银杏苦内酯B对麻醉大鼠中枢神经元放电活动的影响
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摘要
银杏(Ginkgo biloba)在地球上已存在约2亿年,曾广泛分布于北半球的欧、亚、美洲,素有裸子植物“活化石”之称。其种子作为“白果”入药已有600多年的历史。
银杏苦内酯(ginkgolides)是银杏提取物中的一种活性成分,包括银杏苦内酯A、B、C、M、J等,均为强血小板活化因子(Platelet activating factor, PAF)拮抗剂。其中银杏苦内酯B(Ginkgolide B,GB)活性最强,迄今对银杏苦内酯B的药理作用研究也最为集中。银杏苦内酯竞争性拮抗PAF与其受体的结合,从而使PAF不能通过G蛋白转导激活磷脂酶C、腺甘酸环化酶和酪氨酸蛋白激酶,从而阻断了PAF受体的信号转导,阻断了PAF的生物学效应。
银杏苦内酯对中枢神经系统多种疾病有一定的防治作用。保护脑缺血、减少再灌注损伤,抗阿尔茨海默病(AD),抑制神经细胞凋亡等诸多方面都表明银杏苦内酯在治疗中枢神经系统疾病方面有着光明的前景。
关于银杏内酯B的中枢保护作用机制,特别是电生理不甚明确。海马结构简单,易于分离,且与心血管中枢相关核团有纤维联系,是神经电生理研究常用部位。下丘脑室旁核(paraventricular nucleus, PVN)是非常重要的心血管活动调控整合部位,接受来自海马的穹隆纤维。目前,有关银杏内酯B对大鼠中枢神经元电生理特性的影响尚未见报道。因此本论文对以上两部位进行了研究。
Ⅰ银杏苦内酯B对大鼠海马CA1区神经元自发放电的影响
目的:研究银杏苦内酯B(Ginkgolide B, BN52021)对静息状态下的海马脑片神经元活动的影响。
方法:实验选用20±3天的雄性Sprague-Dawley大鼠。将大鼠快速断头,剥去颅骨和硬脑膜,取出脑组织,置于0-4℃预先用95% O_2和5% CO_2的混合气体饱和的人工脑脊液中,快速分离出一侧海马,切成厚度为350-500μm的脑片。然后将脑片移入人工脑脊液中,连续通以95% O_2和5% CO_2,室温下孵育60-90 min。应用细胞外记录单位放电技术,观察银杏苦内酯B对大鼠海马脑片神经元放电的影响。
结果:(1)在43个CA1区神经元放电单位给予银杏苦内酯B(0.1,1,10μmol/L)2分钟,有42个放电单位(97.67%)放电频率明显降低,且呈剂量依赖性;(2)预先用0.2 mmol/L的L-glutamate (L-Glu)灌流海马脑片, 10个放电单位放电频率明显增加,表现为癫痫样放电,在此基础上灌流银杏苦内酯B(1μmol/L)2分钟,其癫痫样放电全部被抑制;(3)预先用L型钙通道开放剂Bay K 8644灌流8个海马脑片,8个单位(100%)全部放电增加,在此基础上灌流银杏苦内酯B(1μmol/L)2分钟,7个放电单位(87.5%)放电频率明显减低;(4)在8个CA1区神经元放电单位上,银杏苦内酯B(1μmol/L)的抑制效应可被广泛钾通道阻断剂(tetraethylammonium, TEA)1 mmol/L完全阻断。
结论:银杏苦内酯B (Ginkgolide B, BN52021)可抑制海马神经元自发放电,并可抑制由L-glutamate诱发的神经元放电。提示银杏苦内酯B对中枢神经元通过降低其活动而具有一定程度的保护作用,这种作用可能与银杏苦内酯B抑制L型钙通道有关,而且可能与延迟整流型钾通道(delayed rectifier potassium channel, KDR)有关。
Ⅱ银杏苦内酯B对大鼠下丘脑室旁核神经元自发放电的影响
目的:研究银杏苦内酯B(Ginkgolide B, BN52021)对静息状态下的下丘脑脑片室旁核神经元活动的影响。
方法:实验选用20±3天的雄性Sprague-Dawley大鼠。将大鼠快速断头,剥去颅骨和硬脑膜,取出脑组织,置于0-4℃预先用95% O_2和5% CO_2的混合气体饱和的人工脑脊液中,根据解剖学标志切得一块含有室旁核的下丘脑脑片,厚度为350-500μm,并置入人工脑脊液中,连续通以95% O_2和5% CO_2,室温下孵育60-90 min。应用细胞外记录单位放电技术,观察银杏苦内酯B对大鼠室旁核神经元放电活动的影响。
结果:(1)在27个下丘脑室旁核神经元放电单位给予银杏苦内酯B(0.1,1,10μmol/L)2分钟,有26个放电单位(96.30%)放电频率明显降低,且呈剂量依赖性;(2)预先用0.2 mmol/L的L-glutamate (L-Glu)灌流下丘脑脑片, 8个放电单位放电频率明显增加,表现为癫痫样放电,在此基础上灌流银杏苦内酯B(1μmol/L)2分钟,其癫痫样放电全部被抑制;(3)预先用L型钙通道开放剂Bay K 8644灌流8个下丘脑脑片,8个单位(100%)全部放电增加,在此基础上灌流银杏苦内酯B(1μmol/L)2分钟,8个放电单位(100%)放电频率明显减低;(4)在8个下丘脑室旁核神经元放电单位上,银杏苦内酯B(1μmol/L)的抑制效应可被广泛钾通道阻断剂(tetraethylammonium, TEA)1 mmol/L完全阻断。
结论:银杏苦内酯B (Ginkgolide B, BN52021)可抑制下丘脑室旁核神经元自发放电,并可抑制由L-glutamate诱发的神经元放电。提示银杏苦内酯B对心血管中枢神经元通过降低其活动而具有一定程度的保护作用,这种作用可能与银杏苦内酯B抑制L型钙通道有关,而且可能与延迟整流型钾通道(delayed rectifier potassium channel, KDR)有关。
Background: Ginkgolide B is one of the major constituents of the terpenoid fraction of Ginkgo biloba extract (GbE). Previous investigations suggested that ginkgolide B is a potent platelet-activating factor receptor antagonist, which is also regarded as having neuroprotective effects in the CNS. Recent evidence suggests that GbE protects against neuronal death in global brain ischemia and in glutamate-induced excitotoxicity. The mechanisms underlying ginkgolide B’s beneficial effects on central neurons activity still need to be clarified as yet and the effect of ginkgolide B on spontaneous discharge of hippocampal neurons has not been reported.
