银杏叶提取物（EGb）对糖尿病大鼠学习记忆障碍保护作用的机制研究
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摘要
长期糖尿病除了可引起全身多脏器结构和功能损害外,还可引起糖尿病神经病变,包括外周神经病变以及中枢神经神经病变。以往对于糖尿病神经病变的研究、治疗和药物的保护往往着重于外周神经病变方面,而对于糖尿病中枢性损伤的相关研究比较少。因此进行糖尿病脑损伤机制的研究,并寻找相应的保护剂有着十分重要的意义。银杏叶提取物(EGb)主要成分为黄酮类、萜内酯类等,是一有效的抗氧化剂和自由基清除剂,具有明显改善血液流变和组织代谢的作用,对中枢神经系统有独特的保护效应,对应激因素和外伤因素所致的认知缺陷有治疗作用。因此EGb对中枢神经系统退行性疾病,如AD,有广泛的应用价值。
本论文以Wistar大鼠为研究对象,在链脲佐菌素(Streptozotocin)诱导的糖尿病模型上,从形态功能学、分子生物学等方面对EGb糖尿病海马损伤的保护作用及其机制进行了探讨。
(一)形态功能学方面
(1)大鼠腹腔注射Streptozotocin 55mg.kg-1后,出现典型的体重下降、多尿、多饮、血糖升高等表现。6 个月后,Nissl 染色观察表明海马细胞稀疏、无序,神经细胞密度降低;取海马进行其超微结构观察,见大鼠海马锥体细胞出现细胞器结构不清楚,胞体及突起明显肿胀,胞浆空泡化,粗面内质网和游离核糖体明显减少,线粒体肿胀、破坏、溶解,细胞膜崩解等表现以及神经纤维不清楚、神经丝模糊、突触间隙明显增宽、突触后膜致密物厚度(PSD)明显变薄。EGb(100 mg.kg-1)治疗组海马细胞的超微结果得到改善,突触间隙明显缩小,PSD 明显增厚,神经细胞密度有所提高。
(2)为了探讨糖尿病大鼠海马损伤的机制,大鼠糖尿病后6 个月,用电子显微镜和TUNEL 方法观察到海马的细胞凋亡现象,表明海马细胞存在着明显的凋亡现象,TUNEL阳性细胞表达的凋亡细胞数明显增加,EGb(100 mg.kg-1)治疗组对海马细胞凋亡增加现象有明显的抑制作用,TUNEL 阳性细胞表达的凋亡细胞数明显减少。
(3)糖尿病6个月后,大鼠海马Na+-K+-ATPase活性的由正常的16.07±3.60(μmolPi.mgPr-1.h-1),下降到10.52±3.02,EGb(100、50 mg.kg-1)治疗组对糖尿病大鼠海马Na+-K+-ATPase的活性分别提高到15.50±2.76,14.67±3.55。提示了银杏叶提取物对作为神经元质膜功能状
Chronic diabetes mellitus can result in structural and functional lesions of multiple organsin human. Even more, it will cause diabetic neuropathy, including peripheral and centralneuropathy. In the early stage, more basic researches had been done on the peripheralneuropathy to find effective neuroprotection. Unfortunately, less attention had been paidto the central neuropathy. For this reason, it is significant to investigate the diabetic braininjury and to find the corresponding neuroprotective agents. Gingko biloba extract (EGb)is a well-defined plant extract containing two major groups of constituents, i.e.flavonoids and terpenoids. Possessing antioxidant and free radical-scanvenging activities,EGb improves blood rheology and tissue metabolism. It has markedly neuroprotectiveeffects on CNS and counteracts the cognitive deficits that follow stress or traumatic braininjury. It is viewed as a polyvalent agent with a possible therapeutic use in the treatmentof neurodengenerative diseases of multifactional origin, e.g. AD.
In the present study with streptozotocin-induced diabetes in Wistar rats as objects, we have
investigated the protective effects of EGb on brain in morphological, functional and molecularbiology aspects.
