银杏内酯抗脑缺血作用及其机制的研究
摘要
银杏内酯(Total Ginkgolides,TG)是银杏叶提取物(EGb)中的一类帖烯内酯成分，它主要包括单体内酯A、B、C、M、J和白果内酯。关于EGb的心脑血管药理作用已有许多研究报道，关于单体内酯B及白果内酯等的抗血小板活化因子(PAF)作用及神经保护作用也有一些报道。TG与EGb相比是相对纯的中药药用有效部位，与单体内酯A、B、白果内酯等相比，前者含量远高于各单体成分，易得且价廉，并且推测它可能会有各单体协同作用的优势，此外，抗脑缺血药及神经保护剂的开发研究是目前亟待解决的课题，鉴于此，本文以银杏内酯为研究对象，从整体到分子水平研究了其抗脑缺血作用及作用机理。
首先，研究了TG对小鼠密闭缺氧、急性脑缺血和大鼠局灶性脑缺血的保护作用。采用小鼠密闭缺氧实验，观察了TG对小鼠在密闭缺氧条件下的存活时间，并用测氧仪测定了容器内的氧含量变化情况；将标准体重的雄性小鼠双侧颈总动脉及迷走神经共同结扎，造成脑缺血合并血压下降，观察了TG对小鼠死亡率及死亡时间的影响；将标准体重的雄性小鼠急性断头造成全脑缺血，观察了断头后瞬时小鼠的喘气时间变化情况；电凝雄性大鼠一侧大脑中动脉造成局灶性脑缺血(MCAO)，观察了TG对大鼠行为障碍、脑梗塞面积、脑组织病理变化及脑水含量的影响。结果表明，各剂量TG对密闭容器内小鼠全身缺氧的耗氧量及死亡时间无明显保护作用；TG32mg·kg~(-1)可显著降低结扎双侧颈总动脉及迷走神经后小鼠在120min内的死亡率，显著延长小鼠的存活时间；TG16和32mg·kg~(-1)可显著延长急性断头后小鼠的喘气时间；TG8和16mg·kg~(-1)可显著改善大鼠MCAO后6h的行为功能障碍，TG4,8和16mg·kg~(-1)可显著改善大鼠MCAO后24h的行为功能障碍；TG4,8和16mg·kg~(-1)可显著减少MCAO后大鼠的脑梗塞面积；MCAO后大鼠脑组织的病理学检查结果表明，TG各剂量组可不同程度地减轻大鼠缺血侧脑组织的神经元受损形态；TG8和16mg·kg~(-1)可明显降低大鼠MCAO后的脑组织水含量。
然后，研究了TG对体外培养的大鼠胎鼠皮质神经细胞不同损伤模型的影响。用1mM谷氨酸(终浓度，以下所有浓度均指在培养液中的终浓度)和0.2mM H_2O_2分别与皮质神经细胞温育8h，造成培养的皮质神经细胞损伤；另向培养液中加入20nM KCN使细胞化学性缺氧并同时完全撤除培养液中的葡萄糖，造成细胞缺糖缺氧性损
博士学位论文：银杏内酯抗脑缺血作用及其机制的研究 摘要
伤，测定细胞培养液中的乳酸脱氢酶队DH）活性，并用MTT法测定细胞的可见性，
观察TG对H种细胞损伤模型的保护作用。结果表明，在谷氨酸损伤模型上，TG各
剂量在谷氨酸损伤处理的同时加入培养液中，可明显增加细胞活力，TG10”‘和 10”’
g·L’可明显降低LDH的释放JG在谷氨酸损伤之前预先与细胞温育12h，TG10’，10”‘
和 10－’g·L－’可明显增加细胞活力，TG 10’g·L”’可明显降低 LDH的释放。在 HZOZ
损伤模型上，TG与 HZOZ同时给细胞温育 12 h，所有剂量均未见其对细胞损伤的保护
作用，而大剂量TG门－’和10‘’g·L－’）预给细胞孵育12h后再用H。O；损伤处理，可见
其明显地增加细胞活力并降低 LDH释放。TG各剂量预处理细胞 12 h后，再进行缺
糖缺氧性损伤，未见TG有保护作用。
随后，研究了TG对栓线法致局灶性脑缺血大鼠脑组织内自由基防御系统的影响。
实验采用可逆的大脑中动脉阻断模型，造成大鼠局灶性脑缺血 2 h再灌注 24 h，观察