Aim: To examine the effects of Ginkgolide B (BN52021) on the discharges of neurons in CA1 area of hippocampal slices.
Methods: Using extracellular recording technique.
Results: (1) In response to the application of ginkgolide B (0.1, 1, 10μmol/L; n=43) into the perfusate for 2 min, the spontaneous discharge rates (SDR) of 42/43 (97.67%) neurons were significantly decreased in a dose-dependent manner. (2) Pretreatment with L-glutamate (L-Glu, 0.2mmol/L) led to a marked increase in the SDR of all 10 (100%) neurons in an epileptiform pattern. The increased discharges were suppressed significantly after ginkgolide B (1μmol/L) was applied into the perfusate for 2 min. (3) In 8 neurons, perfusion of the selective L-type calcium channel agonist, Bay K 8644 (0.1μmol/L), induced a significant increase in the discharge rate of 8/8 (100%) neurons. Ginkgolide B (1μmol/L) applied into the perfusate inhibited the discharges of 7/8 (87.5%) slices. (4) In 8 neurons, the broad potassium channels blocker, tetraethylammonium (TEA, 1mmol/L) completely blocked the inhibitory effect of ginkgolide B (1μmol/L).
Conclusion: These results suggest that ginkgolide B can inhibit the electrical activity of CA1 neurons. The inhibitory effect may be related to the blockade of L-type voltage-activated calcium channel and may be concerned with delayed rectifier potassium channel (KDR),which indicated that ginkgolide B play a protective role on the central neurons.
Background: Ginkgolide B is one of the major constituents of the terpenoid fraction of Ginkgo biloba extract (GbE). Previous investigations suggested that ginkgolide B is a potent platelet-activating factor receptor antagonist, which is also regarded as having protective effects in cardiovascular system and CNS. Recent evidence suggests that GbE protects against neuronal death in global brain ischemia and in glutamate-induced excitotoxicity. The mechanisms underlying ginkgolide B’s beneficial effects on central neurons activity still need to be clarified as yet.
Aim: To study the central role of Ginkgolide B (BN52021) in regulating cardiovascular function of nervous center by examining the effects of GST on the electrical activity of rat paraventricular nucleus (PVN) neurons in hypothalamic slice preparation and to elucidate the mechanism involved.
Methods: Using extracellular single-unit discharge recording technique.
Results: (1) In response to the application of ginkgolide B (0.1, 1, 10μmol/L; n=27) into the perfusate for 2 min, the spontaneous discharge rates (SDR) of 26/27 (96.30%) neurons were significantly decreased in a dose-dependent manner. (2) Pretreatment with L-glutamate (L-Glu, 0.2mmol/L) led to a marked increase in the SDR of all 8 (100%) neurons in an epileptiform pattern. The increased discharges were suppressed significantly after ginkgolide B (1μmol/L) was applied into the perfusate for 2 min. (3) In 8 neurons, perfusion of the selective L-type calcium channel agonist, Bay K 8644 (0.1μmol/L), induced a significant increase in the discharge rate of 8/8 (100%) neurons. Ginkgolide B (1μmol/L) applied into the perfusate inhibited the discharges of 8/8 (100%) slices. (4) In 8 neurons, the broad potassium channels blocker, tetraethylammonium (TEA, 1mmol/L) completely blocked the inhibitory effect of ginkgolide B (1μmol/L).
Conclusion: These results suggest that ginkgolide B can inhibit the electrical activity of paraventricular neurons. The inhibitory effect may be related to the blockade of L-type voltage-activated calcium channel and may be concerned with delayed rectifier potassium channel (KDR).
银杏苦内酯(ginkgolides)是银杏提取物中的一种活性成分,包括银杏苦内酯A、B、C、M、J等,均为强血小板活化因子(Platelet activating factor, PAF)拮抗剂。其中银杏苦内酯B(Ginkgolide B,GB)活性最强,迄今对银杏苦内酯B的药理作用研究也最为集中。银杏苦内酯竞争性拮抗PAF与其受体的结合,从而使PAF不能通过G蛋白转导激活磷脂酶C、腺甘酸环化酶和酪氨酸蛋白激酶,从而阻断了PAF受体的信号转导,阻断了PAF的生物学效应。
银杏苦内酯对中枢神经系统多种疾病有一定的防治作用。保护脑缺血、减少再灌注损伤,抗阿尔茨海默病(AD),抑制神经细胞凋亡等诸多方面都表明银杏苦内酯在治疗中枢神经系统疾病方面有着光明的前景。
关于银杏内酯B的中枢保护作用机制,特别是电生理不甚明确。海马结构简单,易于分离,且与心血管中枢相关核团有纤维联系,是神经电生理研究常用部位。下丘脑室旁核(paraventricular nucleus, PVN)是非常重要的心血管活动调控整合部位,接受来自海马的穹隆纤维。目前,有关银杏内酯B对大鼠中枢神经元电生理特性的影响尚未见报道。因此本论文对以上两部位进行了研究。
Ⅰ银杏苦内酯B对大鼠海马CA1区神经元自发放电的影响
目的:研究银杏苦内酯B(Ginkgolide B, BN52021)对静息状态下的海马脑片神经元活动的影响。
方法:实验选用20±3天的雄性Sprague-Dawley大鼠。将大鼠快速断头,剥去颅骨和硬脑膜,取出脑组织,置于0-4℃预先用95% O_2和5% CO_2的混合气体饱和的人工脑脊液中,快速分离出一侧海马,切成厚度为350-500μm的脑片。然后将脑片移入人工脑脊液中,连续通以95% O_2和5% CO_2,室温下孵育60-90 min。应用细胞外记录单位放电技术,观察银杏苦内酯B对大鼠海马脑片神经元放电的影响。
