针刺对大鼠脑缺血再灌注后线粒体损伤相关因素影响的研究
摘要
脑对缺血极为敏感,脑缺血再灌注损伤后,机体主动或被动地作出广泛的反应,构成
了脑缺血再灌注损伤复杂的病理机制。由于脑缺血后存在着缺血时相改变,为在治疗时间
窗内研究针对性干预,改善大脑功能提供了理论依据。由于缺血半暗区理论提出,使脑缺
血再灌注损伤机制研究重点定位于脑组织出现不可逆之前。脑缺血再灌注损伤后的基本病
理改变脑水肿及细胞凋亡,是各种因素相互作用和相互联系的结果。
虽然线粒体功能恢复在缺血再灌注细胞复苏中必不可少,但线粒体在脑损伤一系列瀑
布反应中起着非常关键作用,围绕着线粒体介导的脑缺血再灌注损伤后细胞凋亡的主要事
件,脑缺血再灌注损伤病理上发生了一系列时间和空间的错综级联反应。脑缺血时,线粒
体氧化磷酸化不能有效进行,ATP 生成减少而水解增多,细胞由于能量不足发生功能障碍,
随着缺血时间延长,线粒体功能和结构受损,ATP 耗竭,细胞功能进一步损害。再灌注时,
线粒体产生大量自由基,同时线粒体钙转运紊乱,发生永久性通透性改变,胞浆钙急剧升
高,在 Bcl-2 家族、半胱天冬酶、细胞色素 C 等凋亡相关因子的作用下,导致细胞凋亡发
生。
脑缺血再灌注损伤可以诱导神经细胞再生,有内源性 NSC 激活现象,脑功能可以发生
重建。神经元再生有分布和移行规律。神经生长因子和神经特异性蛋白等和神经再生关系
密切。在众多的细胞因子中,神经营养因子在神经再生中具有重要作用。靶源性神经营养
因子通过自分泌、旁分泌方式,转输作用于相应神经细胞,只有那些获得足够神经营养因
子的神经元能够成活,否则就会死亡。
脑缺血属于中医学中的中风病范畴。针刺治疗中风在我国已有数千年的临床验证,早在
《黄帝内经》、《甲乙经》及《针灸大全》中即有记载。由于时间治疗窗的提出,针刺疗法
已经从对缺血性中风后遗症和恢复期的治疗转到了对其急性期的治疗研究;针刺治疗脑缺
血再灌注损伤是多途径、多因素综合作用的结果。针刺对脑缺血再灌注损伤的保护作用研
究涉及面较广,从对大鼠神经功能行为缺损的干预、脑组织的病理形态学的改变、脑功能
代谢和脑微循环的改善到缺血性神经元凋亡信号转导的影响等方面都有所及。对针刺机理
的研究已经不是仅限于器官和系统水平的整体分析,对针刺效应的研究已经在微观水平层
面上逐渐开展。虽然针灸的脑保护作用机制还未十分明确,但很可能是通过激发机体的潜
能,启动包括内源性抗缺血损伤的能力在内的多种调控机制,共同发挥抗损伤的脑保护作
用。这种脑保护作用也可能促进了内源性神经干细胞参与病损的修复。
本研究利用线拴法闭塞大鼠大脑中动脉造成局灶性脑缺血再灌注模型和在体外培养海
马神经元模拟脑缺血再灌注损伤模型,进行了下列主要研究工作:① 从脑损伤后起关键作
用的线粒体改变入手,分别观察线粒体膜电势变化、细胞内钙变化,以及与其密切相关的
能说明体内自由基产生和清除状况的脑组织中丙二醛(MDA)、谷胱甘肽(GSH)动态变化。
② 从与抗脑损伤有相应关系的神经再生营养角度,观察局灶性脑缺血再灌注损伤后神经生
长相关肽(GAP-43)表达和血清转化生长因子(TGF-β)含量变化和二者的相关关系。③ 电
中文摘要 - 2 -
针曲池、足三里、百会穴对脑组织中 MDA、GSH 动态变化的影响。电针对海马部位 GAP-43
表达和血清 TGF-β含量变化的影响。④ 将电针曲池、足三里、百会穴的正常大鼠和局灶
性脑缺血再灌注模型大鼠的血清,加入到海马神经元模拟脑缺血再灌注损伤模型的培养液
中,观察针刺血清对线粒体膜电势及细胞内钙的变化的影响。
本研究共分 4 部分进行:
1. 脑缺血再灌注损伤后行为学和病理形态学变化及针刺的影响:神经功能缺损是 MCAO
大鼠重要表现体征。用单盲法在 MCAO 大鼠脑缺血再灌注后的 6h、24h、48h、72h 不用时间
点内,对大鼠的相关行为表现进行评分。发现用大鼠神经功能评分方法结合 TTC 染色和 HE
染色方法,可以作为大鼠局灶性脑缺血再灌注模型检测的方法之一。电针可以降低神经行
为等级评分,说明电针能有效改变大鼠神经功能缺损。
2. 脑缺血再灌注损伤后 MDA 和 GSH 动态变化及针刺的影响:在脑缺血再灌注时自由基
产生增加,自由基清除系统的功能低下导致脂质过氧化作用增强。自由基可以过度消耗抗
氧化酶 GSH,并生成大量的脂质过氧化物代谢终产物丙二醛(MDA),介导神经元不可逆损
伤。在 MCAO 大鼠脑缺血再灌注后的 6h、24h、48h、72h 不用时间点内,发现大鼠再灌注后,
脑组织的 MDA 含量明显增加,24h 以后升高明显;GSH 的活性显著下降,在脑缺血再灌注
6h 时最低。针刺有助于降低 MDA 水平和提高 GSH 活性,尤其对再灌注较长时相组作用明显。
针刺可以降低 MDA 水平和提高 GSH 活性,因而说明抑制自由基生成、整合内源性抗氧化系
统,促进自由基清除、抗脂质过氧化。
3. 脑缺血再灌注损伤后 GAP-43 和 TGF-β表达及针刺的影响:GAP-43 是神经元发育和
可塑性的分子标志物。TGF-β可以作为脑损伤的标记。在用免疫组织化学染色和 ELISA 方
法观察 MCAO 大鼠造模后 72h,损伤脑组织的生长相关蛋白 GAP-43、血清转移生长因子 TGF-?