TG对大鼠脑缺血后 6 h和 24 h的行为障碍和缺血侧及对照侧大脑皮质、海马及纹状
体组织核团的重量变化。测定了缺血再灌注后大鼠外周血清中乳酸脱氢酶儿DH和肌
酸激酶厂以的活性：测定了大鼠缺血再灌注后缺血侧及对照侧大脑皮质的过氧化氢酶
KAT卜谷脱甘肽过氧化物酶（GSPX）的活性及还原型谷脱甘肽（GSH的含量：测定
了大鼠缺血再灌注后皮质、海马及纹状体的超氧化物歧化酶瞩OD）的活性和脂质过氧
化物丙二醛（MDA）的含量。结果表明，在缺血 6 h，TG 8 mg上g－’可显著改善大鼠的行
为功能障碍；在缺血 24 h，TG 8和 16 mg·kg‘可显著改善大鼠的行为功能障碍；TG
16 mg·kg－‘可显著减少缺血侧海马脑区的水肿，而各组对照侧海马和纹状体无明显水
肿发生。TG mg·kg”‘可明显降低外周血清中的 LDH活性，对 CK活性也有降低的
作用趋势；TG 16 mg屿－‘可显著增加缺血侧皮质的 CAT活性，TG 4，8和 16 mg·kg”‘
三个剂量均可明显降低缺血侧皮质的GSHPX活性：各组对照侧皮质的CAT和
GSHPx活性均无显著差异。TG 8和 16 mg·kg”’可明显增加缺血侧纹状体内的SOD
活性，对缺血侧皮质和海马脑区的SOD活性无显著影响；各组对照侧皮质、海马及
纹状体内的SOD活性无显著差异。TG各剂量有增加缺血侧皮质内GSH含量的作用
趋势，TG 8和 16 mg·kg“’可明显降低缺血侧皮质内的 MDA含量，同时 TG mg·kg－’
可明显降低缺血侧纹状体内的MDA含量，但对缺血侧海马脑区的MDA含量无明显
影晌。对照侧皮质的GSH和对照侧皮质、海马及纹状体内的Nil3A含量各组均无显
著差异。
最后
Ginkgolides (TG) is terpenoid constituents of Ginkgo biloba extract (EGb), which includes ginkgolides A, B, C, M, J and bilobalide. Many reports have been read about the effects of EGb on blood vessels of heart and brain. And also there were some papers about that Gin B and bolobalide have antagonistic effects on platelet activity factor (PAF). Comparing to EGb, TG is a relative pure effective fraction of Chinese traditional medicine and comparing to the mono-ginkgolides, TG is much more easily prepared. Moreover, it is known that medicines for treating ischemia and medicines having neuroprotection are more necessary in clinic. Therefore, we made attempt to study the putative cerebreprotective activity and the possible mechanism of TG in vivo and in vitro.