结果:(1)在43个CA1区神经元放电单位给予银杏苦内酯B(0.1,1,10μmol/L)2分钟,有42个放电单位(97.67%)放电频率明显降低,且呈剂量依赖性;(2)预先用0.2 mmol/L的L-glutamate (L-Glu)灌流海马脑片, 10个放电单位放电频率明显增加,表现为癫痫样放电,在此基础上灌流银杏苦内酯B(1μmol/L)2分钟,其癫痫样放电全部被抑制;(3)预先用L型钙通道开放剂Bay K 8644灌流8个海马脑片,8个单位(100%)全部放电增加,在此基础上灌流银杏苦内酯B(1μmol/L)2分钟,7个放电单位(87.5%)放电频率明显减低;(4)在8个CA1区神经元放电单位上,银杏苦内酯B(1μmol/L)的抑制效应可被广泛钾通道阻断剂(tetraethylammonium, TEA)1 mmol/L完全阻断。
结论:银杏苦内酯B (Ginkgolide B, BN52021)可抑制海马神经元自发放电,并可抑制由L-glutamate诱发的神经元放电。提示银杏苦内酯B对中枢神经元通过降低其活动而具有一定程度的保护作用,这种作用可能与银杏苦内酯B抑制L型钙通道有关,而且可能与延迟整流型钾通道(delayed rectifier potassium channel, KDR)有关。
Ⅱ银杏苦内酯B对大鼠下丘脑室旁核神经元自发放电的影响
目的:研究银杏苦内酯B(Ginkgolide B, BN52021)对静息状态下的下丘脑脑片室旁核神经元活动的影响。
方法:实验选用20±3天的雄性Sprague-Dawley大鼠。将大鼠快速断头,剥去颅骨和硬脑膜,取出脑组织,置于0-4℃预先用95% O_2和5% CO_2的混合气体饱和的人工脑脊液中,根据解剖学标志切得一块含有室旁核的下丘脑脑片,厚度为350-500μm,并置入人工脑脊液中,连续通以95% O_2和5% CO_2,室温下孵育60-90 min。应用细胞外记录单位放电技术,观察银杏苦内酯B对大鼠室旁核神经元放电活动的影响。
结果:(1)在27个下丘脑室旁核神经元放电单位给予银杏苦内酯B(0.1,1,10μmol/L)2分钟,有26个放电单位(96.30%)放电频率明显降低,且呈剂量依赖性;(2)预先用0.2 mmol/L的L-glutamate (L-Glu)灌流下丘脑脑片, 8个放电单位放电频率明显增加,表现为癫痫样放电,在此基础上灌流银杏苦内酯B(1μmol/L)2分钟,其癫痫样放电全部被抑制;(3)预先用L型钙通道开放剂Bay K 8644灌流8个下丘脑脑片,8个单位(100%)全部放电增加,在此基础上灌流银杏苦内酯B(1μmol/L)2分钟,8个放电单位(100%)放电频率明显减低;(4)在8个下丘脑室旁核神经元放电单位上,银杏苦内酯B(1μmol/L)的抑制效应可被广泛钾通道阻断剂(tetraethylammonium, TEA)1 mmol/L完全阻断。
结论:银杏苦内酯B (Ginkgolide B, BN52021)可抑制下丘脑室旁核神经元自发放电,并可抑制由L-glutamate诱发的神经元放电。提示银杏苦内酯B对心血管中枢神经元通过降低其活动而具有一定程度的保护作用,这种作用可能与银杏苦内酯B抑制L型钙通道有关,而且可能与延迟整流型钾通道(delayed rectifier potassium channel, KDR)有关。
Background: Ginkgolide B is one of the major constituents of the terpenoid fraction of Ginkgo biloba extract (GbE). Previous investigations suggested that ginkgolide B is a potent platelet-activating factor receptor antagonist, which is also regarded as having neuroprotective effects in the CNS. Recent evidence suggests that GbE protects against neuronal death in global brain ischemia and in glutamate-induced excitotoxicity. The mechanisms underlying ginkgolide B’s beneficial effects on central neurons activity still need to be clarified as yet and the effect of ginkgolide B on spontaneous discharge of hippocampal neurons has not been reported.
Aim: To examine the effects of Ginkgolide B (BN52021) on the discharges of neurons in CA1 area of hippocampal slices.
Methods: Using extracellular recording technique.
Results: (1) In response to the application of ginkgolide B (0.1, 1, 10μmol/L; n=43) into the perfusate for 2 min, the spontaneous discharge rates (SDR) of 42/43 (97.67%) neurons were significantly decreased in a dose-dependent manner. (2) Pretreatment with L-glutamate (L-Glu, 0.2mmol/L) led to a marked increase in the SDR of all 10 (100%) neurons in an epileptiform pattern. The increased discharges were suppressed significantly after ginkgolide B (1μmol/L) was applied into the perfusate for 2 min. (3) In 8 neurons, perfusion of the selective L-type calcium channel agonist, Bay K 8644 (0.1μmol/L), induced a significant increase in the discharge rate of 8/8 (100%) neurons. Ginkgolide B (1μmol/L) applied into the perfusate inhibited the discharges of 7/8 (87.5%) slices. (4) In 8 neurons, the broad potassium channels blocker, tetraethylammonium (TEA, 1mmol/L) completely blocked the inhibitory effect of ginkgolide B (1μmol/L).
Conclusion: These results suggest that ginkgolide B can inhibit the electrical activity of CA1 neurons. The inhibitory effect may be related to the blockade of L-type voltage-activated calcium channel and may be concerned with delayed rectifier potassium channel (KDR),which indicated that ginkgolide B play a protective role on the central neurons.
Background: Ginkgolide B is one of the major constituents of the terpenoid fraction of Ginkgo biloba extract (GbE). Previous investigations suggested that ginkgolide B is a potent platelet-activating factor receptor antagonist, which is also regarded as having protective effects in cardiovascular system and CNS. Recent evidence suggests that GbE protects against neuronal death in global brain ischemia and in glutamate-induced excitotoxicity. The mechanisms underlying ginkgolide B’s beneficial effects on central neurons activity still need to be clarified as yet.
Aim: To study the central role of Ginkgolide B (BN52021) in regulating cardiovascular function of nervous center by examining the effects of GST on the electrical activity of rat paraventricular nucleus (PVN) neurons in hypothalamic slice preparation and to elucidate the mechanism involved.
Methods: Using extracellular single-unit discharge recording technique.
