的抑制剂，结果表明在再灌注初期eNOS／nNOS起主要作用，与iNOS没有关系，在这个过程中海马内释放的NO对受损脑组织起到了保护和损伤双重作用。
4．在离体培养的大鼠海马神经元细胞实验上，通过共聚焦显微镜得到了NO在OGD／复氧复糖模型中的变化过程。该过程实验结果与在体大鼠实验结果相比，NO释放的变化过程显得较为简单。在OGD／复氧复糖过程中，NO的表达均有明显上升，并在再灌注10-12 min后达到稳定的平台期。
5．利用在体检测NO技术，实验发现缺血后处理(post-conditioning)能够使大鼠海马内NO的释放缓慢增加，从而进一步增加脑内血流量。我们认为，脑缺血后处理所引起的NO缓慢而大量的释放能够抑制NO的毒性作用而进一步加大NO对于脑血流的积极增加作用，从而减少脑缺血／再灌注损伤。不同后处理方法对于脑内NO释放的影响不同。
6．对比6组不同的后处理方法(即改变缺血和再灌注的时间长短及交替的次数)，实验发现缺血后处理都可以一定程度上减少脑部梗死面积，提高大鼠海马内神经细胞的存活率。但其中3次30s／30s的再灌注／缺血循环能够最有效的减少大脑损伤。我们认为该方法可能能够最大程度的激发脑内NO的缓慢大量释放，说明NO很有可能是post-conditioning改善脑损伤的一条作用途径。
本论文采用实时、连续、在体检测NO结合荧光标记与激光共聚焦实时扫描技术的方法，分别从整体与细胞两个层次上对脑缺血／再灌注过程中大鼠海马内NO浓度进行了检测，全面的阐述了该过程中NO的变化情况以及对脑组织的双重作用。另一方面，利用NO的在体检测技术，首次检测了在缺血后处理过程中NO的变化情况，揭示了NO可能是该干预方法作用的一个途径，并通过对比多种缺血后处理方法对于缺血／再灌注损伤的保护作用，进一步对该干预方法进行优化。
NO在脑缺血／再灌注疾病中发挥着重要的作用，清楚了解NO在脑缺血／再灌注过程中的变化及其作用机制对于防治中风药物的开发与筛选以及临床上治疗中风引起的神经损伤都具有重要的指导意义。
Brain ischemic injury is a complex pathophysiologic progress and it causes theneurons ischemic injuries. It was considered that these injuries were a kind of celldeath because of the energy insufficiency in the cerebral cells after the cerebral bloodflow was interrupted. Recently many researches found that cerebral ischemia andreperfusion caused cell injuries through a series of at least 4 reactions, includingenergy barriers and excitatory amino acid toxicity, depolarization of infarct area,inflammation and program cell death. Abundant animal experiments and clinicalresearches approved that there was a complicated pathophysiologic progress incerebral ischemia and reperfusion. The reperfusion could save the dying cells. On theother hand it could aggravate the cell injury and cause cell death.
Nitric oxide (NO) plays an important role in this process. As an importantmolecular messenger, NO works as a nerve mediator as well as a detrimental factor innervous system. In central and peripheral nervous systems NO participates in manyforms of synaptic transmission and pathological progress. Recently its dual effectbecomes a hot spot in experimental and clinical researches, especially under the statusof cerebral ischemia and reperfusion (I/R).
In the present study, we measured NO levels in rat hippocampus using acarbon-fiber NO sensor during the process of global cerebral ischemia and the initialstage of reperfusion. Meanwhile, we separately observed the effects of two differentNOS inhibitors to the production of NO in this process. Based on the real-timemeasurement of NO concentration in rat hippocampus, the dynamic variance of NOconcentration in global cerebral ischemia and reperfusion has been revealed. Besidesthe animal experiments, we cultured hippocampal neurons in 20 min OGD andreperfusion to detect the changes of NO in OGD/reperfusion neurons. So we revealedthe dynamic changes of NO during ischemia and reperfusion, both in animal and celllevels.
Although extensive research for I/R injury treatment has been performed in thepast several decades, few neuroprotectants and methods have been successfully translated from basic research into a clinical application. Recently ischemicpost-conditioning is a relatively novel concept. Unlike pre-conditioning,post-conditioning is composed of several repeated cycles of brief reperfusion andreocculusion of the artery applied at the onset of full reperfusion. Thie method hasbeen proved had powerful protective effects on ischemia, and may eventually lead tomore extensive clinical application. However, the underlying protective mechanism ofpost-conditioning remains illusive and in our experiment, we detected the dynamicchange of NO during the ischemic postconditioning against global cerebral I/R in vivo,and compared the effects of different numbers of cycles and periods forreperfusion/occlusion, to investigate the role of NO in ischemic postconditioning.Combining the cerebral blood flow (CBF) and the death ratio of neuron cells in rathippocampus, we could explore the mechanisms underlying the interruptingreperfusion. Furthermore, our results discover the best parameters that generate thestrongest protection and may provide important clues for cerebral I/R treatment.
The results as follows:
1. Alternation of NO levels in hippocampus resulted in a change of arterial bloodpressure and the electrochemical signal of NO could be recorded in real time.Intravenous administration of L-NAME (50mg/mL, 20μL-30μL) induced adecrease in NO concentration (4.5nM-6nM).
2. In global cerebral ischemia and the initial stage of reperfusion, the whole NOconcentration profile could be divided into four stages as follows: the earlyischemia stage, during which there was a rapid and significant decrease of NOconcentration.; after the NO declined to the minimum, there was a platform withNO concentration keeping roughly unchanged; upon the onset of reperfusion, therewas an acute elevation stage lasted for 15 minutes; another steady stage appearedafter NO concentration reached the peak of reperfusion.
3. We also observed the effects of two inhibitors of NOS on NO concentration.The two inhibitors (7-NI and 1400W) were respectively administratedintravenously at the onset of reperfusion and 1 h later. NO biosynthesis during the initial stage of reperfusion was mainly nNOS-dependent.
4. We observed the dynamic changes of NO in hippocampal neurons inOGD/reperfusion. NO concentration was increased slowly and reached a platformafter 10-12 min.
5. The speed of NO concentration increase was slowed down, but the extent onincrease was remarkably enlarged after ischemic post-conditioning, and CBF wasalso increased. We thought that post-conditioning induced a gentle and increasedNO synthesis, which inhibited the NO toxicity and strengthened the effect of NO toCBF, and finally decreased I/R lesion.
6. Different numbers of cycles as well as different durations of reperfusion andocclusion had different effect to I/R injury. We found that 3 cycles of 30 sreperfusion and 30 s occlusion had the best protective effect.
In conclusion, we detected the NO concentration in rat hippocampus in globalcerebral ischemia and the initial stage of reperfusion in vivo, and calculated thechange concentration of NO during this process. Meanwhile, we observed thechanges of NO in hippocampal neurons in 20 min OGD and reperfusion. So werevealed the dynamic changes of NO during ischemia and reperfusion, both inanimal and cell levels. It is very useful to reveal the behavior of NO concentrationin stroke and reperfusion. For post-conditioning, we detected the dynamic changeof NO during the ischemic postconditioning, and compared the effects of differentnumbers of cycles and periods for reperfusion/occlusion. We believed that NO alsoworked as an essential infactor in post-conditioning pathway.
Our dynamic measurements of NO during this process would offer a timetherapeutic window for I/R treatment, which is very helpful for clinical therapies inthe future.