To investigate the protective effects of TG on anoxia and acute cerebral ischemia in mice and focal cerebral ischemia in rats, anoxia was produced by close hypoxia and the surviving time and oxygen content were detected. Acute cerebral ischemia was produced by the occlusion of bilateral common carotid arteries with vague nerves of mice and the effects of TG on mortality and surviving time in mice were also detected. Ischemia of whole brain was produced by cutting out mice heads and the effect of TG on gasping time was observd. Focal cerebral ischemia was produced by permanent occlusion of the proximal of the left middle cerebral artery (MCAO). The effects of TG on neurologic deficits and content of water in the damaged brain of rats, and also the pathological examination were observed. Results showed that no significant effects of TG on the surviving time and oxygen content in mice subjected to close hypoxia. TG 32 mg-kg-1 significantly prolonged the surviving time of mice subjected to acute ischemia by occl
usion of bilateral carotid arteries and decreased the death rate. TG 16 and 32 mg-kg-1 could significantly prolong the gasping time in mice subjected to being cut out heads. TG 8 and 16 mg-kg-1 markedly decreased the infarct size and ameliorated neurologic deficits score of rats subjected to MCAO. Moreover, TG could decrease the water content in the damaged brain in rats subjected to MCAO.
We tried to find out whether TG could rescue cultured cortical neurons from
neurotoxicity damages. In cortical neuronal cultures from fetal rats, damage was induced by exposure to 1 mM L-glutamate (GIu) for 6-12 h in serum-free medium, by exposure to 0.2 mM hydrogen peroxide (H2O2) for 6-12 h, and by exposure to free-glucose and hypoxia medium for 4 h. Neuronal viability was confirmed by the assay of the absorbance of 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium (MTT) solution on a spectrophotometer using a test wavelength of 570 nm and a reference wavelength of 630 nm. Cell membrane damage was assessed by measuring the release of lactate dehydrogenase (LDH) using the colorimetry. TG (10-5 to 10-1 g-L-1) added to the growth medium 12h before and simultaneously protected cortical neurons from glutamate-induced damage. The cytoprotective effects of TG on the damage induced by H2O2 were observed only when it was added 12 h prior to the onset of the injury. No effect of TG was found on the insult induced by free-glucose and hypoxia.
The influence of TG on the lipid peroxide product, malondialdehyde (MDA), glutathione (GSH) and catalase (CAT), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) activities in rat brain as well as lactate dehydrogenase (LDH) and creatine kinase (CK)activities in rat blood serum after occlusion of middle cerebral artery (MCAO) following reperfusion was investigated. Experimental model of the reversible middle cerebral artery occlusion without craniectomy of rat focal cerebral ischemia-reperfusion was used. Compared to sham-operated animals, rats subjected ischemia followed reperfusion exhibited severe neurologic deficits, ischemia followed reperfusion increased blood serum LDH and CK activities as well as brain GSH-Px activity and decreased SOD activity as well as GSH and MDA content. Administration of TG (4, 8, 16 mg-kg
