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Paradoxical effects of ginkgolide b on cardiomyocyte contractile function in normal and high-glucose environments

Acta Pharmacologica Sinica 2006年第5期27卷 536-542页

作者： JihyeKIM CindyXFANG Center for Cardiovascular Research and Alternative Medicine Division of Pharmaceutical Sciences Laramie USA University of Wyoming WY 82071

Aim:Ginkgo biloba extract is a natural product used widely for cerebral andcardiovascular *** is mainly composed of terpene lactones (ginkgolide Aand b) and flavone glycosides (eg quercetin and kaempferol).To better under-stand the cardiac electromechanical action of Ginkgo biloba extract in normal anddiabetic states,this study was designed to examine the effect of ginkgolide b oncardiomyocyte contractile function under normal and high-glucose ***:Isolated adult rat ventricular myocytes were cultured for 6h in a serum-free medium containing either normal (NG;5.5mmol/L) or high (HG;25.5mmol/L)glucose with or without ginkgolide b (0.5-2.0μg/mL).Mechanical propertieswere evaluated using the IonOptix MyoCam *** properties ana-lyzed included peak shortening (PS),maximal velocity of shortening/relengthening(±dl/dt),time-to-PS (TPS) and time-to-90% relengthening (TR90).Levels of essen-tial Ca2+regulatory proteins sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2a),phospholamban (PLb) and Na~+-Ca2+exchanger (NCX) were assessed by ***:ginkgolide b nullified HG-induced prolongation in ***,ginkgolide b depressed PS,±dl/dt and shortened TPS in NG and *** b also prolonged TR90in NG *** blot analysis re-vealed that HG upregulated SERCA2a and downregulated PLb expression with-out affecting that of *** b disrupted the NG-HG response pattern inSERCA2a and NCX without affecting that of ***:ginkgolide baffects cardiomyocyte contractile function under NG or HG environments in aparadoxical manner,which may be attributed to uneven action on Ca2+regulatoryproteins under NG and HG conditions.

关键词： ginkgolide b cardiomyocytes contraction Ca2+ regulatory protein

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Anti-atherosclerotic effects and molecular targets of ginkgolide b from Ginkgo biloba

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Acta Pharmaceutica Sinica b 2024年第1期14卷 1-19页

作者： Weile Ye Jiaojiao Wang Peter JLittle Jiami Zou Zhihua Zheng Jing Lu Yanjun Yin Hao Liu Dongmei Zhang Peiqing Liu Suowen Xu Wencai Ye Zhiping Liu International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education(MOE)of China Jinan UniversityGuangzhou 510632China Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research College of PharmacyJinan UniversityGuangzhou 510632China State Key Laboratory of bioactive Molecules and Druggability Assessment Jinan UniversityGuangzhou 510632China Pharmacy Australia Centre of Excellence School of PharmacyUniversity of QueenslandWoolloongabba QLD 4102Australia Sunshine Coast Health Institute and School of Health and behavioural Sciences University of the Sunshine CoastBirtinya QLD 4575Australia National-Local Joint Engineering Lab of Druggability and New Drugs Evaluation Guangdong Provincial Key Laboratory of New Drug Design and EvaluationSun Yat-sen UniversityGuangzhou 510006China School of Pharmacy Bengbu Medical CollegeBengbu 233030China Institute of Endocrine and Metabolic Diseases the First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefei 230026China

bioactive compounds derived from herbal medicinal plants modulate various therapeutic targets and signaling pathways associated with cardiovascular diseases(CVDs),the world’s primary cause of *** biloba,a well-known traditional Chinese medicine with notable cardiovascular actions,has been used as a cardio-and cerebrovascular therapeutic drug and nutraceutical in Asian countries for *** studies have shown that ginkgolide b,a bioactive component in Ginkgo biloba,can ameliorate atherosclerosis in cultured vascular cells and disease *** clinical relevance,several clinical trials are ongoing or being completed to examine the efficacy and safety of ginkgolide b-related drug preparations in the prevention of cerebrovascular diseases,such as ischemia ***,we present a comprehensive review of the pharmacological activities,pharmacokinetic characteristics,and mechanisms of action of ginkgolide b in atherosclerosis prevention and *** highlight new molecular targets of ginkgolide b,including nicotinamide adenine dinucleotide phosphate oxidases(NADPH oxidase),lectin-like oxidized LDL receptor-1(LOX-1),sirtuin 1(SIRT1),platelet-activating factor(PAF),proprotein convertase subtilisin/kexin type 9(PCSK9)and ***,we provide an overview and discussion of the therapeutic potential of ginkgolide b and highlight the future perspective of developing ginkgolide b as an effective therapeutic agent for treating atherosclerosis.