A. Morphological and functinal aspects
1.Administration of STZ (55 mg.kg-1, i.p.) produced diabetic symptoms such as weight loss,polyuria, polydipsia, and hyperglycemia. After 6 months of diabetes, morphological analysis ofthe hippocampal cells by Nissl staining revealed that the neuronal cells were in the state ofraritas and disorder, accompanied by reduced neuronal density in the hippocampus.Ultrastructural analysis of the hippocampal pyramidal neurons by electronmicroscope revealedthat the cell organs of neurons were ambiguous, cell body and nervous process were obviouslyswelling, endochylema was vacuolated, rough endoplasmic reticulum and free ribosome weremarkedly decreased, chondriosome was engorged, lyzed and destructed, cellular membrane wasdisaggregated. The ultrastructural analysis also showed that the nerve fiber and nerve plexuswere ambiguous, synaptic cleft was widened, postsynaptic density (PSD) was attenuated. EGbadministration(100 mg.kg-1)could improve the above morphological changes, obviouslydiminishing synapse cleft and increasing PSD and neuronal density.
2.To explore mechanisms underlying central nervous system complications in diabetes, we alsoexamined hippocampal neuronal apoptosis and the effect of EGb. Apoptosis was demonstratedafter 6 months of diabetes by electronmicroscope observation. Increased numbers ofTdT-mediated dUTP nick-end labeling (TUNEL)-positive cells were shown in the diabetichippocampus. Whereas EGb administration(100 mg.kg-1)could decrease the numbers of positiveapoptotic cells by TUNEL in diabetic hippocampus.
3. After 6 months of diabetes, the activity of Na+-K+-ATPase in diabetic hippocampus wasdescended from the normal 16.07 ±3.60 ( μmolPi.mg Pr-1.h-1 ) to 10.52 ±3.02, EGbadministration 100, 50 mg.kg-1)could enhance the Na+-K+-ATPase to 15.50±2.76, ( 14.67±3.55,respectively. The data suggested that EGb could protect the functional Na+-K+ATPase ofneuronal cytolemma from diabetic injury.
4. After 6 months of diabetes, diabetic rats could swim for more than 3hrs. The open filed testalso showed that the limb’s movements of diabetic rats were not harmed. Accordingly, weobsvered the learning and memory potentia by Morris water maze, and behavior profiles by openfiled test. The result of open field test showed that the center detention time was prolonged,accompanied by decreased numbers of hollow-probing in diabetic rats. The result of Morris
water maze showed that the escaping latency was prolonged, and score of platform-searchingwas decreased on d5 and d8 after training. EGb administration(100, 50 mg.kg-1)could shortencenter detention time, increase numbers of hollow-probing, improve deficient escaping latencyand score of platform-searching in diabetic rats.
B.Molecular biology aspects
Streptozotocin-induced diabetes was produced in another batch
本论文以Wistar大鼠为研究对象,在链脲佐菌素(Streptozotocin)诱导的糖尿病模型上,从形态功能学、分子生物学等方面对EGb糖尿病海马损伤的保护作用及其机制进行了探讨。
(一)形态功能学方面
(1)大鼠腹腔注射Streptozotocin 55mg.kg-1后,出现典型的体重下降、多尿、多饮、血糖升高等表现。6 个月后,Nissl 染色观察表明海马细胞稀疏、无序,神经细胞密度降低;取海马进行其超微结构观察,见大鼠海马锥体细胞出现细胞器结构不清楚,胞体及突起明显肿胀,胞浆空泡化,粗面内质网和游离核糖体明显减少,线粒体肿胀、破坏、溶解,细胞膜崩解等表现以及神经纤维不清楚、神经丝模糊、突触间隙明显增宽、突触后膜致密物厚度(PSD)明显变薄。EGb(100 mg.kg-1)治疗组海马细胞的超微结果得到改善,突触间隙明显缩小,PSD 明显增厚,神经细胞密度有所提高。
(2)为了探讨糖尿病大鼠海马损伤的机制,大鼠糖尿病后6 个月,用电子显微镜和TUNEL 方法观察到海马的细胞凋亡现象,表明海马细胞存在着明显的凋亡现象,TUNEL阳性细胞表达的凋亡细胞数明显增加,EGb(100 mg.kg-1)治疗组对海马细胞凋亡增加现象有明显的抑制作用,TUNEL 阳性细胞表达的凋亡细胞数明显减少。
(3)糖尿病6个月后,大鼠海马Na+-K+-ATPase活性的由正常的16.07±3.60(μmolPi.mgPr-1.h-1),下降到10.52±3.02,EGb(100、50 mg.kg-1)治疗组对糖尿病大鼠海马Na+-K+-ATPase的活性分别提高到15.50±2.76,14.67±3.55。提示了银杏叶提取物对作为神经元质膜功能状
Chronic diabetes mellitus can result in structural and functional lesions of multiple organsin human. Even more, it will cause diabetic neuropathy, including peripheral and centralneuropathy. In the early stage, more basic researches had been done on the peripheralneuropathy to find effective neuroprotection. Unfortunately, less attention had been paidto the central neuropathy. For this reason, it is significant to investigate the diabetic braininjury and to find the corresponding neuroprotective agents. Gingko biloba extract (EGb)is a well-defined plant extract containing two major groups of constituents, i.e.flavonoids and terpenoids. Possessing antioxidant and free radical-scanvenging activities,EGb improves blood rheology and tissue metabolism. It has markedly neuroprotectiveeffects on CNS and counteracts the cognitive deficits that follow stress or traumatic braininjury. It is viewed as a polyvalent agent with a possible therapeutic use in the treatmentof neurodengenerative diseases of multifactional origin, e.g. AD.