The brain is sensitive to ischemia. After the injury of ischemia-reperfusion, the
organism will respond initiatively or passively. it forms the complex pathologic
mechanism of brain injury of ischemia-reperfusion.Because there are changes of
phase of ischemia after the brain ischemia, it provides the theoretical proof for
studying pertinent interference and improving the function of brain in the windows of
theraputic time.The recovery of mitochondria function is absolutely necessarily for
cells in ischemia-reperfusion, mitochondria is rery important in series of waterfall
responses in brain injury. Around the main affairs of cell programme death conducted
by mitochondria after brain injury of ischemia-reperfusion, there are series of
complex pathologic cascade of damage of time and space.In the brain ischemia, the
oxidative-phosphorylation of mitochondria cann’t process efficiently, and the creation
of ATP decreased and hydrolyzation increased, the cells get function obstruction for
deficiency of energy. With the extension of the time of ischemia, the struction and
function of mitochondria damaged, and ATP exhausted, and the function of cells
damaged more. In reperfusion, the mitochondria manufactures many free radicles. In
the same time, the transfer of calcium of mitochondria is inordinate, it turns to
permanent penetrate, the calcium in cell plasm raises sharply. It conducts to the
programme death in the function of correlative factors such as family of Bcl-2,
enzyme of cysteine-asparagine, cytochrome-C, et.c.The brain injury of
ischemia-reperfusion can induce to regeneration of nerve cells. There is endogenesic
NSC activation and the function of brain can reconstruct. There is distributing and
moving regulation of regeneration of NSC. The relation between nerve-gowth-factor
and nerve-special-protein and regeneration of nerve cells is close. In many cell factors,
nerve-nutriton-factors is important in the regeneration of nerve. The target-inducing
nerve-nutriton-factors act on corresponding nerve cells by self-secret, para-secret,
transfering. The nerve cells gained enough nerve-nutrition-factors can survive, others
will die.