关键词： Cardiovascular disease Atherosclerosis Ginkgo biloba ginkgolide b Endothelial dysfunction LOX-1 PCSK9 PAF-R antagonist

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Action of aluminum on high voltage-dependent calcium current and its modulation by ginkgolide b

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Acta Pharmacologica Sinica 2005年第5期26卷 539-545页

作者： Jurgen HESCHLER Cologne D-50931 Germany Neurophysiology University of Cologne

Aim:To investigate the effect of aluminum(Al)on high voltage-dependent cal-cium current(IHVA)and its modulation by ginkgolide b(Gin b).Methods:Thewhole-cell,patch-clamp technique was used to record IHVAfrom acutely isolatedhippocampal CA1 pyramydal neurons in ***:A1 0.1 mmol/L(lowconcentration)reduced IHVA;A1 0.75 and 1.0 mmol/L(high concentrations)in-creased IHVA,and Al decreased and increased IHVAat intermediate concentrationsof 0.25 and 0.5 mmol/*** increase of IHVAby Al 1.0 mmol/L was enhanced by theadenylyl cyclase(AC)agonist forskolin and was partly abolished by the cyclicadenosine monophosphate(cAMP)-dependent protein kinase A(PKA)antago-nist H-89,whereas the decrease observed with Al 0.1 mmol/L was neither reversedby forskolin nor affected by *** b had no effect on IHVAin normal neurons,but canceled the increase in IHVAby 1.0 mmol/L ***:The resultsindicate that the mechanism of Al affecting IHVAdiffers at different concentrations,and this may be attributed to its complex *** b could prevent neuronsfrom injury by inhibiting calcium influx.

关键词： hippocampus aluminum voltage-dependent calcium channels ginkgolide b patch-clamp technique

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Mechanism and dose-effect of ginkgolide b on severe acute pancreatitis of rats

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World Journal of Gastroenterology 2011年第17期17卷 2241-2247页

作者： Run-Li Ji Shi-Hai Xia, Yao Di Wei Xu Department of Hepatopancrea-tobiliary and Splenic Medicine Affiliated Hospital of Medical College of Chinese People's Armed Police Force Tianjin 300162 China Department of Physiology Medical College of Chinese People's Armed Police Force Tianjin 300162 China

AIM:To determine the optimal dosage and mechanism of ginkgolide b(bN52021) on severe acute pancreatitis(SAP) of ***:Seventy male Wistar rats were randomly divided into seven groups(10 for each group).Shamoperation group(SO),SAP model group(SAP),dimethyl sulfoxide(DMSO) contrast group(DMSO),and groups treated with 2.5 mg/kg bN52021(bN1),5 mg/kg bN52021(bN2),10 mg/kg bN52021(bN3),and 20 μg/kg Sandostatin(SS).The SAP model was established in Wistar rats by injecting 5% sodium taurocholate retrogradely into the common bilio-pancreatic *** rats of SO,DMSO and bN52021 were injected with 0.9% NaCl,0.5% DMSO and bN52021 through femoral vein 15 min after the *** SS group was injected with Sandostatin *** rats were anaesthetized at 6 h after operation,and venous blood was collected to determine the levels of serum amylase and phospholipase A2(PLA2),and pancreas tissue was harvested and ***:There was no significant difference between the SAP and DMSO groups in serum amylase level,PLA2,ascites and pathologic score,but significant difference was found in SAP/DMSO groups compared with those in SO group(P bN1,bN2,bN3 and SS groups than in the SAP and DMSO groups(P bN1,bN2,bN3 and SS groups,bN2 had the best effect in decreasing the levels of serum amylase and PLA2(P between the SAP and DMSO groups,or among bN1,bN2,bN3 and SS groups,but there was remarkable difference between SAP/DMSO group and SO group(P bN1,bN2,bN3 and SS groups than in the SAP and DMSO groups(P bserved in the nucleus and cytoplasm of pancreatic islet cells in Wistar rats by ***:by iv injection,5 mg/kg of bN52021 i

关键词： Pancreatitis ginkgolide b Dose-effect Phospholipase A2 Platelet activating factor receptor

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Selective ischemic-hemisphere targeting ginkgolide b liposomes with improved solubility and therapeutic efficacy for cerebral ischemia-reperfusion injury

