银杏叶提取物对局灶性脑缺血模型大鼠的保护作用

目的:探讨银杏叶提取物(EGB)对局灶性脑缺血模型大鼠的保护作用.方法:采用三氯化铁局部贴敷大脑中动脉,制成局灶性脑缺血大鼠模型,通过对模型大鼠神经症状、脑梗塞范围以及血液流变学指标的测定,以阐明银杏叶提取物天保宁片对模型大鼠的保护作用.结果:EGB可以明显改善模型大鼠的神经症状,缩小其脑梗塞范围,并可降低其在高切(200S-1)、中切(30S-1)、低切(5S-1、1S-1)状态时的全血黏度.但在本实验条件下,未观察到药物对模型动物血浆黏度的影响.结论:降低MCAT大鼠的全血黏度,抑制血栓形成,可能是EGB抑制脑缺血损伤的作用机制之一.     

银杏叶提取物对大鼠局灶性脑缺血后炎症反应的影响(英文)

目的 :探讨银杏叶提取物 (GbE)对缺血 再灌注后脑组织炎性细胞浸润及白细胞介素 1 β(IL 1 β)表达的影响。方法 :2 3 0～ 2 70 g雄性SD大鼠 3 2只 ,随机分成 4组 (n=8) :假手术组、模型对照组、2个不同剂量的银杏叶提取物治疗组 (7.5mg·kg-1或 1 5mg·kg-1)。大脑中动脉线栓法建立局灶性脑缺血 再灌注模型 ,经 2h缺血和 2 2h再灌注后 ,用髓过氧化物酶 (MPO)定量测定法评价缺血后脑组织中中性粒细胞浸润程度 ,逆转录 聚合酶链反应(RT PCR)法以检测缺血脑组织内IL 1 βmRNA表达情况。结果 :脑缺血 2h再灌注 2 2h后 ,大鼠脑组织内MPO活性和IL 1 βmRNA表达较假手术组明显升高 (P <0 .0 5 ) ;与模型组相比 ,GbE 7.5mg·kg-1和 1 5mg·kg-1能明显降低脑组织MPO活性 ,抑制IL 1 βmRNA的过度表达 (P <0 .0 5 ) ,但在此剂量范围内无明显的剂量依赖性。结论 :GbE可抑制缺血后中性粒细胞介导的炎症反应 ,此效应可能是其神经保护作用机制之一。     

银杏叶提取物对大鼠美托洛尔药动学的影响

目的：探讨银杏叶提取物对大鼠美托洛尔药动学的影响。方法：将大鼠随机分为美托洛尔组和美托洛尔联合银杏叶提取物组,美托洛尔组口服给予美托洛尔40 mg·kg^-1,美托洛尔联合银杏叶提取物组口服给予银杏叶片28.8 mg·kg^-1（按黄酮醇苷量）和美托洛尔40 mg·kg^-1。给药后2,5,10,20,40,60,90,120,240,360,480,720 min股动脉采血,液相色谱串联质谱（LC-MS/MS）测定美托洛尔及代谢物血药浓度。结果：美托洛尔组联合灌胃给予银杏叶提取物与美托洛尔后,美托洛尔K_a和AUC_0-t显著降低（P<0.05）,t_max显著增加（P<0.05）,美托洛尔代谢产物O-去甲基美托洛尔和α-羟基化美托洛尔AUC_0-t显著增加（P<0.05）,而CL显著减小（P<0.05）。结论：银杏叶提取物能够显著降低美托洛尔的血药浓度,抑制其代谢物O-去甲基美托洛尔和α-羟基化美托洛尔的清除。     

