摘要
第一部分在体研究皮层扩散性抑制动物模型的建立
目的：用KCl和针刺分别在鼠皮层诱导皮层扩散性抑制(Cortical SpreadingDepression，CSD)，建立大鼠CSD动物模型，并评价其光学特性和电生理特性，为进一步的研究奠定基础。
方法：采用Spangue-Dawley大鼠25只，随机分为针刺诱导组(n=10)、KCl诱导组(n=10)和NaCl对照组(n=5)，用牙科钻在大鼠颅骨上分别钻磨出诱导窗口和观测窗口，分别在诱导窗口用针刺和滴加KCl棉片浸敷大鼠皮层的方法诱导大鼠脑CSD，对照组在诱导窗口滴加NaCl，并用电生理记录和光学成像的方法来描记CSD的产生与传播，分析其特点。
结果：在针刺诱导组和KCl诱导组，均可以在观测窗口观察到向外周扩散的明暗相间的弧形波，针刺诱导的CSD波成典型的同心圆样向四周均匀扩散，KCl诱导的CSD波则是呈不规则的圆弧形波向外周扩散，针刺组每次只诱发一次CSD波，而KCl组则可以诱导多次CSD波。在产生CSD波的同时，伴随着去极化电位的产生。而在NaCl对照组没有发现以上现象的发生。
结论：用本方法制作CSD动物模型，方法简单易行，可以用光学成像的方法直观观测CSD的产生、发展和传播，并结合电生理观测到一直结果，适于在体研究CSD，为进一步研究CSD的发生机制及其可能的作用提供了一种有效手段。
第二部分皮层扩散性抑制预处理对大鼠脑缺血性损伤的保护作用的在体研究
目的：研究KCl诱导皮层扩散性抑制(CSD)预处理对鼠大脑中动脉阻塞后脑血流灌注和梗死体积的影响，验证CSD对脑缺血性损伤的保护作用。
方法：24只SD大鼠分为实验组和对照组，各12只，试验组用5mKCl棉片敷于大鼠颅骨小孔上，每20min更换一次，持续2h，在大鼠大脑皮层诱发CSD，3d后插线法栓塞大脑中动脉制备大鼠局灶性脑缺血模型，利用激光散斑衬比光学成像技术监测缺血2h大脑血流动力学变化，并测定大脑梗死病灶体积。对照组用NaCl代替KCl，其余相同。比较血流动力学变化和大脑梗死灶体积的大小。
结果：经CSD预处理后3d再缺血时，实验组缺血病灶血液灌注水平高于对照组，实验组总梗死体积及皮层梗死体积均小于对照组，皮层下梗死体积与对照组无明显差异。
结论：利用激光散斑衬比光学成像技术可以在体检测脑血流的变化，同时验证了CSD预处理可提高缺血病灶皮层的血液灌注水平，减少总梗死体积和皮层梗死体积，可以减轻脑缺血后的脑功能损害程度。
第三部分皮层扩散性抑制预处理对大鼠脑缺血性损伤后神经再生的影响
目的：研究皮层扩散性抑制(cortical spreading depression，CSD)对成年大鼠脑缺血后缺血侧神经再生的影响。探讨CSD对缺血性脑损伤保护作用的机制。
方法：用KCl诱导鼠皮层扩散性抑制，采用线栓法制作大脑中动脉阻塞(MCAO)模型。72只S-D大鼠动物分为6组：1)正常鼠诱导CSD组；2) KCl诱导CSD预处理缺血组；3) N-甲基-D-天门冬氨酸(NMDA)受体拮抗剂MK-801阻断CSD缺血组；4) NaCl预处理缺血组；5)非预处理缺血组；6)空白对照组：即非CSD、非缺血假手术组。采用免疫组化法观察脑缺血后1，3，7，与14d四个不同时相BrdU免疫阳性细胞的表达情况。
结果：空白对照组少见BrdU免疫阳性细胞表达，组1及脑缺血后各组不同时相缺血侧皮质、海马齿状回和纹状体均有BrdU免疫阳性细胞表达，其中7d时的阳性细胞数量明显增加；且组2与组3、4、5、6有显著性差异(p＜0.05)。组1在d7和d14均较组6比较有显著性差异(p＜0.05)。
结论：CSD可诱导正常大鼠脑和脑缺血相关脑区BrdU免疫阳性细胞表达，且CSD可进一步激发脑缺血后神经再生的潜能，提示CSD激发鼠脑神经再生可能是其诱导脑缺血保护的主要机制之一。
Part I
Establishment of cortical spreading depression model in cats
for study in vivo
Objective: To establish an animal model of cortical spreading depression(CSD) in rats by application of kcl and needling and valuate the opticalintrinsic signal imaging
(OIIS ) and electrophysiological characteristics in vivo and for the father study.