而在这个复杂的过程中，一氧化氮(Nitric Oxide，NO)起着十分重要的作用。其作为一种新型信使分子，同时具有神经介质和神经毒性作用。尤其在脑部的组织中的双重作用更是近年来研究的重点。一方面它能够增加皮层供血量，缩小梗死面积；另一方面它能够与缺血产生的氧自由基协同造成神经细胞损伤。
本论文通过在体检测脑缺血及再灌注过程中大鼠脑海马内NO的释放情况，真实反应了该过程中NO的释放变化情况，为进一步研究NO的神经介质作用和神经毒性作用奠定基础。并以培养的大鼠海马神经细胞的缺氧缺糖(OGD)为离体脑缺血／再灌注模型(即对培养的海马神经细胞进行缺氧缺糖复氧复糖)，利用荧光标记和激光共聚焦实时扫描技术，对海马神经细胞内释放的NO变化进行了检测，从而完成了对脑缺血／再灌注过程中NO的动态变化过程的整体与细胞两个层面的研究。
最新的关于脑缺血及再灌注损伤的治疗方法的研究是通过对再灌注过程的干预(post-conditioning)来减少脑部梗死面积，但该过程中NO的变化情况、具体的作用机理及究竟哪种干预方法更有效均未见报道。通过使用本论文中的在体检测NO方法，实时、连续地记录了该干预过程中NO的变化情况，从而阐明了NO确实参与了缺血后处理，提示NO通路有可能是该方法对脑缺血／再灌注损伤保护作用的一条途径。同时，利用TTC染色与流式细胞技术对比了不同后处理方法对于大脑的保护作用，为进一步优化该干预方法提供了一定的理论基础。
所得结果如下：
1．海马内NO释放减少，对血管的舒张作用降低，继而大鼠血压上升。这与理论“内皮依赖性舒张因子(endothelium-derived relaxing factor，EDRF)和一氧化氮同质”相符，进而验证了该在体检测NO技术的真实性和稳定性。同时得出结论，静脉注射一氧化氮合酶(nitric oxide synthase，NOS)抑制剂L-NAME 20μL-30μL后，NO的释放量减少了4．5 nM-6nM。
2．大鼠脑缺血／再灌注初期中，海马内NO的变化经历了四个阶段：在脑缺血的最初10min，由于大脑供血的迅速减少，NO的释放量也迅速下降，并达到最低点；之后稳定维持在一个低水平；在再灌注初期，由于血液的恢复，NO释放量迅速升高，并在10．15min内达到最高点；之后维持在一个稳定的高水平。同时通过拟合定标曲线，计算得出：在脑缺血过程中海马内NO释放的减少浓度为0．806±0．221μM，在再灌注初期NO释放量增加浓度为0．768±0．029μM。
3．在不同的时间点分别静脉注射内皮型NOS (eNOS)／神经元型NOS(nNOS)和诱生型NOS(iNOS)的抑制剂，结果表明在再灌注初期eNOS／nNOS起主要作用，与iNOS没有关系，在这个过程中海马内释放的NO对受损脑组织起到了保护和损伤双重作用。
4．在离体培养的大鼠海马神经元细胞实验上，通过共聚焦显微镜得到了NO在OGD／复氧复糖模型中的变化过程。该过程实验结果与在体大鼠实验结果相比，NO释放的变化过程显得较为简单。在OGD／复氧复糖过程中，NO的表达均有明显上升，并在再灌注10-12 min后达到稳定的平台期。
5．利用在体检测NO技术，实验发现缺血后处理(post-conditioning)能够使大鼠海马内NO的释放缓慢增加，从而进一步增加脑内血流量。我们认为，脑缺血后处理所引起的NO缓慢而大量的释放能够抑制NO的毒性作用而进一步加大NO对于脑血流的积极增加作用，从而减少脑缺血／再灌注损伤。不同后处理方法对于脑内NO释放的影响不同。
6．对比6组不同的后处理方法(即改变缺血和再灌注的时间长短及交替的次数)，实验发现缺血后处理都可以一定程度上减少脑部梗死面积，提高大鼠海马内神经细胞的存活率。但其中3次30s／30s的再灌注／缺血循环能够最有效的减少大脑损伤。我们认为该方法可能能够最大程度的激发脑内NO的缓慢大量释放，说明NO很有可能是post-conditioning改善脑损伤的一条作用途径。
本论文采用实时、连续、在体检测NO结合荧光标记与激光共聚焦实时扫描技术的方法，分别从整体与细胞两个层次上对脑缺血／再灌注过程中大鼠海马内NO浓度进行了检测，全面的阐述了该过程中NO的变化情况以及对脑组织的双重作用。另一方面，利用NO的在体检测技术，首次检测了在缺血后处理过程中NO的变化情况，揭示了NO可能是该干预方法作用的一个途径，并通过对比多种缺血后处理方法对于缺血／再灌注损伤的保护作用，进一步对该干预方法进行优化。
NO在脑缺血／再灌注疾病中发挥着重要的作用，清楚了解NO在脑缺血／再灌注过程中的变化及其作用机制对于防治中风药物的开发与筛选以及临床上治疗中风引起的神经损伤都具有重要的指导意义。
Brain ischemic injury is a complex pathophysiologic progress and it causes theneurons ischemic injuries. It was considered that these injuries were a kind of celldeath because of the energy insufficiency in the cerebral cells after the cerebral bloodflow was interrupted. Recently many researches found that cerebral ischemia andreperfusion caused cell injuries through a series of at least 4 reactions, includingenergy barriers and excitatory amino acid toxicity, depolarization of infarct area,inflammation and program cell death. Abundant animal experiments and clinicalresearches approved that there was a complicated pathophysiologic progress incerebral ischemia and reperfusion. The reperfusion could save the dying cells. On theother hand it could aggravate the cell injury and cause cell death.
Nitric oxide (NO) plays an important role in this process. As an importantmolecular messenger, NO works as a nerve mediator as well as a detrimental factor innervous system. In central and peripheral nervous systems NO participates in manyforms of synaptic transmission and pathological progress. Recently its dual effectbecomes a hot spot in experimental and clinical researches, especially under the statusof cerebral ischemia and reperfusion (I/R).
In the present study, we measured NO levels in rat hippocampus using acarbon-fiber NO sensor during the process of global cerebral ischemia and the initialstage of reperfusion. Meanwhile, we separately observed the effects of two differentNOS inhibitors to the production of NO in this process. Based on the real-timemeasurement of NO concentration in rat hippocampus, the dynamic variance of NOconcentration in global cerebral ischemia and reperfusion has been revealed. Besidesthe animal experiments, we cultured hippocampal neurons in 20 min OGD andreperfusion to detect the changes of NO in OGD/reperfusion neurons. So we revealedthe dynamic changes of NO during ischemia and reperfusion, both in animal and celllevels.
Although extensive research for I/R injury treatment has been performed in thepast several decades, few neuroprotectants and methods have been successfully translated from basic research into a clinical application. Recently ischemicpost-conditioning is a relatively novel concept. Unlike pre-conditioning,post-conditioning is composed of several repeated cycles of brief reperfusion andreocculusion of the artery applied at the onset of full reperfusion. Thie method hasbeen proved had powerful protective effects on ischemia, and may eventually lead tomore extensive clinical application. However, the underlying protective mechanism ofpost-conditioning remains illusive and in our experiment, we detected the dynamicchange of NO during the ischemic postconditioning against global cerebral I/R in vivo,and compared the effects of different numbers of cycles and periods forreperfusion/occlusion, to investigate the role of NO in ischemic postconditioning.Combining the cerebral blood flow (CBF) and the death ratio of neuron cells in rathippocampus, we could explore the mechanisms underlying the interruptingreperfusion. Furthermore, our results discover the best parameters that generate thestrongest protection and may provide important clues for cerebral I/R treatment.
The results as follows:
1. Alternation of NO levels in hippocampus resulted in a change of arterial bloodpressure and the electrochemical signal of NO could be recorded in real time.Intravenous administration of L-NAME (50mg/mL, 20μL-30μL) induced adecrease in NO concentration (4.5nM-6nM).
2. In global cerebral ischemia and the initial stage of reperfusion, the whole NOconcentration profile could be divided into four stages as follows: the earlyischemia stage, during which there was a rapid and significant decrease of NOconcentration.; after the NO declined to the minimum, there was a platform withNO concentration keeping roughly unchanged; upon the onset of reperfusion, therewas an acute elevation stage lasted for 15 minutes; another steady stage appearedafter NO concentration reached the peak of reperfusion.
3. We also observed the effects of two inhibitors of NOS on NO concentration.The two inhibitors (7-NI and 1400W) were respectively administratedintravenously at the onset of reperfusion and 1 h later. NO biosynthesis during the initial stage of reperfusion was mainly nNOS-dependent.
4. We observed the dynamic changes of NO in hippocampal neurons inOGD/reperfusion. NO concentration was increased slowly and reached a platformafter 10-12 min.
5. The speed of NO concentration increase was slowed down, but the extent onincrease was remarkably enlarged after ischemic post-conditioning, and CBF wasalso increased. We thought that post-conditioning induced a gentle and increasedNO synthesis, which inhibited the NO toxicity and strengthened the effect of NO toCBF, and finally decreased I/R lesion.
6. Different numbers of cycles as well as different durations of reperfusion andocclusion had different effect to I/R injury. We found that 3 cycles of 30 sreperfusion and 30 s occlusion had the best protective effect.
In conclusion, we detected the NO concentration in rat hippocampus in globalcerebral ischemia and the initial stage of reperfusion in vivo, and calculated thechange concentration of NO during this process. Meanwhile, we observed thechanges of NO in hippocampal neurons in 20 min OGD and reperfusion. So werevealed the dynamic changes of NO during ischemia and reperfusion, both inanimal and cell levels. It is very useful to reveal the behavior of NO concentrationin stroke and reperfusion. For post-conditioning, we detected the dynamic changeof NO during the ischemic postconditioning, and compared the effects of differentnumbers of cycles and periods for reperfusion/occlusion. We believed that NO alsoworked as an essential infactor in post-conditioning pathway.
Our dynamic measurements of NO during this process would offer a timetherapeutic window for I/R treatment, which is very helpful for clinical therapies inthe future.