银杏叶提取物与阿托伐他汀联合应用对大鼠CYP450蛋白水平的影响

目的观察银杏叶提取物与阿托伐他汀联合应用对大鼠CYP450蛋白水平的影响。方法将24只SD大鼠随机分为生理盐水(NS)组、阿托伐他汀(AV-T)组、银杏叶提取物(GBE)组、GBE联合AV-T组,每组6只。NS组用生理盐水1 m L/(kg·d)灌胃,AV-T组1 mg/(kg·d)AV-T灌胃,GBE组50 mg/(kg·d)GBE灌胃,GBE联合AV-T组GBE 50 mg/(kg·d)联合AV-T 1 mg/(kg·d)灌胃。6周后,取大鼠肝脏,制备肝微粒体,CO-还原差示光谱法检测肝微粒体CYP450酶含量;Western blot检测肝脏组织中CYP3A4和CYP2C9蛋白的表达。结果与NS组及AV-T组相比,GBE组、GBE+AV-T组CYP450酶含量明显升高(P<0.01)。与NS组及AV-T组相比,GBE组、GBE+AV-T组CYP3A4的表达显著降低(P<0.01,P<0.05);GBE组、GBE+AV-T组CYP2C9的表达显著上升(P均<0.01)。结论 GBE与AV-T联合应用后,使大鼠肝微粒体CYP450含量增高,且影响CYP3A4和CYP2C9的蛋白表达,由此可能会影响AV-T的疗效。     

Effect of methylguanidine in carrageenan-induced acute inflammation in the rats

In vitro and in vivo studies have demonstrated that methylguanidine, an inhibitor of nitric oxide synthase (NOS), is also able to reduce tumour necrosis factor-alpha (TNF-alpha) release. In the present study, we evaluated the anti-inflammatory potential of methylguanidine treatment in two models of acute inflammation (carrageenan-induced paw edema and pleurisy) where oxyradical, nitric oxide (NO) and prostaglandins play a crucial role in the inflammatory processes. Our data show that methylguanidine, given intraperitoneally at the dose of 30 mg/kg, inhibits the inflammatory response reducing significantly (P<0.05) paw swelling, pleural exudates formation, mononuclear cell infiltration and histological injury. Furthermore, our data suggests that there is a significant (P<0.05) reduction in the activity and expression both of the inducible NOS (iNOS) and of cyclooxygenase-2 in lung tissue of pleurisy model. Methylguanidine is also able to reduce the appearance of nitrotyrosine and of the nuclear enzyme poly(adenosine diphosphate [ADP]-ribose) synthase immunoreactivity in the inflamed lung tissues. Treatment with aminoguanidine, the reference drug, significantly reduced all the evaluated pro-inflammatory parameters in carrageenan-treated rats. Taken together, the present results demonstrate that methylguanidine exerts potent anti-inflammatory effects that could be, in part, related to an inhibition of the expression/activity of the iNOS and cyclooxygenase-2 and, another part, may be related to a reduction of TNF-alpha release.     

Effect of Ginkgo biloba extract on microsomal enzyme induction

Twenty-four healthy volunteers were divided in three groups who were randomly assigned different treatments for 13 days: group I received 400 mg/day of a defined Ginkgo biloba extract (GBE), group II 300 mg/day of phenytoin and group III a placebo. The elimination half-life of antipyrine was measured with a high performance liquid chromatographic technique initially and on the last day of the administration of the treatments. The results show that the half-life of antipyrine was not affected by GBE and placebo treatments, whereas it was significantly decreased (p less than 0.05) frm 12.2 to 6.8 h after phenytoin control treatment. This study demonstrates that GBE has no effect on the hepatic microsomal drug oxidation system.     

Protective effect of melatonin in carrageenan-induced acute local inflammation.