首先，研究了TG对小鼠密闭缺氧、急性脑缺血和大鼠局灶性脑缺血的保护作用。采用小鼠密闭缺氧实验，观察了TG对小鼠在密闭缺氧条件下的存活时间，并用测氧仪测定了容器内的氧含量变化情况；将标准体重的雄性小鼠双侧颈总动脉及迷走神经共同结扎，造成脑缺血合并血压下降，观察了TG对小鼠死亡率及死亡时间的影响；将标准体重的雄性小鼠急性断头造成全脑缺血，观察了断头后瞬时小鼠的喘气时间变化情况；电凝雄性大鼠一侧大脑中动脉造成局灶性脑缺血(MCAO)，观察了TG对大鼠行为障碍、脑梗塞面积、脑组织病理变化及脑水含量的影响。结果表明，各剂量TG对密闭容器内小鼠全身缺氧的耗氧量及死亡时间无明显保护作用；TG32mg·kg~(-1)可显著降低结扎双侧颈总动脉及迷走神经后小鼠在120min内的死亡率，显著延长小鼠的存活时间；TG16和32mg·kg~(-1)可显著延长急性断头后小鼠的喘气时间；TG8和16mg·kg~(-1)可显著改善大鼠MCAO后6h的行为功能障碍，TG4,8和16mg·kg~(-1)可显著改善大鼠MCAO后24h的行为功能障碍；TG4,8和16mg·kg~(-1)可显著减少MCAO后大鼠的脑梗塞面积；MCAO后大鼠脑组织的病理学检查结果表明，TG各剂量组可不同程度地减轻大鼠缺血侧脑组织的神经元受损形态；TG8和16mg·kg~(-1)可明显降低大鼠MCAO后的脑组织水含量。
然后，研究了TG对体外培养的大鼠胎鼠皮质神经细胞不同损伤模型的影响。用1mM谷氨酸(终浓度，以下所有浓度均指在培养液中的终浓度)和0.2mM H_2O_2分别与皮质神经细胞温育8h，造成培养的皮质神经细胞损伤；另向培养液中加入20nM KCN使细胞化学性缺氧并同时完全撤除培养液中的葡萄糖，造成细胞缺糖缺氧性损
博士学位论文：银杏内酯抗脑缺血作用及其机制的研究 摘要
伤，测定细胞培养液中的乳酸脱氢酶队DH）活性，并用MTT法测定细胞的可见性，
观察TG对H种细胞损伤模型的保护作用。结果表明，在谷氨酸损伤模型上，TG各
剂量在谷氨酸损伤处理的同时加入培养液中，可明显增加细胞活力，TG10”‘和 10”’
g·L’可明显降低LDH的释放JG在谷氨酸损伤之前预先与细胞温育12h，TG10’，10”‘
和 10－’g·L－’可明显增加细胞活力，TG 10’g·L”’可明显降低 LDH的释放。在 HZOZ
损伤模型上，TG与 HZOZ同时给细胞温育 12 h，所有剂量均未见其对细胞损伤的保护
作用，而大剂量TG门－’和10‘’g·L－’）预给细胞孵育12h后再用H。O；损伤处理，可见
其明显地增加细胞活力并降低 LDH释放。TG各剂量预处理细胞 12 h后，再进行缺
糖缺氧性损伤，未见TG有保护作用。
随后，研究了TG对栓线法致局灶性脑缺血大鼠脑组织内自由基防御系统的影响。
实验采用可逆的大脑中动脉阻断模型，造成大鼠局灶性脑缺血 2 h再灌注 24 h，观察
TG对大鼠脑缺血后 6 h和 24 h的行为障碍和缺血侧及对照侧大脑皮质、海马及纹状
体组织核团的重量变化。测定了缺血再灌注后大鼠外周血清中乳酸脱氢酶儿DH和肌
酸激酶厂以的活性：测定了大鼠缺血再灌注后缺血侧及对照侧大脑皮质的过氧化氢酶
KAT卜谷脱甘肽过氧化物酶（GSPX）的活性及还原型谷脱甘肽（GSH的含量：测定
了大鼠缺血再灌注后皮质、海马及纹状体的超氧化物歧化酶瞩OD）的活性和脂质过氧
化物丙二醛（MDA）的含量。结果表明，在缺血 6 h，TG 8 mg上g－’可显著改善大鼠的行
为功能障碍；在缺血 24 h，TG 8和 16 mg·kg‘可显著改善大鼠的行为功能障碍；TG
16 mg·kg－‘可显著减少缺血侧海马脑区的水肿，而各组对照侧海马和纹状体无明显水
肿发生。TG mg·kg”‘可明显降低外周血清中的 LDH活性，对 CK活性也有降低的
作用趋势；TG 16 mg屿－‘可显著增加缺血侧皮质的 CAT活性，TG 4，8和 16 mg·kg”‘
三个剂量均可明显降低缺血侧皮质的GSHPX活性：各组对照侧皮质的CAT和
GSHPx活性均无显著差异。TG 8和 16 mg·kg”’可明显增加缺血侧纹状体内的SOD
活性，对缺血侧皮质和海马脑区的SOD活性无显著影响；各组对照侧皮质、海马及
纹状体内的SOD活性无显著差异。TG各剂量有增加缺血侧皮质内GSH含量的作用
趋势，TG 8和 16 mg·kg“’可明显降低缺血侧皮质内的 MDA含量，同时 TG mg·kg－’
可明显降低缺血侧纹状体内的MDA含量，但对缺血侧海马脑区的MDA含量无明显
影晌。对照侧皮质的GSH和对照侧皮质、海马及纹状体内的Nil3A含量各组均无显
著差异。
最后
Ginkgolides (TG) is terpenoid constituents of Ginkgo biloba extract (EGb), which includes ginkgolides A, B, C, M, J and bilobalide. Many reports have been read about the effects of EGb on blood vessels of heart and brain. And also there were some papers about that Gin B and bolobalide have antagonistic effects on platelet activity factor (PAF). Comparing to EGb, TG is a relative pure effective fraction of Chinese traditional medicine and comparing to the mono-ginkgolides, TG is much more easily prepared. Moreover, it is known that medicines for treating ischemia and medicines having neuroprotection are more necessary in clinic. Therefore, we made attempt to study the putative cerebreprotective activity and the possible mechanism of TG in vivo and in vitro.