Results: (1) In response to the application of ginkgolide B (0.1, 1, 10μmol/L; n=27) into the perfusate for 2 min, the spontaneous discharge rates (SDR) of 26/27 (96.30%) neurons were significantly decreased in a dose-dependent manner. (2) Pretreatment with L-glutamate (L-Glu, 0.2mmol/L) led to a marked increase in the SDR of all 8 (100%) neurons in an epileptiform pattern. The increased discharges were suppressed significantly after ginkgolide B (1μmol/L) was applied into the perfusate for 2 min. (3) In 8 neurons, perfusion of the selective L-type calcium channel agonist, Bay K 8644 (0.1μmol/L), induced a significant increase in the discharge rate of 8/8 (100%) neurons. Ginkgolide B (1μmol/L) applied into the perfusate inhibited the discharges of 8/8 (100%) slices. (4) In 8 neurons, the broad potassium channels blocker, tetraethylammonium (TEA, 1mmol/L) completely blocked the inhibitory effect of ginkgolide B (1μmol/L).
Conclusion: These results suggest that ginkgolide B can inhibit the electrical activity of paraventricular neurons. The inhibitory effect may be related to the blockade of L-type voltage-activated calcium channel and may be concerned with delayed rectifier potassium channel (KDR).
引文
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12 Wang G, Ding S, Yunokuchi K. Glutamate-induced increases in intracellular Ca2+ in cultured rat neocortical neurons. Neuroreport, 2002, 13(8): 1051~1056.
13 DeLorenzo R J, Pal S, Sombati S. Prolonged activation of the N-methyl-D-aspartate receptor-Ca2+ transduction pathway causes spontaneous recurrent epileptiform discharges in hippocampal neurons in culture. Proc NatlAcad Sci USA, 1998, 95(24): 14482~14487.
14 Wang Z M, Sun G Q, Wang Z A, et al. Effects of agmatine on discharges of neurons in rat hippocampal CA1 area. Acta Physiol Sin, 2003, 55 (6): 617~622.
15 Wang H, Wang ZA, He RR. Adenosine inhibits spontaneous and glutamate-induced discharges of hippocampal CA1 neurons. Acta Physiol Sin, 2000, 52(4): 281~286.
16 Zablocka B, Lukasiuk K, Lazarewicz J W, et al. Modulation of ischemic signal by antagonists of N-methyl-D-aspartate, nitric oxide synthase, and platelet-activating factor in gerbil hippocampus. J. Neurosci, 1995, Res. 40: 233~240.
17 Kuribara H, Weintraub ST, Yoshihama T, et al. An anxiolytic-like effect of Ginkgo biloba extract and its constituent, ginkgolide-A, in mice. J Natural Products 2003, 66: 1333~1337.
18 Bennett SA, Chen J, Pappas BA, et al. Platelet-activating actor receptor expression is associated with neuronal apoptosis in an in vivo model of excitotoxicity. Cell Death Differ, 1998, 5(10): 867~875.
19 Bito H, Nakamura M, Honda Z, et al. Platelet-activating factor (PAF) receptor in rat brain: PAF mobilizes intracellular Ca2+ in hippocampal neurons. Neuron, 1992, 9: 285~294.
20 Braquet P. The ginkgolides: potent platelet-activating factorantagonists isolated from Ginkgo biloba L.: chemistry, pharmacology and clinical applications. Drugs Future, 1987, 12: 643~699.
21 Yue T L, Gleason M M, Hallenbeck J, et al. Characterization of platelet-activating factor-induced elevation of cytosolic free-calcium level in neurohybrid NCB-20 cells. Neuroscience, 1991, 41: 177~185.
22 Choi DW, Rothman SM. The role of glutamate neurotoxicity in hypoxic-ischemic neuronal death. Annu Rev Neurosci, 1990, 13: 171~182.
23 Chen L, Liu CJ, Tang M, et al. Action of beta-amyloid peptide (1-40) on I (HVA) and its modulation by ginkgolide B. Acta Physiol Sin (Chin), 2006, 58:14~20.
24 仰礼真, 张翼, 李进禧. 银杏苦内酯 B 对豚鼠心室肌细胞单动作电位及 L-钙通道的影响. 中国药理学通报, 2000, 16(2): 195~198.
25 祁小燕, 张志雄, 崔启启. 银杏苦内酯 B 对缺血豚鼠心室肌动作电位 L-型钙电流和延迟整流钾电流的作用. 中国应用生理学杂志, 2004, 20(1): 24~28.
26 Rudy B. Diversity and ubiquity of K+ channels. Neuroscience, 1988, 25(3): 729~749.
27 Tohse N. Calcium-sensitive delayed rectifier potassium current in guinea-pig ventricular cells. Am. J. Physiol, 1990, 258: H1200~H1207.
28 Nitta J, Furukawa T, Marumo F, et al. Subcellular mechanism for Ca2+-dependent enhancement of delayedrectifier K+ current in isolated membrane patches of guinea-pig ventricular myocytes. Circ. Res, 1994, 74: 96~104.
1 Maclennan K M, Darlington C L, Smith P F. The CNS effects of Ginkgo biloba extracts and ginkgolide B. Prog. Neurobiol., 2002, 67: 235~257.
2 Ahlemeyer B, Krieglstein J. Neuroprotective effects of Ginkgo biloba extract. Cell. Mol. Life Sci, 2003, 60: 1779~1792.
3 Kecskemeti V, Balogh I. Cardiac ultrastructural effect of the platelet-activating factor and its antagonist BN 52021. Exp Toxicol Pathol, 1995: 463~470.
4 Li S, Meng Q, Zhang L. Experimental therapy of a platelet-activating factor antagonist (Ginkgolide B) on photochemically induced thrombotic cerebral ischaemia in tree shrews. Clin. Exp. Pharmacol. Physiol, 1999, 26: 824~825.
5 Ahlemeyer B, Mowes A, Krieglstein J. Inhibition of serum deprivation- and staurosporine-induced neuronal apoptosis by Ginkgo biloba extract and some of its constituents. Eur. J. Pharmacol, 1999, 367: 423~430.
6 Kondratskaya E L, Pankratov Y V, Lalo U V, et al. Inhibition of hippocampal LTP by ginkgolide B is mediated by its blocking action on PAF rather than glycine receptors. Neurochem, 2004, Int. 44: 171~177.