The aim of the present study was to investigate the protective effect of the pineal hormone melatonin in a model of acute local inflammation (carrageenan-induced paw oedema). Inflammation was assessed by measurement of nitric oxide (NO), Malondialdehyde (MDA) and glutathione levels in the paw tissue in rats. The intraplantar injection of carrageenan elicited an inflammatory response that was characterised by a time-dependent increase in paw oedema, increased level of nitrite/nitrate and MDA, a lipid peroxidation product and decreased glutathione levels in the paw tissue. The maximal increase in paw volume was observed at 4h after administration (maximal in paw volume 160+/-3.34 ml). In addition, NO level and MDA were markedly increased in the carrageenan-treated paw (59.96+/-6.58 and 19.33+/-3.35 micromol g(-1), respectively), versus in the control paw glutathione level decreased in paw tissue (3.24+/-0.24 micromol g(-1)). However, carrageenan-induced paw oedema was significantly reduced in a dose-dependent manner by treatment with melatonin (given at 5 and 10 mg kg(-1)) at 1, 2, 3, 4, 5 and 6h after injection of carrageenan. Melatonin treatment also caused a significant reduction of the NO and MDA levels, while increasing glutathione level in the paw tissue. Our findings support the view that melatonin exerts anti-inflammatory effects. Part of these anti-inflammatory effect may be related to an inhibition of the NO and MDA production, while another part may be related to increase of the glutathione level in the paw tissue.     

银杏叶提取物对大鼠实验性结肠炎肿瘤坏死因子-α表达的影响

目的观察银杏叶提取物对三硝基苯磺酸灌肠诱导大鼠实验性结肠炎肿瘤坏死因子-α(TNF-α)的影响及其作用机制。方法大鼠随机分为正常对照组、三硝基苯磺酸模型组、阳性药物对照组、EGB组4组。用三硝基苯磺酸灌肠诱导大鼠实验性结肠炎,评估结肠组织大体形态和组织学评分;生化法检测大鼠肠组织谷胱苷肽过氧化物酶(GSH-Px)活性及一氧化氮(NO)含量;免疫组化检测肠组织TNF-α,核因子-κBp65(NF-κBp65)蛋白表达。逆转录聚合酶链反应(RT-PCR)检测肠组织诱生型一氧化氮合酶(iNOS)表达。结果EGB组大体形态和组织学评分较模型组明显下降,GSH-Px活性明显增高,NO含量明显减少,结肠黏膜TNF-α,NF-KBp65和iNOS表达明显降低。结论EGB可能通过抑制TNF-α的表达和NF-κBp65及iNOS的激活从而抑制炎症级联来保护TNBS诱导的实验性结肠炎。     

磁共振波谱分析银杏叶提取物对大鼠急性脑缺血的影响

目的:研究银杏叶提取物(GbE)对大鼠急性脑缺血的干预影响。方法:大鼠随机分成假手术组、缺血组、预防组和治疗组。用磁共振波谱分析动态观测脑缺血后48小时内生化代谢的变化及GbE(100mg/kg,ip,qd)的干预影响。结果:(1)大鼠急性脑缺血后90min梗塞区出现乳酸峰,并随着时间的延长而持续上升。预防组乳酸峰轻度升高(P<0.01,n=6);治疗组较预防组升高(P<0.05,n=6)。(2)缺血组在缺血后4h内N-乙酰基天门冬氨酸下降(P<0.05,n=6)并持续降低(P<0.01,n=6);治疗组及预防组24h后N-乙酰基天门冬氨酸略下降(P<0.05,m=6)。(3)缺血后24h缺血组及治疗组胆碱略升高(P<0.05,n=6),肌酸略降低(P<0.05,n=6);预防组在48h后才发生上述变化。结论:GbE对脑缺血具有预防及治疗作用,预防给药效果较佳。     

Brain monoamines during carrageenan-induced acute paw inflammation in rats

Paw inflammation was induced in rats by sub-plantar administration of carrageenan. Significant inflammatory oedema was observed 1 h later and the peak effect was noted between 3-4 h. The oedema was markedly reduced after 12-24 h. Steady state levels of whole brain and hypothalamic monoamines were estimated spectrofluorometrically during the course of the carrageenan-induced paw inflammation. In addition, the rate of accumulation of the brain 5-hydroxytryptamine (5-HT) and noradrenaline (NA) was assessed in clorgyline-pretreated rats during the inflammation. The whole brain and hypothalamic concentrations of 5-HT and NA were augmented during the early phase of the inflammation, but fell below control values when peak inflammation was achieved. Thereafter, the monoamine levels tended to normalize by 24 h when the inflammation had virtually subsided. On the contrary, whole brain and hypothalamic dopamine levels remained largely unaffected. The rate of accumulation of brain 5-HT and NA were enhanced during carrageenan inflammation, indicating that the turnover of these monoamines is augmented during the inflammatory process. The results suggest that acute peripheral inflammation may significantly affect central 5-HT and noradrenergic activity in rats.     