To investigate the protective effects of TG on anoxia and acute cerebral ischemia in mice and focal cerebral ischemia in rats, anoxia was produced by close hypoxia and the surviving time and oxygen content were detected. Acute cerebral ischemia was produced by the occlusion of bilateral common carotid arteries with vague nerves of mice and the effects of TG on mortality and surviving time in mice were also detected. Ischemia of whole brain was produced by cutting out mice heads and the effect of TG on gasping time was observd. Focal cerebral ischemia was produced by permanent occlusion of the proximal of the left middle cerebral artery (MCAO). The effects of TG on neurologic deficits and content of water in the damaged brain of rats, and also the pathological examination were observed. Results showed that no significant effects of TG on the surviving time and oxygen content in mice subjected to close hypoxia. TG 32 mg-kg-1 significantly prolonged the surviving time of mice subjected to acute ischemia by occl
usion of bilateral carotid arteries and decreased the death rate. TG 16 and 32 mg-kg-1 could significantly prolong the gasping time in mice subjected to being cut out heads. TG 8 and 16 mg-kg-1 markedly decreased the infarct size and ameliorated neurologic deficits score of rats subjected to MCAO. Moreover, TG could decrease the water content in the damaged brain in rats subjected to MCAO.
We tried to find out whether TG could rescue cultured cortical neurons from
neurotoxicity damages. In cortical neuronal cultures from fetal rats, damage was induced by exposure to 1 mM L-glutamate (GIu) for 6-12 h in serum-free medium, by exposure to 0.2 mM hydrogen peroxide (H2O2) for 6-12 h, and by exposure to free-glucose and hypoxia medium for 4 h. Neuronal viability was confirmed by the assay of the absorbance of 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium (MTT) solution on a spectrophotometer using a test wavelength of 570 nm and a reference wavelength of 630 nm. Cell membrane damage was assessed by measuring the release of lactate dehydrogenase (LDH) using the colorimetry. TG (10-5 to 10-1 g-L-1) added to the growth medium 12h before and simultaneously protected cortical neurons from glutamate-induced damage. The cytoprotective effects of TG on the damage induced by H2O2 were observed only when it was added 12 h prior to the onset of the injury. No effect of TG was found on the insult induced by free-glucose and hypoxia.
The influence of TG on the lipid peroxide product, malondialdehyde (MDA), glutathione (GSH) and catalase (CAT), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) activities in rat brain as well as lactate dehydrogenase (LDH) and creatine kinase (CK)activities in rat blood serum after occlusion of middle cerebral artery (MCAO) following reperfusion was investigated. Experimental model of the reversible middle cerebral artery occlusion without craniectomy of rat focal cerebral ischemia-reperfusion was used. Compared to sham-operated animals, rats subjected ischemia followed reperfusion exhibited severe neurologic deficits, ischemia followed reperfusion increased blood serum LDH and CK activities as well as brain GSH-Px activity and decreased SOD activity as well as GSH and MDA content. Administration of TG (4, 8, 16 mg-kg
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