7 Chandrasekaran K, Mehrabian Z, Spinnewyn B, et al. Bilobalide, a component of the Ginkgo biloba extract(EGb761) protects against neuronal death in global brain ischemia and glutamate-induced excitotoxicity. Cell Mol Biol (Noisylegrand), 2002, 48(6): 663~669.
8 Nogami K, Hirashima Y, Endo S, Takaku A. Involvement of platelet-activating factor (PAF) in glutamate neurotoxicity in rat neuronal cultures. Brain Res, 1997, Apr 18; 754(1-2): 72~78.
9 Limbrick DD Jr, Sombati S, DeLorenzo RJ. Calcium influx constitutes the ionic basis for the maintenance of glutamate-induced extended neuronal depolarization associated with hippocampal neuronal death. Cell Calcium, 2003, Feb; 33(2): 69~81.
10 Sattler R, Charlton MP, Hafner M, et al. Distinct influx pathways, not calcium load, determine neuronal vulnerability to calcium neurotoxicity. J Neurochem, 1998, 71: 2349~2364.
11 Wang G, Ding S, Yunokuchi K. Glutamate-induced increases in intracellular Ca2+ in cultured rat neocortical neurons. Neuroreport, 2002, 13(8): 1051~1056.
12 DeLorenzo RJ, Pal S, Sombati S. Prolonged activation of the N-methyl-D-aspartate receptor-Ca2+ transduction pathway causes spontaneous recurrent epileptiform discharges in hippocampal neurons in culture. Proc Natl Acad Sci USA, 1998, 95(24): 14482~14487.
13 Wang ZM, Sun GQ, Wang ZA, et al. Effects of agmatine on discharges of neurons in rat hippocampal CA1 area. ActaPhysiol Sin, 2003, 55 (6): 617~622.
14 Wang H, Wang ZA, He RR. Adenosine inhibits spontaneous and glutamate-induced discharges of hippocampal CA1 neurons. Acta Physiol Sin, 2000, 52(4): 281~286.
15 Zablocka B, Lukasiuk K, Lazarewicz J W, et al. Modulation of ischemic signal by antagonists of N-methyl-D-aspartate, nitric oxide synthase, and platelet-activating factor in gerbil hippocampus. Neurosci, 1995, Res. 40: 233~240.
16 Bennett SA, Chen J, Pappas BA, et al. Platelet-activating factor receptor expression is associated with neuronal apoptosis in an in vivo model of excitotoxicity. Cell Death Differ, 1998, 5(10): 867~875.
17 Bito H, Nakamura M, Honda Z, et al. Platelet-activating factor (PAF) receptor in rat brain: PAF mobilizes intracellular Ca2+ in hippocampal neurons. Neuron, 1992, 9: 285~294.
18 Braquet P. The ginkgolides: potent platelet-activating factor antagonists isolated from Ginkgo biloba L.: chemistry, pharmacology and clinical applications. Drugs Future, 1987, 12: 643~699.
19 Yue T L, Gleason M M, Hallenbeck J, et al. Characterization of platelet-activating factor-induced elevation of cytosolic free-calcium level in neurohybrid NCB-20 cells. Neuroscience, 1991, 41: 177~185.
20 Choi DW, Rothman SM. The role of glutamate neurotoxicity in hypoxic-ischemic neuronal death. Annu Rev Neurosci, 1990, 13: 171~182.
21 Chen L, Liu CJ, Tang M, et al. Action of beta-amyloid peptide (1-40) on I (HVA) and its modulation by ginkgolide B. Acta Physiol Sin (Chin) 2006, 58:14~20.
22 仰礼真, 张翼, 李进禧. 银杏苦内酯 B 对豚鼠心室肌细胞单动作电位及 L-钙通道的影响. 中国药理学通报 2000; 16(2): 195~198.
23 祁小燕, 张志雄, 崔启启. 银杏苦内酯 B 对缺血豚鼠心室肌动作电位 L-型钙电流和延迟整流钾电流的作用. 中国应用生理学杂志, 2004, 20(1): 24~28.
24 Tohse N. Calcium-sensitive delayed rectifier potassium current in guinea-pig ventricular cells. Am. J. Physiol, 1990, 258: H1200~H1207.
25 Nitta J, Furukawa T, Marumo F, et al. Subcellular mechanism for Ca2+-dependent enhancement of delayed rectifier K+ current in isolated membrane patches of guinea-pig ventricular myocytes. Circ. Res, 1994, 74: 96~104.
1 Corey EJ, Kang MC, Desai M et al. Total synthesis of ginkgolide B. J Am Chem Soc, 1988, 110(2): 649~651.
2 Braquet P, Touqui L, Shen T Y, et al. Perspectives in platelet-activating factor research. Pharmacol Rev, 1987, 39 (2): 97~145.
3 胡波,梅元武,孙圣刚,等. 银杏叶提取物对大鼠缺血再灌注皮质内氨基酸动态平衡的影响. 脑与神经疾病杂志, 2001, 9(1): 1~3.
4 L Hu, Z Chen, X cheng, et al. Chemistry of ginkolides: structure-activity relationship as PAF antagonists. Pure Appl. Chem, 1999, 71(6): 1153~1156.
5 陈维军,谢笔钧,胡慰望,等.银杏萜内酯的化学结构及药理作用研究进展. 中国药学杂志, 1998, 33(9): 516~519.
6 Yoskikaua T, Naito Y, Kondo M. Ginkgo biloba leaf extract review of biological actions and clinical application. Antioxid Redox Signal, 1999, 1(4): 469~480.
7 Oyama Y. Ginkgo biloba extract protects brain neurons oxidative stress induced by hydrogen peroxide. Brain Res, 2000, 712(4): 349~352.
8 Zhu L, Wu J, Liao H, et al. Antagonistic effect s of Glinkgo biloba on glutamate neurotoxicity. Acta pharmacol sin, 1997, 18(4): 344~347.
9 周龙恩,王文杰,白金叶,等. 银杏内酯B对大鼠中性白细胞花生四烯酸代谢酶和细胞内钙水平的影响. 药学学报,2001, 36(2): 92~95.
10 Chen L, Liu CJ, Tang M, et al. Action of beta-amyloid peptide (1-40) on I (HVA) and its modulation by ginkgolide B. Acta Physiol Sin (Chin) 2006, 58:14~20.