引文
1．王维治．神经病学．北京：北京卫生出版社：2006．
2．邢成名．缺血性脑血管病．北京 人民卫生出版社2003．
3. Zhao H. The protective effect of ischemic postconditioning against ischemic injury: From the heart to the brain. Journal of Neuroimmune Pharmacology. 2007;2(4):313-318
4. Xing B, Chen H, Zhang M, Zhao D, Jiang R, Liu X and Zhang S. Ischemic postconditioning inhibits apoptosis after focal cerebral ischemia/reperfusion injury in the rat. Stroke. 2008;39(8):2362-2369
5. Zhao H. Ischemic postconditioning as a novel avenue to protect against brain injury after stroke. J Cereb Blood Flow Metab. 2009
6. Rifkind JM, Nagababu E, Barbiro-Michaely E, Ramasamy S, Pluta RM and Mayevsky A. Nitrite infusion increases cerebral blood flow and decreases mean arterial blood pressure in rats: A role for red cell no. Nitric Oxide. 2007; 16(4):448-456
7．陈怀红and朱丽君．大鼠大脑中动脉闭塞后基底节nr1和nr2a及nr2b的表达．浙江大学学报以：医学版．2001；30(3)：100-102
8. Li Y, Chopp M, Jiang N and Zaloga C. In situ detection of DNA fragmentation after focal cerebral ischemia in mice. Brain Res Mol Brain Res. 1995 ;28(1): 164-168
9. Koqure T and Koqure K. Molecular and biochemical events within the brain subjected to cerebral ischemia. Clin Neurosci. 1997;4(4): 179-183
10. Martin S, Green D and Cotter T. Dicing with death: Dissecting the components of the apotosis machinery. Trends in biochemical sciences. 1994; 19(1):26-30
11. Kontos and Hermes A. Oxygen radicals in cerebral ischemia: The 2001 willis lecture. Stroke. 2001 ;32(11):2712-2716
12. Althaus J, Andrus P, Williams C, VonVoigtlander P, Cazers A and Hall E. The use of salicylate hydroxylation to detect hydroxyl radical generation in ischemic and traumatic brain injury. Reversal by tirilazad mesylate (u-74006f). Mol Chem Neuropathol. 1993;20(2): 147-162
13. Bates B, Hirt L, Thomas SS, Akbarian S, Le D, Amin-Hanjani S, Whalen M, Jaenisch R and Moskowitz MA. Neurotrophin-3 promotes cell death induced in cerebral ischemia, oxygen-glucose deprivation, and oxidative stress: Possible involvement of oxygen free radicals. Neurobiology of Disease. 2002;9(1):24-37
14. Dirnagl U, Iadecola C and Moskowitz MA. Pathobiology of ischaemic stroke: An integrated view. Trends in Neurosciences. 1999;22(9):391-397
15. Jung K-H, Chu K, Ko S-Y, Lee S-T, Sinn D-I, Park D-K, Kim J-M, Song E-C, Kim M and Roh J-K. Early intravenous infusion of sodium nitrite protects brain against in vivo ischemia-reperfusion injury. Stroke. 2006;37(11):2744-2750
16. Kawabata S, Tsutsumi R, Kohara A, Yamaguchi T, Nakanishi S and Okada M. Control of calcium oscillations by phosphorylation of metabotropic glutamate receptors. Nature. 1996;383(6595):89-92
17. Pocock J and Nicholls D. Exocytotic and nonexocytotic modes of glutamate release from cultured cerebellar granule cells during chemical ischaemia. Journal of Neurochemistry. 1998;70(2):806-813
18. Rossi DJ, Oshima T and Attwell D. Glutamate release in severe brain ischaemia is mainly by reversed uptake. Nature. 2000;403(6767):316-321
19. Mitani A, Andou Y and Kataoka K. Selective vulnerability of hippocampal cal neurons cannot be explained in terms of an increase in glutamate concentration during ischemia in the gerbil: Brain microdialysis study. Neuroscience. 1992;48(2):307-313
20．杨倩，朱武生and吴家幂．大鼠脑缺血再灌注模型icam1表达与白细胞浸润关系及亚低温干预治疗的研究．临床神经病学杂志．2002；15(4)：196-199
21. Lipton P. Ischemic cell death in brain neurons. Physiol Rev. 1999;79(4): 1431-1568
22. Vila N, Castillo J, Davalos A and Chamorro A. Proinflammatory cytokines and early neurological worsening in ischemic stroke. Stroke. 2000;31 (10):2325-2329
23．李岚，赵光东and张健．川芎嗪对局部脑缺血再灌注流模型纹状体内il-1β的影响．中国临床神经科学．2001；9(1)：36-37
24．屠永华and李岚．大鼠局灶脑缺血/再灌流模型中il-1β的表达及作用．医学综述．1998；4(10)：570-572
25. Jiang X, Mu D, Manabat C, Koshy AA, Christen S, Tauber MG, Vexler ZS and Ferriero DM. Differential vulnerability of immature murine neurons to oxygen-glucose deprivation. Experimental Neurology. 2004;190(1):224-232
26. Macdonald R and Stoodley M. Pathophysiology of cerebral ischemia. Neurol Med Chir(Tokyo) 1998;38(1):1-11
27. Clemens JA. Cerebral ischemia: Gene activation, neuronal injury, and the protective role of antioxidants. Free Radical Biology and Medicine. 2000;28(10):1526-1531
28．朱勇飞and王友顺．一氧化氮检测技术的研究进展．中国卫生检验杂志．2000；10(3)：372-374
29．陈啸春，盛超and郑筱祥．一氧化氮抑制海马神经元兴奋的机制研究．生物物理学报．2001；17(3)：469-476
30．史源．一氧化氮及其临床意义．国外医学：儿科学分册．1994；21(2)：89-92
31．夏保芦，张艳and熊希凯．Nos活性在大鼠不同脑区的研究．中国组织化学与细胞化学杂志．2000；9(1)：100-102
32．薛保健，王志安and何瑞荣．No前体和供体对大鼠海马脑片神经元活动的影响．生理学报．1997；49(4)：375-381
33．强文安，刘枝俏and刘捷．脑组织一氧化氮合成酶的特性及其与nadph-diaphorase相关性研究．中国神经免疫学和神经病学杂志．1996；3(4)：191-198
34．张会欣and张建新．一氧化氮与脑缺血．河北医药．2002；24(4)：297-299
35．李宏伟and赵连友．一氧化氮的检测方法及其评价．心功能杂志．1998；10(1)：27-28，32
36. Fujimura M, Gasche Y, Morita-Fujimura Y, Massengale J, Kawase M and Chan P. Early appearance of activated matrix metalloproteinase-9 and blood-brain barrier disruption in mice after focal cerebral ischemia and reperfusion. Brain Res. 1999;842(1):92-100
37. Megson IL. Nitric oxide donor drugs. Drugs of the Future. 2000;25(7):701-715
38. Alderton W, Cooper C and Knowles R. Nitric oxide synthases: Structure, function and inhibition. Biochem J. 2001 ;357(Pt 3):593-615
39. Pont(?)n U, Ratcheson R, Salford L and Siesj(o｜¨). Optimal freezing conditions for cerebral metabolites in rats. Journal of Neurochemistry. 1973 ;21 (5): 1127-1138
40. Ekl(o｜¨)f B and Siesj(o｜¨) B. The effect of bilateral carotid artery ligation upon the blood flow and the energy state of the rat brain. Acta Physiologica Scandinavica. 1972;86(2): 155-165
41. Nordstrom CH, Rehncrona S and Siesjo BK. Effects of phenobarbital in cerebral ischemia. Part ⅱ: Restitution of cerebral energy state, as well as of glycolytic metabolites, citric acid cycle intermediates and associated amino acids after pronounced incomplete ischemia. Stroke. 1978;9(4):335-343
42. Pulsinelli WA and Buchan AM. The four-vessel occlusion rat model: Method for complete occlusion of vertebral arteries and control of collateral circulation. Stroke. 1988;19(7):913-914
43. Kudo M, Aoyama A, Ichimori S and Fukunaga N. An animal model of cerebral infarction. Homologous blood clot emboli in rats. Stroke. 1982; 13(4):505-508
44．李威，邹明辉，李秋风，苗利军and杨宁辉．通腑化痰活血法对大鼠脑梗塞后血液流变学的影响．中药药理与临床．1996：12(3)：3-6
45. Tamura A, Graham D, McCulloch J and Teasdale G. Focal cerebral ischaemia in the rat: 1. Description of technique and early neuropathological consequences following middle cerebral artery occlusion. J Cereb Blood Flow Metab. 1981;1(1):53-60
46. Watson B, Dietrich W, Busto R, Wachtel M and Ginsberg M. Induction of reproducible brain infarction by photochemically initiated thrombosis. Ann Neurol. 1985; 17(5):497-504
47. Koizumi J, Yoshida Y, Nakazawa T and Ooneda G. Experimental studies of ischemic brain edema. I. A new experimental model of cerebral embolism in rats in which recirculation can be introduced in the ischemic area. Jpn J Stroke. 1986;8(1-8
48. Longa EZ, Weinstein PR, Carlson S and Cummins R. Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke. 1989;20(1): 84-91
49. Goldberg MP, Monyer H, Weiss JH and Choi DW. Adenosine reduces cortical neuronal injury induced by oxygen or glucose deprivation in vitro. Neurosci Lett 1988;89(3):323-327
50．汪晖．药物代谢的体外筛选系统．中国药理通讯．2005；22(3)：12
51．杜冠华．高通量药物筛选技术进展与新药开发策略．中国生物学文摘．2005；19(1)：32-37
52. Palmer R, Ferrige A and S SM. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987;327(524-526
53. Ignarro LJ, Buga GM, Wood KS, Byrns RE and Chaudhuri G. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. PNAS. 1987;84(24):9265-9269
54. Burnett A, Lowenstein C, Bredt D, Chang T and Snyder S. Nitric oxide: A physiologic mediator of penile erection. Science. 1992;257(5068):401-403
55．李莉萍，罗超权and刘丽．动力蛋白轻链/一氧化氮合酶抑制剂．生命的化学．2003；23(4)：270-272
56．朱勇飞．化学发光方法检测一氧化氮．国外医学临床生物化学与检验学分册．2000；21(1)：6-8
57．彭图治and杨丽菊．生命科学中的电分析化学．杭州：杭州大学出版社；1999
58. Flam BR, Eichler DC and Solomonson LP. Endothelial nitric oxide production is tightly coupled to the citrulline-no cycle. Nitric Oxide. 2007; 17(3-4): 115-121
59. Privat C, Stepien O, David-Dufilho M, Brunet A, Bedioui F, Marche P, Devynck J and Devynck M. Superoxide release from interleukin-lb-stimulated human vascular cells: In situ electrochemical measurement. Free Radic Biol Med. 1999;27(5-6):554-559
60. Malinski T and Huk I. Measurement of nitric oxide in single cells and tissue using a porphyrinic microsensor. Current protocols in neuroscience. John Wiley & Sons, Inc.; 2001.