Ginkgo biloba extract markedly induces pentoxyresorufin O-dealkylase activity in rats

We examined the effect of Ginkgo biloba extract (GBE) on hepatic drug-metabolizing enzymes, particularly cytochrome P450 (CYP), in rats. Rats were fed a GBE-containing diet or received GBE by intragastric gavage. The concentration of CYP and activity of various CYP enzymes in the liver were increased in a dose- and time-dependent manner. Significant increases in the concentration and activities of CYP enzymes were detected on day 1 of feeding of a 0.5% GBE diet and after administration of 10 mg GBE/kg body weight for 5 days by intragastric gavage. Among the CYP enzymes, the activity of pentoxyresorufin O-dealkylase (PROD), a CYP2B enzyme, was especially markedly increased. The induction of CYP2B enzyme by GBE was confirmed by Western blot analysis. Addition of GBE to a CYP assay system in vitro caused concentration-dependent inhibition of various CYP enzyme activities. The inhibition was more marked for the microsomal enzymes from GBE-treated rats than for those from control rats and more marked against PROD activity among the CYP enzymes tested. When the inhibition of various CYP enzymes activities by GBE in vitro was compared, no marked difference was observed between rat and human hepatic microsomal enzymes. These results indicate that excess intake of GBE induces CYP enzymes, particularly PROD, and may modify the efficacy of drugs taken simultaneously.     

Effects of Ginkgo biloba extract feeding on salt-induced hypertensive Dahl rats

We previously demonstrated that Ginkgo biloba extract (GBE) produced vasodilation via the nitric oxide synthesis and release by increasing the intracellular calcium level in vascular endothelial cells of rats. The present study aimed to clarify the effects of dietary administration of GBE on the blood pressure and vascular tone of hypertensive Dahl salt-sensitive (Dahl) rats in order to evaluate its therapeutic actions and availability. Dahl rats were fed an 8.0% NaCl diet or an 8.0% NaCl plus 0.5% GBE diet for 24 d. The feeding of GBE did not change the heart rate, but significantly decreased systolic blood pressure. After 24 days' administration, the effects of GBE on the atria and aorta isolated from Dahl rats were examined. The GBE-containing diet did not affect the negative and positive actions of isolated atria that were produced by acetylcholine and isoproterenol, respectively. In the aortic preparations, the relaxation in response to acetylcholine was significantly potentiated by a GBE-containing diet. Sodium nitroprusside-induced relaxation was unchanged by GBE-containing diet. These results demonstrated that GBE reduced salt-related elevation of blood pressure and restored the impaired acetylcholine-induced vasodilation in aortic segments.     

Effect of pre-existing inflammation on carrageenan-induced paw oedema in rats

Twenty-four hours after injection of carrageenan into one hind paw, injection of the same amount into the contralateral paw produced a significantly attenuated inflammatory response. However, when the second injection was given 7 days later, the inflammation induced in the contralateral paw was comparable with the initial response to carrageenan. A time-course study of carrageenan-induced inflammation in rats showed that significant oedema persisted 24 h after carrageenan administration and complete recovery was achieved in 7 days. The attenuated inflammatory response in the contralateral paw after 24 h was antagonized by bilateral adrenalectomy and chemical sympathectomy induced by 6-hydroxydopamine. Carrageenan-induced paw oedema was also significantly less in rats with subacute inflammation induced by the croton oil granuloma pouch technique. This attenuated response was antagonized by pretreatment of the rats with metyrapone, an inhibitor of adrenocorticoid synthesis, and by 6-hydroxydopamine. It is likely that the pre-existing acute or subacute inflammation attenuates the inflammatory response of carrageenan, by acting as a stressor, inducing activation of the sympatho-adrenal system.     