It is thousands of years using acupuncture to cure stroke in clinic of china. It was
recorded in huangdineijing, jiayijing, zhenjiudaquan. For the advance of the windows
of theraputic time, the study of Acupuncture turned from sequelae and convalescence
stage of ischemic stroke to acute period. It is a result of compound function of many
paths and many factors for acupuncture to treat brain injury of ischemia-reperfusion.
The study of acupuncture to protect brain injury of ischemia-reperfusion is wide. It
include interference to damage of nerve function of rat, change of
pathologic-morphology of brain tissue, meliorate of brain metabolize and brain
micro-circle, signal-transfer of ischemic nerve cell Apoptosis. The study of
acupuncture mechanism is not only about integrated analyze of organ and system, but
it is gradually broadly expand on the micro-level.the mechanism of the protecting
function of acupuncture to brain, but it maybe is activating the potential of organism,
and startup many regulatory mechanism including endogenetic anti-injury of ischemia,
英文摘要 - 4 -
all of them educe the protecting function to brain of anti-injury. The protecting
function to brain maybe promote endogenesic nerv stem cells to participate in the
rehabilitation of fault.
We made model of focal brain ischemia-reperfusion injury by middle cerebral artery
occlusion (MCAO) and simulate brain ischemia-reperfusion injury by incubating
hippocampi nerve cells culture in vitro. We carried through these reseaching work: 1.
Begin with mitochondria acting a key after brain ischemia-reperfusion injury, we
observed the change of electric potential of mitochondria, the change of calcium
within cell, and the dynamic change of MDA, GSH in brain tissue tha
了脑缺血再灌注损伤复杂的病理机制。由于脑缺血后存在着缺血时相改变,为在治疗时间
窗内研究针对性干预,改善大脑功能提供了理论依据。由于缺血半暗区理论提出,使脑缺
血再灌注损伤机制研究重点定位于脑组织出现不可逆之前。脑缺血再灌注损伤后的基本病
理改变脑水肿及细胞凋亡,是各种因素相互作用和相互联系的结果。
虽然线粒体功能恢复在缺血再灌注细胞复苏中必不可少,但线粒体在脑损伤一系列瀑