61．唐省三．一氧化氮的检测及改良方法．生物技术．2002；12(2)：F002-003
62. Broderick PA, Hope O and Jeannot P.Mechanism of triazolo-benzodiazepine and benzodiazepine action in anxiety and depression: Behavioral studies with concomitant in vivo cal hippocampal norepinephrine and serotonin release detection in the behaving animal. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 1998;22(2):353-386
63. Nargi-Aizenman JL, Havert MB, Zhang M, Irani DN, Rothstein JD and Griffin DE. Glutamate receptor antagonists protect from virus-induced neural degeneration. Annals of Neurology. 2004;55(4):541-549
64. Stys PK. White matter injury mechanisms. Current Molecular Medicine.2004;4(2): 113-130
65. Arvidsson A, Kirik D, Lundberg C, Mandel RJ, Andsberg G, Kokaia Z and Lindvall O. Elevated gdnf levels following viral vector-mediated gene transfer can increase neuronal death after stroke in rats. Neurobiology of Disease.2003;14(3):542-556
66. Murry CE, Jennings RB and Reimer KA. Preconditioning with ischemia: A delay of lethal cell injury in ischemic myocardium. Circulation. 1986;74(5):1124-1136
67. Kitagawa K, Matsumoto M, Tagaya M, Hata R, Ueda H, Niinobe M, Handa N,Fukunaga R, Kimura K and Mikoshiba K. 'ischemic tolerance' phenomenon found in the brain. Brain Res. 1990;528(1):21-24
68. Perez-Pinzon MA. Neuroprotective effects of ischemic preconditioning in brain mitochondria following cerebral ischemia. J Bioenerg Biomembr. 2004;36(4):323-327
69. Shpargel KB, Jalabi W, Jin Y, Dadabayev A, Penn MS and Trapp BD.Preconditioning paradigms and pathways in the brain. Cleve Clin J Med.2008;75(Suppl 2):S 77-82
70. Kitagawa K, Matsumoto M, Kuwabara K, Tagaya M, Ohtsuki T, Hata R, Ueda H,Handa N, Kimura K and Kamada T. 'ischemic tolerance' phenomenon detected in various brain regions. Brain Research. 1991 ;561(2):203-211
71. Glazier S, O'Rourke D, Graham D and Welsh F. Induction of ischemic tolerance following brief focal ischemia in rat brain. J Cereb Blood Flow Metab.1994;14(4):545-553
72. Simon R, Niiro M and Gwinn R. Prior ischemic stress protects against experimental stroke. Neurosci Lett. 1993;163(2):135-137
73. Chen J, Graham SH, Zhu RL and Simon RP. Stress proteins and tolerance to focal cerebral ischemia. J Cereb Blood Flow Metab. 1996;16(4):566-577
74. Chen T, Kato H, Liu X-H, Araki T, Itoyama Y and Kogure K. Ischemic tolerance can be induced repeatedly in the gerbil hippocampal neurons. Neuroscience Letters.1994;177(1-2):159-161
75. Weih M, Prass K, Ruscher K, Trendelenburg G, Dirnagl U, Riepe M and Meisel A.Ischemia tolerance; model for research, hope for clinical practice? Nervenarzt.2001;72(4):255-260
76. Lange-Asschenfeldt C, Raval AP, Dave KR, Mochly-Rosen D, Sick TJ and Perez-Pinzon MA. Epsilon protein kinase c mediated ischemic tolerance requires activation of the extracellular regulated kinase pathway in the organotypic hippocampal slice. J Cereb Blood Flow Metab. 2004;24(6):636-645
77. Perez-Pinzon MA, Dave KR and Raval AP. Role of reactive oxygen species and protein kinase c in ischemic tolerance in the brain. Antioxid Redox Signal.2005;7(9-10):1150-1157
78. Ginis I, Jaiswal R, Klimanis D, Liu J, Greenspon J and Hallenbeck JM.Tnf-alpha-induced tolerance to ischemic injury involves differential control of nf-kappab transactivation: The role of nf-kappab association with p300 adaptor. J Cereb Blood Flow Metab. 2002;22(2): 142-152
79. Jones NM and Bergeron M. Hypoxic preconditioning induces changes in hif-1 target genes in neonatal rat brain. J Cereb Blood Flow Metab. 2001 ;21(9): 1105-1114
80. Patel A, van de Poll MC, Greve JW, Buurman WA, Fearon KC, McNally SJ,Harrison EM, Ross JA, Garden OJ, Dejong CH and Wigmore SJ. Early stress protein gene expression in a human model of ischemic preconditioning. Transplantation.2004;78(10):1479-1487
81. Speechly-Dick ME, Mocanu MM and Yellon DM. Protein kinase c. Its role in ischemic preconditioning in the rat. Circ Res. 1994;75(3):586-590
82. Pignataro G, Scorziello A, Di Renzo G and Annunziato L. Post-ischemic brain damage: Effect of ischemic preconditioning and postconditioning and identification of potential candidates for stroke therapy. Febs J. 2009;276(1):46-57
83. Kawai K, Nakagomi T, Kirino T, Tamura A and Kawai N. Preconditioning in vivo ischemia inhibits anoxic long-term potentiation and functionally protects cal neurons in the gerbil. J Cereb Blood Flow Metab. 1998; 18(3):288-296
84. Abele A and Miller R. Potassium channel activators abolish excitotoxicity in cultured hippocampal pyramidal neurons. Neurosci Lett. 1990;115(2-3): 195-200
85. Heurteaux C, Lauritzen I, Widmann C and Lazdunski M. Essential role of adenosine, adenosine a1 receptors, and atp-sensitive k+ channels in cerebral ischemic preconditioning. Proc Natl Acad Sci U S A. 1995;92(10):4666-4670
86. Grabb MC and Choi DW. Ischemic tolerance in murine cortical cell culture:Critical role for nmda receptors. J Neurosci. 1999; 19(5): 1657-1662
87. Posmantur R, Kampfl A, Liu S, Heck K, Taft W, Clifton G and Hayes R. Cytoskeletal derangements of cortical neuronal processes three hours after traumatic brain injury in rats: An immunofluorescence study. J Neuropathol Exp Neurol.1996;55(1):68-80
88. Marini A and Paul S. N-methyl-d-aspartate receptor-mediated neuroprotection in cerebellar granule cells requires new rna and protein synthesis. Proc Natl Acad Sci U S A. 1992;89(14):6555-6559
89. Nowak TJ. Synthesis of a stress protein following transient ischemia in the gerbil.J Neurochem. 1985;45(5):1635-1641
90. Simon RP, Cho H, Gwinn R and Lowenstein DH. The temporal profile of 72-kda heat-shock protein expression following global ischemia. J Neurosci. 1991;11(3):881-889
91. Liu Y, Kato H, Nakata N and Kogure K. Temporal profile of heat shock protein 70 synthesis in ischemic tolerance induced by preconditioning ischemia in rat hippocampus. Neuroscience. 1993;56(4):921 -927
92. Kobayashi S, Harris V and Welsh F. Spreading depression induces tolerance of cortical neurons to ischemia in rat brain. J Cereb Blood Flow Metab.1995;15(5):721-727
93. Kato H, Kogure K, Araki T and Itoyarna Y. Induction of jun-like immunoreactivity in astrocytes in gerbil hippocampus with ischemic tolerance. Neuroscience Letters.1995;189(1):13-16
94. Linnik MD, Zahos P, Geschwind MD and Federoff HJ. Expression of bcl-2 from a defective herpes simplex virus? Vector limits neuronal death in focal cerebral ischemia. Stroke. 1995;26(9):1670-1675
95. Chen J, Graham S, Chan P, Lan J, Zhou R and Simon R. Bcl-2 is expressed in neurons that survive focal ischemia in the rat. Neuroreport. 1995;6(2):394-398
96. Shimazaki K, Ishida A and Kawai N. Increase in bcl-2 oncoprotein and the tolerance to ischemia-induced neuronal death in the gerbil hippocampus. Neurosci Res.1994;20(1):95-99
97. Bolli R. Cardioprotective function of inducible nitric oxide synthase and role of nitric oxide in myocardial ischemia and preconditioning: An overview of a decade of research. J Mol Cell Cardiol. 2001;33(11):1897-1918
98. Murphy S and Gibson CL. Nitric oxide, ischaemia and brain inflammation.Biochem Soc Trans. 2007;35(Pt 5):1133-1137
99. Atochin DN, Clark J, Demchenko IT, Moskowitz MA and Huang PL. Rapid cerebral ischemic preconditioning in mice deficient in endothelial and neuronal nitric oxide synthases. Stroke. 2003;34(5):1299-1303
100. Cho S, Park EM, Zhou P, Frys K, Ross ME and Iadecola C. Obligatory role of inducible nitric oxide synthase in ischemic preconditioning. J Cereb Blood Flow Metab. 2005;25(4):493-501
101.Gidday JM, Shah AR, Maceren RG, Wang Q, Pelligrino DA, Holtzman DM and Park TS. Nitric oxide mediates cerebral ischemic tolerance in a neonatal rat model of hypoxic preconditioning. J Cereb Blood Flow Metab. 1999;19(3):331-340
102.Gonzalez-Zulueta M, Feldman AB, Klesse LJ, Kalb RG, Dillman JF, Parada LF, Dawson TM and Dawson VL. Requirement for nitric oxide activation of p21(ras)/extracellular regulated kinase in neuronal ischemic preconditioning. Proc Natl AcadSci U S A. 2000;97(1):436-441
103.Shiva S, Sack MN, Greer JJ, Duranski M, Ringwood LA, Burwell L, Wang X,MacArthur PH, Shoja A, Raghavachari N, Calvert JW, Brookes PS, Lefer DJ and Gladwin MT. Nitrite augments tolerance to ischemia/reperfusion injury via the modulation of mitochondrial electron transfer. J Exp Med. 2007;204(9):2089-2102