11 Iadecola C, Zhang F, Inducible nitric oxide synthase gene expression in brain following cerebral ischemia. J Cereb Blood Flow Metab, 1995, 15: 378~384.
12 Endoh M, Maiese K, Wagner J. Expression of the inducible from nitric oxide synthase by reactive astrocyter after transient global ischemia. Brain Res, 1994, 651: 92~100.
13 Kader A, Frazzini VI, Solomon RA, et al. Nitric oxide production during focal cerebral ischemia in rats. Stroke, 1993, 24:1709~1716.
14 Zhao HW, Li XY. Ginkgolide A, B, and huperzine A inhibit nitric oxide production from rat C6 and human BT325 glioma cells. Acta Pharmacol Sin (Chin), 1999, 20: 941~943.
15 Zhao HW, Li XY. Ginkgolide A, B, and huperzine A inhibit nitric oxide-induced neurotoxicity. Int Immunopharmacol, 2002, 2: 1551~1556.
16 Huang SH, Duke RK, Chebib M, et al. Ginkgolides, diterpene trilactones of Ginkgo biloba, as antagonists at recombinant α1β2γ2L GABAA receptors. Eur J Pharmacol, 2004, 494: 131~138.
17 Kondratskaya EL, Lishko PV, Chatterjee SS, et al. BN52021, a platelet activating factor antagonist, is a selective blockerof glycine-gated chloride channel. Neurochem Int, 2002, 40: 647~653.
18 Kondratskaya EL, Fisyunov AI, Chatterjee SS, et al. Ginkgolide B preferentially blocks chloride channels formed by heteromeric glycine receptors in hippocampal pyramidal neurons of rat. Brain Res Bull, 2004, 63: 309~314.
19 Zablocka B, Lukasiuk K, Lazarewicz J W, et al. Modulation of ischemic signal by antagonists of N-methyl-D-aspartate, nitric oxide synthase, and platelet-activating factor in gerbil hippocampus. J. Neurosci, 1995, Res. 40: 233~240.
20 Bito H, Nakamura M, Honda Z, et al. Platelet-activating factor (PAF) receptor in rat brain: PAF mobilizes intracellular Ca2+ in hippocampal neurons. Neuron, 1992, 9: 285~294.
21 Chandrasekaran K, Mehrabian Z, Spinnewyn B, et al. Neuroprotective effects of bilobalide, a component of Ginkgo biloba extract (EGb 761) in global brain ischemia and in excitotoxicity-induced neuronal death. Pharmacopsychiatry, 2003, Jun; 36 Suppl 1:S89~94.
22 Zhu L, wu J, Liao H, et al. Antagonistic effects of extract from leaves of ginkgo biloba on glutamate neurotoxicity. Zhongguo Yao Li Xue Bao, 1997, Jul; 18(4): 344~347.
23 Marrache AM, Fernand G Jr, Sylvie G, et al. Proinflammatory Gene Induction by Platelet-Activating Factor Mediated Via Its Cognate Nuclear Receptor. The Journal of Immunology, 2002, 169: 6474~6481.
24 Xu J P, Sun L S, Yang X M. Protective effects of Ginkgolide on cerebral ischemia-reperfusion injury in rats. Chin J Integr Tradit West Med Intensive Crit Care, 2003, 10(1): 31~33.
25 Wu X F, Wang Q J, Lou F C. Protective effect of ginkgolides on rat focal brain ischemia. J China Pharm Univ, 2001, 32(2): 141~145.
26 Li J L, Li S Q. Relations between cerebral ischemia and IL-8 and protection of ginkgolide B in tree shrews. Chin J Pathophysiol, 2001, 1(10): 63~67.
27 Wang H, Qiu X Y, Yang L S. Experimental research on effects of ginkgolides made in China on cerebral ischemia injury in rats. Chin J Basic Med Tradit Chin Med, 2002, 8(6): 17~18.
28 Wu X M, Chen H S, Jing S Y, et al. Effects of ginkgolides against injury of neurocytes induced by H2O2 and expression of ginkgolides immediate early genes. Chin J Clin Pharmacol Ther, 2003, 34(4): 401~403.
29 王兴鹏,袁耀宗,徐家裕.银杏苦内酯对急性胰腺炎大鼠的治疗作用.中国药理学通报, 1995, 11(3): 199~201.
30 Diserbo M, Cand F, Ziade M, et al. Stimulation of platelet-activating factor(PAF) receptors increases inositol phosphate production and cytosolic free Ca2+ concentrations in N1E-115 neuroblastoma cells. Cell Calcium, 1995, 17(6): 442~452.
31 聂珍贵, 王文杰. 银杏苦内酯B对血小板活化因子刺激的鼠中性粒细胞功能的影响. 药学学报, 2003, 38(2):98~102.
32 Collins L C, Roberts A M. Effects of platelet-activating factor on arteriolar and venular tone in rat trachea. Microvasc Res, 1997, 53(1):63~72.
33 Xu Y, Tao Y X. Involvement of the NMDA receptor/nitric oxide signal pathway in platelet-activating factor -induced neurotoxicity. Neuroreport, 2004, 15(2): 263~266.
34 李清春, 蒋天盛, 吕心瑞等. 银杏内酯对拟AD模型大鼠空间学习记忆能力和脑内ChAT表达的影响. 中国药理学通报, 2007, 23(4): 497~501.
35 Gao X D, Chen P, Liu J Y, et al. Improving effects of Ginkgolide A on nucleus basalis of Meynert lesion-induced learning and memory deficits in SD rats. Chin Tradit Herb Drugs, 2002, 33(4): 346~348.
2 Ahlemeyer B, Krieglstein J. Neuroprotective effects of Ginkgo biloba extract. Cell. Mol. Life Sci, 2003, 60: 1779~1792.
3 Krieglstein J, Ausmeier F, EI-Abhar H, et al. Neuro protective effects of ginkgo biloba constituents. Eur. J. Pharm. Sci, 1995, 3: 39~49.
4 Kecskemeti V, Balogh I. Cardiac ultrastructural effect of the platelet-activating factor and its antagonist BN 52021. Exp Toxicol Pathol, 1995: 463~470.