布反应中起着非常关键作用,围绕着线粒体介导的脑缺血再灌注损伤后细胞凋亡的主要事
件,脑缺血再灌注损伤病理上发生了一系列时间和空间的错综级联反应。脑缺血时,线粒
体氧化磷酸化不能有效进行,ATP 生成减少而水解增多,细胞由于能量不足发生功能障碍,
随着缺血时间延长,线粒体功能和结构受损,ATP 耗竭,细胞功能进一步损害。再灌注时,
线粒体产生大量自由基,同时线粒体钙转运紊乱,发生永久性通透性改变,胞浆钙急剧升
高,在 Bcl-2 家族、半胱天冬酶、细胞色素 C 等凋亡相关因子的作用下,导致细胞凋亡发
生。
脑缺血再灌注损伤可以诱导神经细胞再生,有内源性 NSC 激活现象,脑功能可以发生
重建。神经元再生有分布和移行规律。神经生长因子和神经特异性蛋白等和神经再生关系
密切。在众多的细胞因子中,神经营养因子在神经再生中具有重要作用。靶源性神经营养
因子通过自分泌、旁分泌方式,转输作用于相应神经细胞,只有那些获得足够神经营养因
子的神经元能够成活,否则就会死亡。
脑缺血属于中医学中的中风病范畴。针刺治疗中风在我国已有数千年的临床验证,早在
《黄帝内经》、《甲乙经》及《针灸大全》中即有记载。由于时间治疗窗的提出,针刺疗法
已经从对缺血性中风后遗症和恢复期的治疗转到了对其急性期的治疗研究;针刺治疗脑缺
血再灌注损伤是多途径、多因素综合作用的结果。针刺对脑缺血再灌注损伤的保护作用研
究涉及面较广,从对大鼠神经功能行为缺损的干预、脑组织的病理形态学的改变、脑功能
代谢和脑微循环的改善到缺血性神经元凋亡信号转导的影响等方面都有所及。对针刺机理
的研究已经不是仅限于器官和系统水平的整体分析,对针刺效应的研究已经在微观水平层
面上逐渐开展。虽然针灸的脑保护作用机制还未十分明确,但很可能是通过激发机体的潜
能,启动包括内源性抗缺血损伤的能力在内的多种调控机制,共同发挥抗损伤的脑保护作
用。这种脑保护作用也可能促进了内源性神经干细胞参与病损的修复。
本研究利用线拴法闭塞大鼠大脑中动脉造成局灶性脑缺血再灌注模型和在体外培养海
马神经元模拟脑缺血再灌注损伤模型,进行了下列主要研究工作:① 从脑损伤后起关键作
用的线粒体改变入手,分别观察线粒体膜电势变化、细胞内钙变化,以及与其密切相关的
能说明体内自由基产生和清除状况的脑组织中丙二醛(MDA)、谷胱甘肽(GSH)动态变化。
② 从与抗脑损伤有相应关系的神经再生营养角度,观察局灶性脑缺血再灌注损伤后神经生
长相关肽(GAP-43)表达和血清转化生长因子(TGF-β)含量变化和二者的相关关系。③ 电
中文摘要 - 2 -
针曲池、足三里、百会穴对脑组织中 MDA、GSH 动态变化的影响。电针对海马部位 GAP-43
表达和血清 TGF-β含量变化的影响。④ 将电针曲池、足三里、百会穴的正常大鼠和局灶
性脑缺血再灌注模型大鼠的血清,加入到海马神经元模拟脑缺血再灌注损伤模型的培养液
中,观察针刺血清对线粒体膜电势及细胞内钙的变化的影响。
本研究共分 4 部分进行:
1. 脑缺血再灌注损伤后行为学和病理形态学变化及针刺的影响:神经功能缺损是 MCAO
大鼠重要表现体征。用单盲法在 MCAO 大鼠脑缺血再灌注后的 6h、24h、48h、72h 不用时间
点内,对大鼠的相关行为表现进行评分。发现用大鼠神经功能评分方法结合 TTC 染色和 HE
染色方法,可以作为大鼠局灶性脑缺血再灌注模型检测的方法之一。电针可以降低神经行
为等级评分,说明电针能有效改变大鼠神经功能缺损。
2. 脑缺血再灌注损伤后 MDA 和 GSH 动态变化及针刺的影响:在脑缺血再灌注时自由基
产生增加,自由基清除系统的功能低下导致脂质过氧化作用增强。自由基可以过度消耗抗
氧化酶 GSH,并生成大量的脂质过氧化物代谢终产物丙二醛(MDA),介导神经元不可逆损
伤。在 MCAO 大鼠脑缺血再灌注后的 6h、24h、48h、72h 不用时间点内,发现大鼠再灌注后,
脑组织的 MDA 含量明显增加,24h 以后升高明显;GSH 的活性显著下降,在脑缺血再灌注
6h 时最低。针刺有助于降低 MDA 水平和提高 GSH 活性,尤其对再灌注较长时相组作用明显。
针刺可以降低 MDA 水平和提高 GSH 活性,因而说明抑制自由基生成、整合内源性抗氧化系
统,促进自由基清除、抗脂质过氧化。
3. 脑缺血再灌注损伤后 GAP-43 和 TGF-β表达及针刺的影响:GAP-43 是神经元发育和
可塑性的分子标志物。TGF-β可以作为脑损伤的标记。在用免疫组织化学染色和 ELISA 方
法观察 MCAO 大鼠造模后 72h,损伤脑组织的生长相关蛋白 GAP-43、血清转移生长因子 TGF-?