104. Scorziello A, Santillo M, Adornetto A, Dell'aversano C, Sirabella R, Damiano S, Canzoniero LM, Renzo GF and Annunziato L. No-induced neuroprotection in ischemic preconditioning stimulates mitochondrial mn-sod activity and expression via ras/erk1/2 pathway. J Neurochem. 2007; 103(4): 1472-1480
105. Kato H, Kogure K, Araki T and Itoyama Y. Astroglial and microglial reactions in the gerbil hippocampus with induced ischemic tolerance. Brain Research. 1994;664(1-2):69-76
106. Zhao Z, Corvera J, Halkos M, Kerendi F, Wang N, Guyton R and Vinten-Johansen J. Inhiibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic precondtitioning. Am J Physiol Heart Circ Physiol. 2003 ;285(2) :H579-588
107. Staat P, Rioufol G, Piot C, Cottin Y, Cung TT, L'Huillier I, Aupetit J-F, Bonnefoy E, Finet G, Andre-Fouet X and Ovize M. Postconditioning the human heart. Circulation. 2005; 112(14):2143-2148
108. Jiang X, Shi E, Nakajima Y and Sato S. Postconditioning, a series of brief interruptions of early reperfusion, prevents neurologic injury after spinal cord ischemia. Ann Surg. 2006;244(1): 148-153
109. Zhao H, Sapolsky RM and Steinberg GK. Interrupting reperfusion as a stroke therapy: Ischemic postconditioning reduces infarct size after focal ischemia in rats. J Cereb Blood Flow Metab. 2006;26(9): 1114-1121
110. Pignataro G, Meller R, Inoue K, Ordonez AN, Ashley MD, Xiong Z, Gala R and Simon RP. In vivo and in vitro characterization of a novel neuroprotective strategy for stroke: Ischemic postconditioning. J Cereb Blood Flow Metab. 2008;28(2):232-241
111. #12
112.Wang J-y, Shen J, Gao Q, Ye Z-g, Yang S-y, Liang H-w, Bruce IC, Luo B-y and Xia Q. Ischemic postconditioning protects against global cerebral ischemia/reperfusion-induced injury in rats. Stroke. 2008;39(3):983-990
113.Rehni A and Singh N. Role of phosphoinositide 3-kinase in ischemic postconditioning -- induced attenuation of cerebral ischemia -- evoked behavioral deficits in mice. Pharmacol Rep. 2007;59(2):192-198
114.Xing B, Chen H, Zhang M, Zhao D, Jiang R, Liu X and Zhang S. Ischemic post-conditioning protects brain and reduces inflammation in a rat model of focal cerebral ischemia/reperfusion. Journal of Neurochemistry. 2008;105(5):1737-1745
115.Danielisov(?) V, N(?)methov(?) M, Gottlieb M and Burda J. The changes in endogenous antioxidant enzyme activity after postconditioning. Cellular and Molecular Neurobiology. 2006;26(7): 1179-1189
116.Scartabelli T, Gerace E, Landucci E, Moroni F and Pellegrini-Giampietro DE.Neuroprotection by group i mglu receptors in a rat hippocampal slice model of cerebral ischemia is associated with the pi3k-akt signaling pathway: A novel postconditioning strategy? Neuropharmacology. 2008;55(4):509-516
117.Gao X, Zhang H, Takahashi T, Hsieh J, Liao J, Steinberg GK and Zhao H. The akt signaling pathway contributes to postconditioning's protection against stroke; the protection is associated with the mapk and pkc pathways. J Neurochem. 2008;105(3):943-955
118.Berliocchi L, Bano D and Nicotera P. Ca2+ signals and death programmes in neurons. Philos Trans R Soc Lond B Biol Sci. 2005;360(1464):2255-2258
119.Tissier R, Berdeaux A, Ghaleh B, Couvreur N, Krieg T, Cohen MV and Downey JM. Making the heart resistant to infarction: How can we further decrease infarct size?Front Biosci. 2008;13(284-301
120. Krolikowski JG, Weihrauch D, Bienengraeber M, Kersten JR, Warltier DC and Pagel PS. Role of erk1/2, p70s6k, and enos in isoflurane-induced cardioprotection during early reperfusion in vivo. Can J Anesth. 2006;53(2): 174-182
121. Antonawich FJ. Translocation of cytochrome c following transient global ischemia in the gerbil. Neuroscience Letters. 1999;274(2):123-126
122. Zhao H, Yenari MA, Cheng D, Sapolsky RM and Steinberg GK. Biphasic cytochrome c release after transient global ischemia and its inhibition by hypothermia. J Cereb Blood Flow Metab. 2005;25(9):1119-1129
123. Muranyi M and Li P-A. Bongkrekic acid ameliorates ischemic neuronal death in the cortex by preventing cytochrome c release and inhibiting astrocyte activation. Neuroscience Letters. 2005;384(3):277-281
124. Viktorov I. The role of nitric oxide and other free radicals in ischemic brain pathology. Vestn Ross Akad Med Nauk. 20004):5-10
125. Vlasov T, Vivulanets E, Mindukshev I, Petrishchev N and Tvereva E. Functional activity of blood platelets during cerebral ischemia/reperfusion in rats. Ross Fiziol Zh Im I M Sechenova. 2000;86(4):422-426
126．陈应柱and顾永健．一氧化氮与缺血缺氧性脑损伤时的神经元凋亡．国外医学脑血管疾病分册．2002；10(4)：308-310
127．许燕and钱晖．脑缺血再灌注损伤对大鼠不同脑区丙二醛、谷胱甘肽含量及谷胱甘肽过氧化物酶活性的影响．中国危重病急救医学．1997；9(6)：321-323
128．申丽红and张均田．海马区神经发生研究进展(综述)．中国神经免疫学和神经病学杂志．2004；11(3)：180-181，183
129．尹翠芬and王子灿．沙土鼠短暂性脑缺血后海马损伤的形态学特征．昆明医学院学报．1991；12(4)：5-8
130. Zhang X. Advantages and applications of wpi nitric oxide sensor. World Precision Instruments, Inc. 2002:19-24
131. Zhang X, Cardosa L, Broderik M and Hein H. An integrated nitric oxide selective ultramicrosensor. Free Radical Biological & Medicine. 1999;27(Supplement 1):89
132. Liu K, Ning G and Zheng X. In vivo detection of nitric oxide in rat hippocampus. Proceedings of the 2005 IEEE Engineering in Medicine and Biology 27th Annual Conference; September 1-4, 2005; Shanghai, China; 2005.1039-1042.
133. Vallance P, Patton S, Bhagat K, MacAllister R, Radomski M, Moncada S and Malinski T. Direct measurement of nitric oxide in human beings. Lancet. 1995 ;346(8968): 153-154
134. Kader A, Frazzini Ⅵ, Solomon RA and Trifiletti RR. Nitric oxide production during focal cerebral ischemia in rats. Stroke. 1993 ;24(11):1709-1716
135. Lei B, Adachi N, Nagaro T, Arai T and Koehler RC. Nitric oxide production in the cal field of the gerbil hippocampus after transient forebrain ischemia : Effects of 7-nitroindazole and ng-nitro-1-arginine methyl ester. Stroke. 1999;30(3):669-677
136. Samdani AF, Dawson TM and Dawson VL. Nitric oxide synthase in models of focal ischemia. Stroke. 1997;28(6):1283-1288
137. Wang D and Zhang S. Mild hypothermic cerebral protection. In: Wang D and Zhang S, eds. Mild hypothermic cerebral protection and isehemic animal model, nitric oxide and cerebral ischemia. Beijing: Science Publishing Company; 2002:135,173.
138. Fang L, Wang N, Wu Z, Lin M and Murong S. The double role of nitric oxide synthase in reperfusion following focal cerebral ischemia. ChinJNeuroimmunol & Neurol. 2004;11(1):29-38
139. Al-Mehdi A, Song C, Tozawa K and Fisher A. Ca2+- and phosphatidylinositol 3-kinase-dependent nitric oxide generation in lung endothelial cells in situ with ischemia. J Biol Chem. 2000;275(51):39807-39810
140. Xu X, Zhang S, Zhang L, Yan W and Zheng X. The neuroprotection of puerarin against cerebral ischemia is associated with the prevention ofapoptosis in rats. Planta Med. 2005;71(7):585-591
141． 陶荣，宁钢民，杨勇and郑筱祥．培养的大鼠海马神经元胞内ca2+和no双标记方法研究．生物纪学与生物物理进展．2005；32(8)：788-793
142. Giri BK, Krishnappa IK, Bryan RM, Jr., Robertson C and Watson J. Regional cerebral blood flow after cortical impact injury complicated by a secondary insult in rats Stroke. 2000;31 (4):961-967
143. Jiang MH, Kaku T, Hada J and Hayashi Y. Different effects of enos and nnos inhibition on transient forebrain i schemia. Brain Research. 2002;946(1): 139-147
144. Willmot M, Gibson C, Gray L, Murphy S and Bath E Nitric oxide synthase inhibitors in experimental ischemic stroke and their effects on infarct size and cerebral blood flow: A systematic review. Free Radical Biology and Medicine. 2005;39(3):412-425
145. Fisher M and Brott TG. Emerging therapies tbr acute ischemic stroke: New therapies on trial. Stroke. 2003;34(2):359-361
146.Smith B, Stechman M, Gibson M, Torrie E, Magee T and Galland R.Subintimal angioplasty for superficial femoral artery occlusion: Poor patency in critical ischaemia. Ann R Coll Surg Engl. 2005;87(5):361-365
147.Chan PH. Role of oxidants in ischemic brain damage. Stroke.1996;27(6):1124-1129
148.Merkle S, Frantz S, Schon MP, Bauersachs J, Buitrago M, Frost RJA,Schmitteckert EM, Lohse MJ and Engelhardt S. A role for caspase-1 in heart failure.Circ Res. 2007;100(5):645-653
149. Zhao H, Wang J, Shimohata T, Sun G, Yenari M, Sapolsky R and Steinberg G Conditions of protection by hypothermia and effects on apoptotic pathways in a rat model of permanent middle cerebral artery occlusion. J Neurosurg.2007;107(3):636-641
150.Vinten-Johansen J, Zhao ZQ, Zatta AJ, Kin H, Halkos ME and Kerendi F.Postconditioning--a new link in nature's armor against myocardial ischemia-reperfusion injury. Basic Res Cardiol. 2005; 100(4):295-310