5 Li S, Meng Q, Zhang L. Experimental therapy of a platelet-activating factor antagonist (Ginkgolide B) on photochemically induced thrombotic cerebral ischaemia in tree shrews. Clin. Exp. Pharmacol. Physiol, 1999, 26: 824~825.
6 Ahlemeyer B, Mowes A, Krieglstein J. Inhibition of serum deprivation- and staurosporine-induced neuronal apoptosis by Ginkgo biloba extract and some of its constituents. Eur. J. Pharmacol, 1999, 367: 423~430.
7 Kondratskaya E L, Pankratov Y V, Lalo U V, et al. Inhibition of hippocampal LTP by ginkgolide B is mediated by its blocking action on PAF rather than glycine receptors.Neurochem, 2004, Int. 44: 171~177.
8 Chandrasekaran K, Mehrabian Z, Spinnewyn B, et al. Bilobalide, a component of the Ginkgo biloba extract (EGb761) protects against neuronal death in global brain ischemia and glutamate-induced excitotoxicity. Cell Mol Biol (Noisylegrand), 2002, 48(6): 663~669.
9 Nogami K, Hirashima Y, Endo S, Takaku A. Involvement of platelet-activating factor (PAF) in glutamate neurotoxicity in rat neuronal cultures. Brain Res, 1997, Apr 18; 754(1-2): 72~78.
10 Limbrick DD Jr, Sombati S, DeLorenzo RJ. Calcium influx constitutes the ionic basis for the maintenance of glutamate-induced extended neuronal depolarization associated with hippocampal neuronal death. Cell Calcium, 2003, Feb; 33(2): 69~81.
11 Sattler R, Charlton MP, Hafner M, et al. Distinct influx pathways, not calcium load, determine neuronal vulnerability to calcium neurotoxicity. J Neurochem, 1998, 71: 2349~2364.
12 Wang G, Ding S, Yunokuchi K. Glutamate-induced increases in intracellular Ca2+ in cultured rat neocortical neurons. Neuroreport, 2002, 13(8): 1051~1056.
13 DeLorenzo R J, Pal S, Sombati S. Prolonged activation of the N-methyl-D-aspartate receptor-Ca2+ transduction pathway causes spontaneous recurrent epileptiform discharges in hippocampal neurons in culture. Proc NatlAcad Sci USA, 1998, 95(24): 14482~14487.
14 Wang Z M, Sun G Q, Wang Z A, et al. Effects of agmatine on discharges of neurons in rat hippocampal CA1 area. Acta Physiol Sin, 2003, 55 (6): 617~622.
15 Wang H, Wang ZA, He RR. Adenosine inhibits spontaneous and glutamate-induced discharges of hippocampal CA1 neurons. Acta Physiol Sin, 2000, 52(4): 281~286.
16 Zablocka B, Lukasiuk K, Lazarewicz J W, et al. Modulation of ischemic signal by antagonists of N-methyl-D-aspartate, nitric oxide synthase, and platelet-activating factor in gerbil hippocampus. J. Neurosci, 1995, Res. 40: 233~240.
17 Kuribara H, Weintraub ST, Yoshihama T, et al. An anxiolytic-like effect of Ginkgo biloba extract and its constituent, ginkgolide-A, in mice. J Natural Products 2003, 66: 1333~1337.
18 Bennett SA, Chen J, Pappas BA, et al. Platelet-activating actor receptor expression is associated with neuronal apoptosis in an in vivo model of excitotoxicity. Cell Death Differ, 1998, 5(10): 867~875.
19 Bito H, Nakamura M, Honda Z, et al. Platelet-activating factor (PAF) receptor in rat brain: PAF mobilizes intracellular Ca2+ in hippocampal neurons. Neuron, 1992, 9: 285~294.
20 Braquet P. The ginkgolides: potent platelet-activating factorantagonists isolated from Ginkgo biloba L.: chemistry, pharmacology and clinical applications. Drugs Future, 1987, 12: 643~699.
21 Yue T L, Gleason M M, Hallenbeck J, et al. Characterization of platelet-activating factor-induced elevation of cytosolic free-calcium level in neurohybrid NCB-20 cells. Neuroscience, 1991, 41: 177~185.
22 Choi DW, Rothman SM. The role of glutamate neurotoxicity in hypoxic-ischemic neuronal death. Annu Rev Neurosci, 1990, 13: 171~182.
23 Chen L, Liu CJ, Tang M, et al. Action of beta-amyloid peptide (1-40) on I (HVA) and its modulation by ginkgolide B. Acta Physiol Sin (Chin), 2006, 58:14~20.
24 仰礼真, 张翼, 李进禧. 银杏苦内酯 B 对豚鼠心室肌细胞单动作电位及 L-钙通道的影响. 中国药理学通报, 2000, 16(2): 195~198.
25 祁小燕, 张志雄, 崔启启. 银杏苦内酯 B 对缺血豚鼠心室肌动作电位 L-型钙电流和延迟整流钾电流的作用. 中国应用生理学杂志, 2004, 20(1): 24~28.
26 Rudy B. Diversity and ubiquity of K+ channels. Neuroscience, 1988, 25(3): 729~749.
27 Tohse N. Calcium-sensitive delayed rectifier potassium current in guinea-pig ventricular cells. Am. J. Physiol, 1990, 258: H1200~H1207.
28 Nitta J, Furukawa T, Marumo F, et al. Subcellular mechanism for Ca2+-dependent enhancement of delayedrectifier K+ current in isolated membrane patches of guinea-pig ventricular myocytes. Circ. Res, 1994, 74: 96~104.
1 Maclennan K M, Darlington C L, Smith P F. The CNS effects of Ginkgo biloba extracts and ginkgolide B. Prog. Neurobiol., 2002, 67: 235~257.
2 Ahlemeyer B, Krieglstein J. Neuroprotective effects of Ginkgo biloba extract. Cell. Mol. Life Sci, 2003, 60: 1779~1792.
3 Kecskemeti V, Balogh I. Cardiac ultrastructural effect of the platelet-activating factor and its antagonist BN 52021. Exp Toxicol Pathol, 1995: 463~470.
4 Li S, Meng Q, Zhang L. Experimental therapy of a platelet-activating factor antagonist (Ginkgolide B) on photochemically induced thrombotic cerebral ischaemia in tree shrews. Clin. Exp. Pharmacol. Physiol, 1999, 26: 824~825.