银杏叶提取物对急性脑梗死大鼠凋亡基因的影响

目的:探讨了银杏叶提取物对急性脑梗死大鼠凋亡基因的影响。方法:运用线栓法构建66只大鼠急性脑梗死模型,并随机分为假手术组、模型组和治疗组,每组22只,其中假手术组只分离血管不插线。治疗组大鼠给予尾静脉注射银杏叶提取物2.5 mg·kg^-1,假手术组和模型组均给予尾静脉注射等体积的PBS溶液。治疗72 h后处死大鼠,取脑组织,采用实时荧光定量PCR分析3组大鼠脑组织中Bcl-2、Bax和caspase-3 mRNA水平;采用免疫组化法测定脑组织凋亡基因相关蛋白Bcl-2、Bax和caspase-3的表达;采用TUNEL染色法分析脑细胞凋亡指数。并分析10 d内3组大鼠的生存曲线。结果:与假手术组比较,建模后模型组和治疗组大鼠脑组织中Bcl-2 mRNA Bax和caspase-3 mRNA和蛋白质水平显著升高(P<0.05)。经治疗后,治疗组大鼠脑组织中caspase-3和Bax mRNA和蛋白质水平较模型组明显下降(P<0.05),而Bcl-2 mRNA和蛋白质水平较模型组显著升高(P<0.05)。建模后,模型组和治疗组大鼠脑组织细胞凋亡指数较假手术组显著升高加(P<0.05),治疗组大鼠治疗后脑组织中细胞凋亡指数较模型组显著下调(P<0.05)。与假手术组比较,模型组和治疗组大鼠10 d内存活率明显下降,但治疗组存活率明显高于模型组(P<0.05)。结论:银杏叶提取物能够有效调节急性脑梗死大鼠凋亡基因及其相关蛋白的表达,从而降低脑组织细胞的凋亡,对脑组织具有一定的保护作用。     

Effect of carrageenan-induced acute inflammation on corticosterone levels in mice

Changes in corticosterone levels in plasma and inflammatory exudate were studied in the 6-day-old air pouch of mice. The pouch inflammation in the test group was induced by the injection of carrageenan prepared in physiological saline while the control received only the physiological saline. The results show that exudate and plasma of both groups showed a rapid rise in corticosterone as measured after 30 min and this early rise was probably due to the resulting effect of the ether used during the injection of irritant or vehicle. In contrast, corticosterone levels in the inflammatory exudate of the test group increased with time, reaching a peak at 24 hours after the carrageenan injection. The increased corticosterone levels in the inflammatory exudate appeared to be closely correlated with the increased exudate cell accumulation. This suggests that the increased accumulation of exudate corticosterone in the pouch might play an important role at the inflammatory site by modulating intensity of the inflammatory reactivity caused by the irritant.     

Hyperbaric oxygen treatment reduces carrageenan-induced acute inflammation in rats.

The present study was designed to assess the anti-inflammatory activity of hyperbaric oxygen treatment by comparing it with that of diclofenac, a nonsteroidal anti-inflammatory drug, and also to investigate whether hyperbaric oxygen treatment enhances the anti-inflammatory effect of diclofenac in carrageenan-induced paw edema which is commonly employed as an acute inflammation model in rats. Hyperbaric oxygen treatment and diclofenac (20 mg/kg) markedly reduced the carrageenan-induced paw edema in rats. In other words, they displayed anti-inflammatory activity. On the other hand, hyperbaric oxygen treatment did not consistently modify the anti-inflammatory effect of diclofenac in this model.     

Ginkgo biloba extract ameliorates ischemia reperfusion-induced renal injury in rats.