In the present study with streptozotocin-induced diabetes in Wistar rats as objects, we have
investigated the protective effects of EGb on brain in morphological, functional and molecularbiology aspects.
A. Morphological and functinal aspects
1.Administration of STZ (55 mg.kg-1, i.p.) produced diabetic symptoms such as weight loss,polyuria, polydipsia, and hyperglycemia. After 6 months of diabetes, morphological analysis ofthe hippocampal cells by Nissl staining revealed that the neuronal cells were in the state ofraritas and disorder, accompanied by reduced neuronal density in the hippocampus.Ultrastructural analysis of the hippocampal pyramidal neurons by electronmicroscope revealedthat the cell organs of neurons were ambiguous, cell body and nervous process were obviouslyswelling, endochylema was vacuolated, rough endoplasmic reticulum and free ribosome weremarkedly decreased, chondriosome was engorged, lyzed and destructed, cellular membrane wasdisaggregated. The ultrastructural analysis also showed that the nerve fiber and nerve plexuswere ambiguous, synaptic cleft was widened, postsynaptic density (PSD) was attenuated. EGbadministration(100 mg.kg-1)could improve the above morphological changes, obviouslydiminishing synapse cleft and increasing PSD and neuronal density.
2.To explore mechanisms underlying central nervous system complications in diabetes, we alsoexamined hippocampal neuronal apoptosis and the effect of EGb. Apoptosis was demonstratedafter 6 months of diabetes by electronmicroscope observation. Increased numbers ofTdT-mediated dUTP nick-end labeling (TUNEL)-positive cells were shown in the diabetichippocampus. Whereas EGb administration(100 mg.kg-1)could decrease the numbers of positiveapoptotic cells by TUNEL in diabetic hippocampus.
3. After 6 months of diabetes, the activity of Na+-K+-ATPase in diabetic hippocampus wasdescended from the normal 16.07 ±3.60 ( μmolPi.mg Pr-1.h-1 ) to 10.52 ±3.02, EGbadministration 100, 50 mg.kg-1)could enhance the Na+-K+-ATPase to 15.50±2.76, ( 14.67±3.55,respectively. The data suggested that EGb could protect the functional Na+-K+ATPase ofneuronal cytolemma from diabetic injury.
4. After 6 months of diabetes, diabetic rats could swim for more than 3hrs. The open filed testalso showed that the limb’s movements of diabetic rats were not harmed. Accordingly, weobsvered the learning and memory potentia by Morris water maze, and behavior profiles by openfiled test. The result of open field test showed that the center detention time was prolonged,accompanied by decreased numbers of hollow-probing in diabetic rats. The result of Morris
water maze showed that the escaping latency was prolonged, and score of platform-searchingwas decreased on d5 and d8 after training. EGb administration(100, 50 mg.kg-1)could shortencenter detention time, increase numbers of hollow-probing, improve deficient escaping latencyand score of platform-searching in diabetic rats.
B.Molecular biology aspects
Streptozotocin-induced diabetes was produced in another batch
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2. 许曼音主编. 糖尿病学[M]. 第1 版. 上海: 上海科学技术出版社, 2003. 189-205
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