2．邢成名．缺血性脑血管病．北京 人民卫生出版社2003．
3. Zhao H. The protective effect of ischemic postconditioning against ischemic injury: From the heart to the brain. Journal of Neuroimmune Pharmacology. 2007;2(4):313-318
4. Xing B, Chen H, Zhang M, Zhao D, Jiang R, Liu X and Zhang S. Ischemic postconditioning inhibits apoptosis after focal cerebral ischemia/reperfusion injury in the rat. Stroke. 2008;39(8):2362-2369
5. Zhao H. Ischemic postconditioning as a novel avenue to protect against brain injury after stroke. J Cereb Blood Flow Metab. 2009
6. Rifkind JM, Nagababu E, Barbiro-Michaely E, Ramasamy S, Pluta RM and Mayevsky A. Nitrite infusion increases cerebral blood flow and decreases mean arterial blood pressure in rats: A role for red cell no. Nitric Oxide. 2007; 16(4):448-456
7．陈怀红and朱丽君．大鼠大脑中动脉闭塞后基底节nr1和nr2a及nr2b的表达．浙江大学学报以：医学版．2001；30(3)：100-102
8. Li Y, Chopp M, Jiang N and Zaloga C. In situ detection of DNA fragmentation after focal cerebral ischemia in mice. Brain Res Mol Brain Res. 1995 ;28(1): 164-168
9. Koqure T and Koqure K. Molecular and biochemical events within the brain subjected to cerebral ischemia. Clin Neurosci. 1997;4(4): 179-183
10. Martin S, Green D and Cotter T. Dicing with death: Dissecting the components of the apotosis machinery. Trends in biochemical sciences. 1994; 19(1):26-30
11. Kontos and Hermes A. Oxygen radicals in cerebral ischemia: The 2001 willis lecture. Stroke. 2001 ;32(11):2712-2716
12. Althaus J, Andrus P, Williams C, VonVoigtlander P, Cazers A and Hall E. The use of salicylate hydroxylation to detect hydroxyl radical generation in ischemic and traumatic brain injury. Reversal by tirilazad mesylate (u-74006f). Mol Chem Neuropathol. 1993;20(2): 147-162
13. Bates B, Hirt L, Thomas SS, Akbarian S, Le D, Amin-Hanjani S, Whalen M, Jaenisch R and Moskowitz MA. Neurotrophin-3 promotes cell death induced in cerebral ischemia, oxygen-glucose deprivation, and oxidative stress: Possible involvement of oxygen free radicals. Neurobiology of Disease. 2002;9(1):24-37
14. Dirnagl U, Iadecola C and Moskowitz MA. Pathobiology of ischaemic stroke: An integrated view. Trends in Neurosciences. 1999;22(9):391-397
15. Jung K-H, Chu K, Ko S-Y, Lee S-T, Sinn D-I, Park D-K, Kim J-M, Song E-C, Kim M and Roh J-K. Early intravenous infusion of sodium nitrite protects brain against in vivo ischemia-reperfusion injury. Stroke. 2006;37(11):2744-2750
16. Kawabata S, Tsutsumi R, Kohara A, Yamaguchi T, Nakanishi S and Okada M. Control of calcium oscillations by phosphorylation of metabotropic glutamate receptors. Nature. 1996;383(6595):89-92
17. Pocock J and Nicholls D. Exocytotic and nonexocytotic modes of glutamate release from cultured cerebellar granule cells during chemical ischaemia. Journal of Neurochemistry. 1998;70(2):806-813
18. Rossi DJ, Oshima T and Attwell D. Glutamate release in severe brain ischaemia is mainly by reversed uptake. Nature. 2000;403(6767):316-321
19. Mitani A, Andou Y and Kataoka K. Selective vulnerability of hippocampal cal neurons cannot be explained in terms of an increase in glutamate concentration during ischemia in the gerbil: Brain microdialysis study. Neuroscience. 1992;48(2):307-313
20．杨倩，朱武生and吴家幂．大鼠脑缺血再灌注模型icam1表达与白细胞浸润关系及亚低温干预治疗的研究．临床神经病学杂志．2002；15(4)：196-199
21. Lipton P. Ischemic cell death in brain neurons. Physiol Rev. 1999;79(4): 1431-1568
22. Vila N, Castillo J, Davalos A and Chamorro A. Proinflammatory cytokines and early neurological worsening in ischemic stroke. Stroke. 2000;31 (10):2325-2329
23．李岚，赵光东and张健．川芎嗪对局部脑缺血再灌注流模型纹状体内il-1β的影响．中国临床神经科学．2001；9(1)：36-37
24．屠永华and李岚．大鼠局灶脑缺血/再灌流模型中il-1β的表达及作用．医学综述．1998；4(10)：570-572
25. Jiang X, Mu D, Manabat C, Koshy AA, Christen S, Tauber MG, Vexler ZS and Ferriero DM. Differential vulnerability of immature murine neurons to oxygen-glucose deprivation. Experimental Neurology. 2004;190(1):224-232
26. Macdonald R and Stoodley M. Pathophysiology of cerebral ischemia. Neurol Med Chir(Tokyo) 1998;38(1):1-11
27. Clemens JA. Cerebral ischemia: Gene activation, neuronal injury, and the protective role of antioxidants. Free Radical Biology and Medicine. 2000;28(10):1526-1531
28．朱勇飞and王友顺．一氧化氮检测技术的研究进展．中国卫生检验杂志．2000；10(3)：372-374
29．陈啸春，盛超and郑筱祥．一氧化氮抑制海马神经元兴奋的机制研究．生物物理学报．2001；17(3)：469-476
30．史源．一氧化氮及其临床意义．国外医学：儿科学分册．1994；21(2)：89-92
31．夏保芦，张艳and熊希凯．Nos活性在大鼠不同脑区的研究．中国组织化学与细胞化学杂志．2000；9(1)：100-102
32．薛保健，王志安and何瑞荣．No前体和供体对大鼠海马脑片神经元活动的影响．生理学报．1997；49(4)：375-381
33．强文安，刘枝俏and刘捷．脑组织一氧化氮合成酶的特性及其与nadph-diaphorase相关性研究．中国神经免疫学和神经病学杂志．1996；3(4)：191-198
34．张会欣and张建新．一氧化氮与脑缺血．河北医药．2002；24(4)：297-299
35．李宏伟and赵连友．一氧化氮的检测方法及其评价．心功能杂志．1998；10(1)：27-28，32
36. Fujimura M, Gasche Y, Morita-Fujimura Y, Massengale J, Kawase M and Chan P. Early appearance of activated matrix metalloproteinase-9 and blood-brain barrier disruption in mice after focal cerebral ischemia and reperfusion. Brain Res. 1999;842(1):92-100
37. Megson IL. Nitric oxide donor drugs. Drugs of the Future. 2000;25(7):701-715
38. Alderton W, Cooper C and Knowles R. Nitric oxide synthases: Structure, function and inhibition. Biochem J. 2001 ;357(Pt 3):593-615
39. Pont(?)n U, Ratcheson R, Salford L and Siesj(o｜¨). Optimal freezing conditions for cerebral metabolites in rats. Journal of Neurochemistry. 1973 ;21 (5): 1127-1138
40. Ekl(o｜¨)f B and Siesj(o｜¨) B. The effect of bilateral carotid artery ligation upon the blood flow and the energy state of the rat brain. Acta Physiologica Scandinavica. 1972;86(2): 155-165
41. Nordstrom CH, Rehncrona S and Siesjo BK. Effects of phenobarbital in cerebral ischemia. Part ⅱ: Restitution of cerebral energy state, as well as of glycolytic metabolites, citric acid cycle intermediates and associated amino acids after pronounced incomplete ischemia. Stroke. 1978;9(4):335-343
42. Pulsinelli WA and Buchan AM. The four-vessel occlusion rat model: Method for complete occlusion of vertebral arteries and control of collateral circulation. Stroke. 1988;19(7):913-914
43. Kudo M, Aoyama A, Ichimori S and Fukunaga N. An animal model of cerebral infarction. Homologous blood clot emboli in rats. Stroke. 1982; 13(4):505-508
44．李威，邹明辉，李秋风，苗利军and杨宁辉．通腑化痰活血法对大鼠脑梗塞后血液流变学的影响．中药药理与临床．1996：12(3)：3-6
45. Tamura A, Graham D, McCulloch J and Teasdale G. Focal cerebral ischaemia in the rat: 1. Description of technique and early neuropathological consequences following middle cerebral artery occlusion. J Cereb Blood Flow Metab. 1981;1(1):53-60
46. Watson B, Dietrich W, Busto R, Wachtel M and Ginsberg M. Induction of reproducible brain infarction by photochemically initiated thrombosis. Ann Neurol. 1985; 17(5):497-504
47. Koizumi J, Yoshida Y, Nakazawa T and Ooneda G. Experimental studies of ischemic brain edema. I. A new experimental model of cerebral embolism in rats in which recirculation can be introduced in the ischemic area. Jpn J Stroke. 1986;8(1-8
48. Longa EZ, Weinstein PR, Carlson S and Cummins R. Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke. 1989;20(1): 84-91
49. Goldberg MP, Monyer H, Weiss JH and Choi DW. Adenosine reduces cortical neuronal injury induced by oxygen or glucose deprivation in vitro. Neurosci Lett 1988;89(3):323-327
50．汪晖．药物代谢的体外筛选系统．中国药理通讯．2005；22(3)：12
51．杜冠华．高通量药物筛选技术进展与新药开发策略．中国生物学文摘．2005；19(1)：32-37
52. Palmer R, Ferrige A and S SM. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987;327(524-526
53. Ignarro LJ, Buga GM, Wood KS, Byrns RE and Chaudhuri G. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. PNAS. 1987;84(24):9265-9269
54. Burnett A, Lowenstein C, Bredt D, Chang T and Snyder S. Nitric oxide: A physiologic mediator of penile erection. Science. 1992;257(5068):401-403
55．李莉萍，罗超权and刘丽．动力蛋白轻链/一氧化氮合酶抑制剂．生命的化学．2003；23(4)：270-272
56．朱勇飞．化学发光方法检测一氧化氮．国外医学临床生物化学与检验学分册．2000；21(1)：6-8
57．彭图治and杨丽菊．生命科学中的电分析化学．杭州：杭州大学出版社；1999
58. Flam BR, Eichler DC and Solomonson LP. Endothelial nitric oxide production is tightly coupled to the citrulline-no cycle. Nitric Oxide. 2007; 17(3-4): 115-121
59. Privat C, Stepien O, David-Dufilho M, Brunet A, Bedioui F, Marche P, Devynck J and Devynck M. Superoxide release from interleukin-lb-stimulated human vascular cells: In situ electrochemical measurement. Free Radic Biol Med. 1999;27(5-6):554-559
60. Malinski T and Huk I. Measurement of nitric oxide in single cells and tissue using a porphyrinic microsensor. Current protocols in neuroscience. John Wiley & Sons, Inc.; 2001.