Methods: 25 Spangue-Dawley rats were divided into three groups. Inducing and obervating windows were drilled by bur drill and CSD was evoked by needling (group 1, n=10) and applying 5M KC1 cotton dap (group 2, n=10) in cortex. Five rats (group 3, n=5) were served as controls with applying 0.9% saline solution in the cortex. CSD waves were recorded by optical images and electrophysiology and analysised.
Results: CSD waves were observed to spread out, in all dirctions, from the region stumulated by Optical Imaging with the characteristics of interval shading bracket-shaped waves and depolarizational potential were recored with the CSD waves both in group 1 and group 2. However, this phenomenon was not found in group 3. The multiple CSD waves induced - kcl were extending away, while the single CSD wave was spreading away when acupuncturing the cortex of the rats once.
Conclusion: The rat CSD model was made easily using this technic.The course of the CSD waves was obersved directly by the OIIS Systems In accordence with the depolarizational potential recorded by recording apparatus. This animal model is suitable to study in vivo and for the farther study of the mechanism and the possible function of the CSD.
Part II
Study of cortical spreading depression preconditioning protecting against brain ischemic injury in vivo in rat
Objective: To study cortical spreading depression (CSD) induced-kcl preconditioning affecting cerebral blood flow and infarct volume after middle cerebral artery occlusion (MCAO) in rat and examine wether CSD can protect brain agaist ischemic injury.
Methods: 24 Sprague-Dawley rats were divided into experimental group(n=12) and control group group(n=12).CSD was induced by applying 5mKCl cotton pad on the cortex thrugh the pinhole of rats' skull, replacing one time every 20 min and contuning 2 hours. The rat cerebral focal ischemic model after middle cerebral artery occlusion was made by the intraluminal suture method three days later in the CSD preconditioning rats. Opitcal imaging technology of laser speckle imaging was used to monitor the cerebral blood flow (CBF) for 2h after MACO and cortical and subcortical infarct volumes were measured 7 days later. Control group was treated as the experimental group only applying Nacl instead of kcl. To compare infarct volume and the hemodynamic changes of the experimental group with control group.
Results: CSD preconditioning group significantly improved CBF during MCAO than control group. CSD preconditioning group reduced the hemispheric and neocortical volume of infarction than control group group. There was no difference between the two groups in the subcortical infarct volume. Conclusion: Opitcal imaging technology of laser speckle imaging can be used to monitor the cerebral blood flow (CBF) in vivo. CSD preconditioning can improve the cortical cerebral blood flow significantly and reduced the hemispheric and neocortical volume of infarction. We conclude that CSD preconditioning can protect ischemic brain impairment.
Part III
Effects of Neurogenesis after focal cerebral ischemia with cortical spreading depression preconditioning in rats
Objective: To study the influence of Neurogenesis after focal cerebral ischemia with cortical spreading depression preconditioning in rats and to explore the mechanism of CSD preconditioning inducing brain protection after ischemic brain injury.
Methods: CSD was induced by kcl and the model of the middle cerebral artery occlusion (MCOA)was made by the intraluminal suture method in 72 major Spangue-Dawley rats, who were divided averagely randomly into six group: group I: noischemic rats with only CSD; group II: ischemic rats with CSD preconditioning by kcl; group III: MCOA with vehicle(saline) preconditioning; group IV: ischemic rats with CSD abolished by the NMDA receptor antagonist, MK-801, which inhibits the propagation of CSD; group V: Only ischemic rats; group VI: blank control: no CSD and no ischemic rats with sham operation. Immunohistochemistry method was used to observe the number of BrdU expression positive cells on the 1st, 3th, 7th and 14th days after ischemia.
Results:There were BrdU positive cells in the cortex, hippocampal dentate gyrus (DG)and striatum at different time points after cerebral ischemia, and the number of BrdU positive cells in various brain regions were increased significantly on the 7th day (p < 0. 05 ) .It was also found that the number of BrdU positive cells in group II was significantly more than that in the other model groups and the number of BrdU positive cells in group I was increased significantly compared with the groupVI on d7 and d14 (p < 0. 05).
Conclusion: CSD could induce BrdU expression positive cells in some brain regions in normal rats and in rats suffering focal cerebral ischemia and could stimulate the potency of neurogenesis after focal cerebral ischemia. It reveals that CSD stimulating neurofenesis could be the important mechanisms of CSD inducing focal cerebral ischeimic protect.
引文
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