5 Ahlemeyer B, Mowes A, Krieglstein J. Inhibition of serum deprivation- and staurosporine-induced neuronal apoptosis by Ginkgo biloba extract and some of its constituents. Eur. J. Pharmacol, 1999, 367: 423~430.
6 Kondratskaya E L, Pankratov Y V, Lalo U V, et al. Inhibition of hippocampal LTP by ginkgolide B is mediated by its blocking action on PAF rather than glycine receptors. Neurochem, 2004, Int. 44: 171~177.
7 Chandrasekaran K, Mehrabian Z, Spinnewyn B, et al. Bilobalide, a component of the Ginkgo biloba extract(EGb761) protects against neuronal death in global brain ischemia and glutamate-induced excitotoxicity. Cell Mol Biol (Noisylegrand), 2002, 48(6): 663~669.
8 Nogami K, Hirashima Y, Endo S, Takaku A. Involvement of platelet-activating factor (PAF) in glutamate neurotoxicity in rat neuronal cultures. Brain Res, 1997, Apr 18; 754(1-2): 72~78.
9 Limbrick DD Jr, Sombati S, DeLorenzo RJ. Calcium influx constitutes the ionic basis for the maintenance of glutamate-induced extended neuronal depolarization associated with hippocampal neuronal death. Cell Calcium, 2003, Feb; 33(2): 69~81.
10 Sattler R, Charlton MP, Hafner M, et al. Distinct influx pathways, not calcium load, determine neuronal vulnerability to calcium neurotoxicity. J Neurochem, 1998, 71: 2349~2364.
11 Wang G, Ding S, Yunokuchi K. Glutamate-induced increases in intracellular Ca2+ in cultured rat neocortical neurons. Neuroreport, 2002, 13(8): 1051~1056.
12 DeLorenzo RJ, Pal S, Sombati S. Prolonged activation of the N-methyl-D-aspartate receptor-Ca2+ transduction pathway causes spontaneous recurrent epileptiform discharges in hippocampal neurons in culture. Proc Natl Acad Sci USA, 1998, 95(24): 14482~14487.
13 Wang ZM, Sun GQ, Wang ZA, et al. Effects of agmatine on discharges of neurons in rat hippocampal CA1 area. ActaPhysiol Sin, 2003, 55 (6): 617~622.
14 Wang H, Wang ZA, He RR. Adenosine inhibits spontaneous and glutamate-induced discharges of hippocampal CA1 neurons. Acta Physiol Sin, 2000, 52(4): 281~286.
15 Zablocka B, Lukasiuk K, Lazarewicz J W, et al. Modulation of ischemic signal by antagonists of N-methyl-D-aspartate, nitric oxide synthase, and platelet-activating factor in gerbil hippocampus. Neurosci, 1995, Res. 40: 233~240.
16 Bennett SA, Chen J, Pappas BA, et al. Platelet-activating factor receptor expression is associated with neuronal apoptosis in an in vivo model of excitotoxicity. Cell Death Differ, 1998, 5(10): 867~875.
17 Bito H, Nakamura M, Honda Z, et al. Platelet-activating factor (PAF) receptor in rat brain: PAF mobilizes intracellular Ca2+ in hippocampal neurons. Neuron, 1992, 9: 285~294.
18 Braquet P. The ginkgolides: potent platelet-activating factor antagonists isolated from Ginkgo biloba L.: chemistry, pharmacology and clinical applications. Drugs Future, 1987, 12: 643~699.
19 Yue T L, Gleason M M, Hallenbeck J, et al. Characterization of platelet-activating factor-induced elevation of cytosolic free-calcium level in neurohybrid NCB-20 cells. Neuroscience, 1991, 41: 177~185.
20 Choi DW, Rothman SM. The role of glutamate neurotoxicity in hypoxic-ischemic neuronal death. Annu Rev Neurosci, 1990, 13: 171~182.
21 Chen L, Liu CJ, Tang M, et al. Action of beta-amyloid peptide (1-40) on I (HVA) and its modulation by ginkgolide B. Acta Physiol Sin (Chin) 2006, 58:14~20.
22 仰礼真, 张翼, 李进禧. 银杏苦内酯 B 对豚鼠心室肌细胞单动作电位及 L-钙通道的影响. 中国药理学通报 2000; 16(2): 195~198.
23 祁小燕, 张志雄, 崔启启. 银杏苦内酯 B 对缺血豚鼠心室肌动作电位 L-型钙电流和延迟整流钾电流的作用. 中国应用生理学杂志, 2004, 20(1): 24~28.
24 Tohse N. Calcium-sensitive delayed rectifier potassium current in guinea-pig ventricular cells. Am. J. Physiol, 1990, 258: H1200~H1207.
25 Nitta J, Furukawa T, Marumo F, et al. Subcellular mechanism for Ca2+-dependent enhancement of delayed rectifier K+ current in isolated membrane patches of guinea-pig ventricular myocytes. Circ. Res, 1994, 74: 96~104.
1 Corey EJ, Kang MC, Desai M et al. Total synthesis of ginkgolide B. J Am Chem Soc, 1988, 110(2): 649~651.
2 Braquet P, Touqui L, Shen T Y, et al. Perspectives in platelet-activating factor research. Pharmacol Rev, 1987, 39 (2): 97~145.
3 胡波,梅元武,孙圣刚,等. 银杏叶提取物对大鼠缺血再灌注皮质内氨基酸动态平衡的影响. 脑与神经疾病杂志, 2001, 9(1): 1~3.
4 L Hu, Z Chen, X cheng, et al. Chemistry of ginkolides: structure-activity relationship as PAF antagonists. Pure Appl. Chem, 1999, 71(6): 1153~1156.
5 陈维军,谢笔钧,胡慰望,等.银杏萜内酯的化学结构及药理作用研究进展. 中国药学杂志, 1998, 33(9): 516~519.
6 Yoskikaua T, Naito Y, Kondo M. Ginkgo biloba leaf extract review of biological actions and clinical application. Antioxid Redox Signal, 1999, 1(4): 469~480.
7 Oyama Y. Ginkgo biloba extract protects brain neurons oxidative stress induced by hydrogen peroxide. Brain Res, 2000, 712(4): 349~352.
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