61．唐省三．一氧化氮的检测及改良方法．生物技术．2002；12(2)：F002-003
62. Broderick PA, Hope O and Jeannot P.Mechanism of triazolo-benzodiazepine and benzodiazepine action in anxiety and depression: Behavioral studies with concomitant in vivo cal hippocampal norepinephrine and serotonin release detection in the behaving animal. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 1998;22(2):353-386
63. Nargi-Aizenman JL, Havert MB, Zhang M, Irani DN, Rothstein JD and Griffin DE. Glutamate receptor antagonists protect from virus-induced neural degeneration. Annals of Neurology. 2004;55(4):541-549
64. Stys PK. White matter injury mechanisms. Current Molecular Medicine.2004;4(2): 113-130
65. Arvidsson A, Kirik D, Lundberg C, Mandel RJ, Andsberg G, Kokaia Z and Lindvall O. Elevated gdnf levels following viral vector-mediated gene transfer can increase neuronal death after stroke in rats. Neurobiology of Disease.2003;14(3):542-556
66. Murry CE, Jennings RB and Reimer KA. Preconditioning with ischemia: A delay of lethal cell injury in ischemic myocardium. Circulation. 1986;74(5):1124-1136
67. Kitagawa K, Matsumoto M, Tagaya M, Hata R, Ueda H, Niinobe M, Handa N,Fukunaga R, Kimura K and Mikoshiba K. 'ischemic tolerance' phenomenon found in the brain. Brain Res. 1990;528(1):21-24
68. Perez-Pinzon MA. Neuroprotective effects of ischemic preconditioning in brain mitochondria following cerebral ischemia. J Bioenerg Biomembr. 2004;36(4):323-327
69. Shpargel KB, Jalabi W, Jin Y, Dadabayev A, Penn MS and Trapp BD.Preconditioning paradigms and pathways in the brain. Cleve Clin J Med.2008;75(Suppl 2):S 77-82
70. Kitagawa K, Matsumoto M, Kuwabara K, Tagaya M, Ohtsuki T, Hata R, Ueda H,Handa N, Kimura K and Kamada T. 'ischemic tolerance' phenomenon detected in various brain regions. Brain Research. 1991 ;561(2):203-211
71. Glazier S, O'Rourke D, Graham D and Welsh F. Induction of ischemic tolerance following brief focal ischemia in rat brain. J Cereb Blood Flow Metab.1994;14(4):545-553
72. Simon R, Niiro M and Gwinn R. Prior ischemic stress protects against experimental stroke. Neurosci Lett. 1993;163(2):135-137
73. Chen J, Graham SH, Zhu RL and Simon RP. Stress proteins and tolerance to focal cerebral ischemia. J Cereb Blood Flow Metab. 1996;16(4):566-577
74. Chen T, Kato H, Liu X-H, Araki T, Itoyama Y and Kogure K. Ischemic tolerance can be induced repeatedly in the gerbil hippocampal neurons. Neuroscience Letters.1994;177(1-2):159-161
75. Weih M, Prass K, Ruscher K, Trendelenburg G, Dirnagl U, Riepe M and Meisel A.Ischemia tolerance; model for research, hope for clinical practice? Nervenarzt.2001;72(4):255-260
76. Lange-Asschenfeldt C, Raval AP, Dave KR, Mochly-Rosen D, Sick TJ and Perez-Pinzon MA. Epsilon protein kinase c mediated ischemic tolerance requires activation of the extracellular regulated kinase pathway in the organotypic hippocampal slice. J Cereb Blood Flow Metab. 2004;24(6):636-645
77. Perez-Pinzon MA, Dave KR and Raval AP. Role of reactive oxygen species and protein kinase c in ischemic tolerance in the brain. Antioxid Redox Signal.2005;7(9-10):1150-1157
78. Ginis I, Jaiswal R, Klimanis D, Liu J, Greenspon J and Hallenbeck JM.Tnf-alpha-induced tolerance to ischemic injury involves differential control of nf-kappab transactivation: The role of nf-kappab association with p300 adaptor. J Cereb Blood Flow Metab. 2002;22(2): 142-152
79. Jones NM and Bergeron M. Hypoxic preconditioning induces changes in hif-1 target genes in neonatal rat brain. J Cereb Blood Flow Metab. 2001 ;21(9): 1105-1114
80. Patel A, van de Poll MC, Greve JW, Buurman WA, Fearon KC, McNally SJ,Harrison EM, Ross JA, Garden OJ, Dejong CH and Wigmore SJ. Early stress protein gene expression in a human model of ischemic preconditioning. Transplantation.2004;78(10):1479-1487
81. Speechly-Dick ME, Mocanu MM and Yellon DM. Protein kinase c. Its role in ischemic preconditioning in the rat. Circ Res. 1994;75(3):586-590
82. Pignataro G, Scorziello A, Di Renzo G and Annunziato L. Post-ischemic brain damage: Effect of ischemic preconditioning and postconditioning and identification of potential candidates for stroke therapy. Febs J. 2009;276(1):46-57
83. Kawai K, Nakagomi T, Kirino T, Tamura A and Kawai N. Preconditioning in vivo ischemia inhibits anoxic long-term potentiation and functionally protects cal neurons in the gerbil. J Cereb Blood Flow Metab. 1998; 18(3):288-296
84. Abele A and Miller R. Potassium channel activators abolish excitotoxicity in cultured hippocampal pyramidal neurons. Neurosci Lett. 1990;115(2-3): 195-200
85. Heurteaux C, Lauritzen I, Widmann C and Lazdunski M. Essential role of adenosine, adenosine a1 receptors, and atp-sensitive k+ channels in cerebral ischemic preconditioning. Proc Natl Acad Sci U S A. 1995;92(10):4666-4670
86. Grabb MC and Choi DW. Ischemic tolerance in murine cortical cell culture:Critical role for nmda receptors. J Neurosci. 1999; 19(5): 1657-1662
87. Posmantur R, Kampfl A, Liu S, Heck K, Taft W, Clifton G and Hayes R. Cytoskeletal derangements of cortical neuronal processes three hours after traumatic brain injury in rats: An immunofluorescence study. J Neuropathol Exp Neurol.1996;55(1):68-80
88. Marini A and Paul S. N-methyl-d-aspartate receptor-mediated neuroprotection in cerebellar granule cells requires new rna and protein synthesis. Proc Natl Acad Sci U S A. 1992;89(14):6555-6559
89. Nowak TJ. Synthesis of a stress protein following transient ischemia in the gerbil.J Neurochem. 1985;45(5):1635-1641
90. Simon RP, Cho H, Gwinn R and Lowenstein DH. The temporal profile of 72-kda heat-shock protein expression following global ischemia. J Neurosci. 1991;11(3):881-889
91. Liu Y, Kato H, Nakata N and Kogure K. Temporal profile of heat shock protein 70 synthesis in ischemic tolerance induced by preconditioning ischemia in rat hippocampus. Neuroscience. 1993;56(4):921 -927
92. Kobayashi S, Harris V and Welsh F. Spreading depression induces tolerance of cortical neurons to ischemia in rat brain. J Cereb Blood Flow Metab.1995;15(5):721-727
93. Kato H, Kogure K, Araki T and Itoyarna Y. Induction of jun-like immunoreactivity in astrocytes in gerbil hippocampus with ischemic tolerance. Neuroscience Letters.1995;189(1):13-16
94. Linnik MD, Zahos P, Geschwind MD and Federoff HJ. Expression of bcl-2 from a defective herpes simplex virus? Vector limits neuronal death in focal cerebral ischemia. Stroke. 1995;26(9):1670-1675
95. Chen J, Graham S, Chan P, Lan J, Zhou R and Simon R. Bcl-2 is expressed in neurons that survive focal ischemia in the rat. Neuroreport. 1995;6(2):394-398
96. Shimazaki K, Ishida A and Kawai N. Increase in bcl-2 oncoprotein and the tolerance to ischemia-induced neuronal death in the gerbil hippocampus. Neurosci Res.1994;20(1):95-99
97. Bolli R. Cardioprotective function of inducible nitric oxide synthase and role of nitric oxide in myocardial ischemia and preconditioning: An overview of a decade of research. J Mol Cell Cardiol. 2001;33(11):1897-1918
98. Murphy S and Gibson CL. Nitric oxide, ischaemia and brain inflammation.Biochem Soc Trans. 2007;35(Pt 5):1133-1137
99. Atochin DN, Clark J, Demchenko IT, Moskowitz MA and Huang PL. Rapid cerebral ischemic preconditioning in mice deficient in endothelial and neuronal nitric oxide synthases. Stroke. 2003;34(5):1299-1303
100. Cho S, Park EM, Zhou P, Frys K, Ross ME and Iadecola C. Obligatory role of inducible nitric oxide synthase in ischemic preconditioning. J Cereb Blood Flow Metab. 2005;25(4):493-501
101.Gidday JM, Shah AR, Maceren RG, Wang Q, Pelligrino DA, Holtzman DM and Park TS. Nitric oxide mediates cerebral ischemic tolerance in a neonatal rat model of hypoxic preconditioning. J Cereb Blood Flow Metab. 1999;19(3):331-340
102.Gonzalez-Zulueta M, Feldman AB, Klesse LJ, Kalb RG, Dillman JF, Parada LF, Dawson TM and Dawson VL. Requirement for nitric oxide activation of p21(ras)/extracellular regulated kinase in neuronal ischemic preconditioning. Proc Natl AcadSci U S A. 2000;97(1):436-441
103.Shiva S, Sack MN, Greer JJ, Duranski M, Ringwood LA, Burwell L, Wang X,MacArthur PH, Shoja A, Raghavachari N, Calvert JW, Brookes PS, Lefer DJ and Gladwin MT. Nitrite augments tolerance to ischemia/reperfusion injury via the modulation of mitochondrial electron transfer. J Exp Med. 2007;204(9):2089-2102