The brain is sensitive to ischemia. After the injury of ischemia-reperfusion, the
organism will respond initiatively or passively. it forms the complex pathologic
mechanism of brain injury of ischemia-reperfusion.Because there are changes of
phase of ischemia after the brain ischemia, it provides the theoretical proof for
studying pertinent interference and improving the function of brain in the windows of
theraputic time.The recovery of mitochondria function is absolutely necessarily for
cells in ischemia-reperfusion, mitochondria is rery important in series of waterfall
responses in brain injury. Around the main affairs of cell programme death conducted
by mitochondria after brain injury of ischemia-reperfusion, there are series of
complex pathologic cascade of damage of time and space.In the brain ischemia, the
oxidative-phosphorylation of mitochondria cann’t process efficiently, and the creation
of ATP decreased and hydrolyzation increased, the cells get function obstruction for
deficiency of energy. With the extension of the time of ischemia, the struction and
function of mitochondria damaged, and ATP exhausted, and the function of cells
damaged more. In reperfusion, the mitochondria manufactures many free radicles. In
the same time, the transfer of calcium of mitochondria is inordinate, it turns to
permanent penetrate, the calcium in cell plasm raises sharply. It conducts to the
programme death in the function of correlative factors such as family of Bcl-2,
enzyme of cysteine-asparagine, cytochrome-C, et.c.The brain injury of
ischemia-reperfusion can induce to regeneration of nerve cells. There is endogenesic
NSC activation and the function of brain can reconstruct. There is distributing and
moving regulation of regeneration of NSC. The relation between nerve-gowth-factor
and nerve-special-protein and regeneration of nerve cells is close. In many cell factors,
nerve-nutriton-factors is important in the regeneration of nerve. The target-inducing
nerve-nutriton-factors act on corresponding nerve cells by self-secret, para-secret,
transfering. The nerve cells gained enough nerve-nutrition-factors can survive, others
will die.
It is thousands of years using acupuncture to cure stroke in clinic of china. It was
recorded in huangdineijing, jiayijing, zhenjiudaquan. For the advance of the windows
of theraputic time, the study of Acupuncture turned from sequelae and convalescence
stage of ischemic stroke to acute period. It is a result of compound function of many
paths and many factors for acupuncture to treat brain injury of ischemia-reperfusion.
The study of acupuncture to protect brain injury of ischemia-reperfusion is wide. It
include interference to damage of nerve function of rat, change of
pathologic-morphology of brain tissue, meliorate of brain metabolize and brain
micro-circle, signal-transfer of ischemic nerve cell Apoptosis. The study of
acupuncture mechanism is not only about integrated analyze of organ and system, but
it is gradually broadly expand on the micro-level.the mechanism of the protecting
function of acupuncture to brain, but it maybe is activating the potential of organism,
and startup many regulatory mechanism including endogenetic anti-injury of ischemia,
英文摘要 - 4 -
all of them educe the protecting function to brain of anti-injury. The protecting
function to brain maybe promote endogenesic nerv stem cells to participate in the
rehabilitation of fault.
We made model of focal brain ischemia-reperfusion injury by middle cerebral artery
occlusion (MCAO) and simulate brain ischemia-reperfusion injury by incubating
hippocampi nerve cells culture in vitro. We carried through these reseaching work: 1.
Begin with mitochondria acting a key after brain ischemia-reperfusion injury, we
observed the change of electric potential of mitochondria, the change of calcium
within cell, and the dynamic change of MDA, GSH in brain tissue tha
引文
1. 韩济生.神经科学原理.北京医科大学出版社,1999 年,1063-1613
2. 吴其夏,余应年,卢建.新编病理生理学.中国协和医科大学出版社,1999 年,192-200
3. 李浩,曲生健,主编.脑血管病中西医汇通.辽宁科学技术出版社,2002:27-35
4. Witte OW, Bidmin HJ, Schiene K, et al. Functional differentiation of multiple
perilesional zones after focal cerebral ischemia[J].J Cereb Blood Flow
Metab,2000,20:1149-1165
5. 孙明,赵育梅,徐超.局灶性脑缺血损伤的时相变化及再灌注损伤的观察[J].基础医学与
临床,2002,22(增刊):85-86Sharp
6. Belayev L, Alonso OF, Rusto R, et al. Middle cerebral artey occlusion in the
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