There is increasing evidence to suggest that reactive oxygen metabolites (ROMs) play a role in the pathogenesis of ischemia/reperfusion injury (I/R) in the kidney. This study was designed to determine the possible protective effect of Ginkgo biloba extract (EGb) on renal ischemia/reperfusion (I/R) injury. Wistar albino rats were unilaterally nephrectomized, and 15 days later they were subjected to 45 min of renal pedicle occlusion followed by 6 h of reperfusion. Ginkgo biloba extract (EGb) (50 mg kg(-1) day(-1)) or saline was administered twice, 15 min prior to ischemia and immediately before the reperfusion period. At the end of the treatment period, all rats were decapitated. Kidney samples were taken for histological examination or determination of the renal malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity and collagen content. Production of reactive oxidants was monitored by chemiluminescence (CL) assay. Creatinine and urea concentrations in blood were measured for the evaluation of renal function. Tumor necrosis factor-alpha (TNF-alpha) and lactate dehydrogenase (LDH) were also assayed in serum samples. Ischemia/reperfusion caused a significant decrease in GSH level, which was accompanied with significant increases in MDA level, MPO activity and collagen content of kidney tissues. Similarly, serum BUN and creatinine levels, as well as LDH and TNF-alpha, were elevated in the I/R group as compared to control group. On the other hand, EGb treatment reversed all these biochemical indices, as well as histopathological alterations, which were induced by I/R. The findings imply that ROMs play a causal role in I/R-induced renal injury and EGb exerts renoprotective effects probably by the radical scavenging and antioxidant activities.     

Induction of propranolol metabolism by Ginkgo biloba extract EGb 761 in rats

Ginkgo biloba is one of the most popular herbal medicines in the world, due to its purported pharmacological effects, including memory-enhancing, cognition-improving, and antiplatelet effects. When used in the elderly, Ginkgo has a high potential for interactions with cardiovascular drugs. This study aimed to investigate the effects of the standard Ginkgo biloba extract (EGB 761) treatment on the pharmacokinetics of propranolol and its metabolism to form N-desisopropylpropranolol (NDP) in rats. We also examined the activity and expression of cytochrome P450 (CYP) 1A and other CYPs in rats treated with EGb 761 at 10 and 100 mg/kg/day for 10 days. A single oral dose of propranolol (10 mg/kg) was administered on day 11 and the concentrations of both propranolol and NDP were determined using validated liquid chromatography-mass spectrometry (LC-MS) methods. The levels of mRNA and protein of various CYPs were determined by RT-PCR and Western blotting analysis, respectively. Pretreatment of EGb 761 at 100 mg/kg, but not 10 mg/kg, for 10 days significantly reduced the area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) of propranolol, whereas those values of NDP were significantly increased. CYP1A1, 1A2, 2B1/2, and 3A1 activities and gene expression in the rat liver were significantly increased in a dose-dependent manner by pretreatment with EGb 761. The ex-vivo formation of NDP in liver microsomes from rats pretreated with EGb 761 was markedly enhanced. The formation of NDP from propranolol in liver microsomes was significantly inhibited by alpha-naphthoflavone (ANF, a selective CYP1A2 inhibitor), but not by quinidine (a CYP2D inhibitor). These results indicated that EGb 761 pretreatment decreased the plasma concentrations of propranolol by accelerated conversion of parental drug to NDP due to induction of CYP1A2. EGb 761 pretreatment also significantly induced CYP2B1/2 and CYP3A1, suggesting potential interactions with substrate drugs for these two enzymes. Further study is needed to explore the potential for gingko-drug interactions and the clinical impact.     

银杏叶提取物的研究进展

银杏是最古老的中生代植物,很早就被用作中药,其提取物近年来弓l起国际高度重视。银杏叶中含有黄酮和二萜内酯等化学成分,具有抗氧化、抗衰老等药理作用。综述银杏叶提取物的研发状况、化学成分和药理作用。