104. Scorziello A, Santillo M, Adornetto A, Dell'aversano C, Sirabella R, Damiano S, Canzoniero LM, Renzo GF and Annunziato L. No-induced neuroprotection in ischemic preconditioning stimulates mitochondrial mn-sod activity and expression via ras/erk1/2 pathway. J Neurochem. 2007; 103(4): 1472-1480
105. Kato H, Kogure K, Araki T and Itoyama Y. Astroglial and microglial reactions in the gerbil hippocampus with induced ischemic tolerance. Brain Research. 1994;664(1-2):69-76
106. Zhao Z, Corvera J, Halkos M, Kerendi F, Wang N, Guyton R and Vinten-Johansen J. Inhiibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic precondtitioning. Am J Physiol Heart Circ Physiol. 2003 ;285(2) :H579-588
107. Staat P, Rioufol G, Piot C, Cottin Y, Cung TT, L'Huillier I, Aupetit J-F, Bonnefoy E, Finet G, Andre-Fouet X and Ovize M. Postconditioning the human heart. Circulation. 2005; 112(14):2143-2148
108. Jiang X, Shi E, Nakajima Y and Sato S. Postconditioning, a series of brief interruptions of early reperfusion, prevents neurologic injury after spinal cord ischemia. Ann Surg. 2006;244(1): 148-153
109. Zhao H, Sapolsky RM and Steinberg GK. Interrupting reperfusion as a stroke therapy: Ischemic postconditioning reduces infarct size after focal ischemia in rats. J Cereb Blood Flow Metab. 2006;26(9): 1114-1121
110. Pignataro G, Meller R, Inoue K, Ordonez AN, Ashley MD, Xiong Z, Gala R and Simon RP. In vivo and in vitro characterization of a novel neuroprotective strategy for stroke: Ischemic postconditioning. J Cereb Blood Flow Metab. 2008;28(2):232-241
111. #12
112.Wang J-y, Shen J, Gao Q, Ye Z-g, Yang S-y, Liang H-w, Bruce IC, Luo B-y and Xia Q. Ischemic postconditioning protects against global cerebral ischemia/reperfusion-induced injury in rats. Stroke. 2008;39(3):983-990
113.Rehni A and Singh N. Role of phosphoinositide 3-kinase in ischemic postconditioning -- induced attenuation of cerebral ischemia -- evoked behavioral deficits in mice. Pharmacol Rep. 2007;59(2):192-198
114.Xing B, Chen H, Zhang M, Zhao D, Jiang R, Liu X and Zhang S. Ischemic post-conditioning protects brain and reduces inflammation in a rat model of focal cerebral ischemia/reperfusion. Journal of Neurochemistry. 2008;105(5):1737-1745
115.Danielisov(?) V, N(?)methov(?) M, Gottlieb M and Burda J. The changes in endogenous antioxidant enzyme activity after postconditioning. Cellular and Molecular Neurobiology. 2006;26(7): 1179-1189
116.Scartabelli T, Gerace E, Landucci E, Moroni F and Pellegrini-Giampietro DE.Neuroprotection by group i mglu receptors in a rat hippocampal slice model of cerebral ischemia is associated with the pi3k-akt signaling pathway: A novel postconditioning strategy? Neuropharmacology. 2008;55(4):509-516
117.Gao X, Zhang H, Takahashi T, Hsieh J, Liao J, Steinberg GK and Zhao H. The akt signaling pathway contributes to postconditioning's protection against stroke; the protection is associated with the mapk and pkc pathways. J Neurochem. 2008;105(3):943-955
118.Berliocchi L, Bano D and Nicotera P. Ca2+ signals and death programmes in neurons. Philos Trans R Soc Lond B Biol Sci. 2005;360(1464):2255-2258
119.Tissier R, Berdeaux A, Ghaleh B, Couvreur N, Krieg T, Cohen MV and Downey JM. Making the heart resistant to infarction: How can we further decrease infarct size?Front Biosci. 2008;13(284-301
120. Krolikowski JG, Weihrauch D, Bienengraeber M, Kersten JR, Warltier DC and Pagel PS. Role of erk1/2, p70s6k, and enos in isoflurane-induced cardioprotection during early reperfusion in vivo. Can J Anesth. 2006;53(2): 174-182
121. Antonawich FJ. Translocation of cytochrome c following transient global ischemia in the gerbil. Neuroscience Letters. 1999;274(2):123-126
122. Zhao H, Yenari MA, Cheng D, Sapolsky RM and Steinberg GK. Biphasic cytochrome c release after transient global ischemia and its inhibition by hypothermia. J Cereb Blood Flow Metab. 2005;25(9):1119-1129
123. Muranyi M and Li P-A. Bongkrekic acid ameliorates ischemic neuronal death in the cortex by preventing cytochrome c release and inhibiting astrocyte activation. Neuroscience Letters. 2005;384(3):277-281
124. Viktorov I. The role of nitric oxide and other free radicals in ischemic brain pathology. Vestn Ross Akad Med Nauk. 20004):5-10
125. Vlasov T, Vivulanets E, Mindukshev I, Petrishchev N and Tvereva E. Functional activity of blood platelets during cerebral ischemia/reperfusion in rats. Ross Fiziol Zh Im I M Sechenova. 2000;86(4):422-426
126．陈应柱and顾永健．一氧化氮与缺血缺氧性脑损伤时的神经元凋亡．国外医学脑血管疾病分册．2002；10(4)：308-310
127．许燕and钱晖．脑缺血再灌注损伤对大鼠不同脑区丙二醛、谷胱甘肽含量及谷胱甘肽过氧化物酶活性的影响．中国危重病急救医学．1997；9(6)：321-323
128．申丽红and张均田．海马区神经发生研究进展(综述)．中国神经免疫学和神经病学杂志．2004；11(3)：180-181，183
129．尹翠芬and王子灿．沙土鼠短暂性脑缺血后海马损伤的形态学特征．昆明医学院学报．1991；12(4)：5-8
130. Zhang X. Advantages and applications of wpi nitric oxide sensor. World Precision Instruments, Inc. 2002:19-24
131. Zhang X, Cardosa L, Broderik M and Hein H. An integrated nitric oxide selective ultramicrosensor. Free Radical Biological & Medicine. 1999;27(Supplement 1):89
132. Liu K, Ning G and Zheng X. In vivo detection of nitric oxide in rat hippocampus. Proceedings of the 2005 IEEE Engineering in Medicine and Biology 27th Annual Conference; September 1-4, 2005; Shanghai, China; 2005.1039-1042.
133. Vallance P, Patton S, Bhagat K, MacAllister R, Radomski M, Moncada S and Malinski T. Direct measurement of nitric oxide in human beings. Lancet. 1995 ;346(8968): 153-154
134. Kader A, Frazzini Ⅵ, Solomon RA and Trifiletti RR. Nitric oxide production during focal cerebral ischemia in rats. Stroke. 1993 ;24(11):1709-1716
135. Lei B, Adachi N, Nagaro T, Arai T and Koehler RC. Nitric oxide production in the cal field of the gerbil hippocampus after transient forebrain ischemia : Effects of 7-nitroindazole and ng-nitro-1-arginine methyl ester. Stroke. 1999;30(3):669-677
136. Samdani AF, Dawson TM and Dawson VL. Nitric oxide synthase in models of focal ischemia. Stroke. 1997;28(6):1283-1288
137. Wang D and Zhang S. Mild hypothermic cerebral protection. In: Wang D and Zhang S, eds. Mild hypothermic cerebral protection and isehemic animal model, nitric oxide and cerebral ischemia. Beijing: Science Publishing Company; 2002:135,173.
138. Fang L, Wang N, Wu Z, Lin M and Murong S. The double role of nitric oxide synthase in reperfusion following focal cerebral ischemia. ChinJNeuroimmunol & Neurol. 2004;11(1):29-38
139. Al-Mehdi A, Song C, Tozawa K and Fisher A. Ca2+- and phosphatidylinositol 3-kinase-dependent nitric oxide generation in lung endothelial cells in situ with ischemia. J Biol Chem. 2000;275(51):39807-39810
140. Xu X, Zhang S, Zhang L, Yan W and Zheng X. The neuroprotection of puerarin against cerebral ischemia is associated with the prevention ofapoptosis in rats. Planta Med. 2005;71(7):585-591
141． 陶荣，宁钢民，杨勇and郑筱祥．培养的大鼠海马神经元胞内ca2+和no双标记方法研究．生物纪学与生物物理进展．2005；32(8)：788-793
142. Giri BK, Krishnappa IK, Bryan RM, Jr., Robertson C and Watson J. Regional cerebral blood flow after cortical impact injury complicated by a secondary insult in rats Stroke. 2000;31 (4):961-967
143. Jiang MH, Kaku T, Hada J and Hayashi Y. Different effects of enos and nnos inhibition on transient forebrain i schemia. Brain Research. 2002;946(1): 139-147
144. Willmot M, Gibson C, Gray L, Murphy S and Bath E Nitric oxide synthase inhibitors in experimental ischemic stroke and their effects on infarct size and cerebral blood flow: A systematic review. Free Radical Biology and Medicine. 2005;39(3):412-425
145. Fisher M and Brott TG. Emerging therapies tbr acute ischemic stroke: New therapies on trial. Stroke. 2003;34(2):359-361
146.Smith B, Stechman M, Gibson M, Torrie E, Magee T and Galland R.Subintimal angioplasty for superficial femoral artery occlusion: Poor patency in critical ischaemia. Ann R Coll Surg Engl. 2005;87(5):361-365
147.Chan PH. Role of oxidants in ischemic brain damage. Stroke.1996;27(6):1124-1129
148.Merkle S, Frantz S, Schon MP, Bauersachs J, Buitrago M, Frost RJA,Schmitteckert EM, Lohse MJ and Engelhardt S. A role for caspase-1 in heart failure.Circ Res. 2007;100(5):645-653
149. Zhao H, Wang J, Shimohata T, Sun G, Yenari M, Sapolsky R and Steinberg G Conditions of protection by hypothermia and effects on apoptotic pathways in a rat model of permanent middle cerebral artery occlusion. J Neurosurg.2007;107(3):636-641
150.Vinten-Johansen J, Zhao ZQ, Zatta AJ, Kin H, Halkos ME and Kerendi F.Postconditioning--a new link in nature's armor against myocardial ischemia-reperfusion injury. Basic Res Cardiol. 2005; 100(4):295-310