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Asian Journal of Pharmaceutical Sciences 2023年第2期18卷 76-93页

作者： Yang Li Miaomiao Zhang Shiyi Li Longlong Zhang Jisu Kim Qiujun Qiu Weigen Lu Jianxin Wang Department of Pharmaceutics School of PharmacyFudan University&Key Laboratory of Smart Drug DeliveryMinistry of EducationShanghai201203China National Pharmaceutical Engineering and Research Center China State Institute of Pharmaceutical IndustryShanghai 201203China

Cerebral ischemia-reperfusion injury(CI/RI)remains the main cause of disability and death in stroke patients due to lack of effective therapeutic *** of the main issues related to CI/RI treatment is the presence of the blood-brain barrier(bbb),which affects the intracerebral delivery of *** b(Gb),a major bioactive component in commercially available products of Ginkgo biloba,has been shown significance in CI/RI treatment by regulating inflammatory pathways,oxidative damage,and metabolic disturbance,and seems to be a candidate for stroke ***,limited by its poor hydrophilicity and lipophilicity,the development of Gb preparations with good solubility,stability,and the ability to cross the bbb remains a ***,we propose a combinatorial strategy by conjugating Gb with highly lipophilic docosahexaenoic acid(DHA)to obtain a covalent complex Gb-DHA,which can not only enhance the pharmacological effect of Gb,but can also be encapsulated in liposomes *** amount of finally constructed Lipo@Gb-DHA targeting to ischemic hemisphere was validated 2.2 times that of free solution in middle cerebral artery occlusion(MCAO)*** to the marketed ginkgolide injection,Lipo@Gb-DHA significantly reduced infarct volume with better neurobehavioral recovery in MCAO rats after being intravenously administered both at 2 h and 6 h *** levels of reactive oxygen species(ROS)and high neuron survival in vitro was maintained via Lipo@Gb-DHA treatment,while microglia in the ischemic brain were polarized from the pro-inflammatory M1 phenotype to the tissue-repairing M2 phenotype,which modulate neuroinflammatory and *** addition,Lipo@Gb-DHA inhibited neuronal apoptosis via regulating the apoptotic pathway and maintained homeostasis by activating the autophagy ***,transforming Gb into a lipophilic complex and loading it into liposomes provides a promising nanomedicine strategy with excellent CI/RI therapeu

关键词： ginkgolide b Cerebral ischemia reperfusion injury(CI/RI) Docosahexaenoic acid Liposomes brain targeting Microglia

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Pharmacological action and mechanisms of ginkgolide b

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Chinese Medical Journal 2007年第10期120卷 922-928页

作者： XIA Shi-hai FANG Dian-chun Department of Gastroenterology Southwest Hospital Third Military Medical University Chongqing 40038 China

Objective To review the recent research progress in pharmacological actions and mechanisms of ginkgolide b. Data sources Information included in this article was identified by searching of PUbMED （1987-2006） online resources using the key terms ＂ginkgolide b＂, ＂platelet activating factor＂, and ＂pharmacological＂. Study selection Mainly original milestone articles and critical reviews written by major pioneer investigators of the field were selected. Results The key issues related to the pharmacological actions and mechanisms of ginkgolide b were summarized. The ginkgolide b possesses a number of beneficial effects such as anti-inflammatory, anti-allergic, antioxidant, and neuroprotective effects. Meantime, their mechaniams were discussed. Conclusions The ginkgolide b is the most potent antagonist of platelet activating factor （PAF） and exhibits therapeutic action in a variety of diseases mainly by the PAF receptor.

关键词： ginkgolide b platelet activating factor pharmacological actions

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Effects of ginkgolide b on neuronal discharges in paraventricular nucleus of rat hypothalamic slices

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Neuroscience bulletin 2008年第6期24卷 345-350页

作者：林悦王茹王昕何瑞荣武宇明河北医科大学基础医学研究所生理室石家庄050017

Objective To study the central role of ginkgolide b （bN52021） in regulating cardiovascular function of nerve center by examining the effects of ginkgolide b on the electrical activity of rat paraventricular nucleus （PVN） neurons in hypothalamic slice preparation and to elucidate the mechanism involved. Methods Extracellular single-unit discharge recording technique. Results （1） In response to the application of ginkgolide t3 （0.1, 1, 10 μmol/L; n = 27） into the perfusate for 2 rain, the spontaneous discharge rates （SDR） of 26 （26/27, 96.30%） neurons were significantly decreased in a dose-dependent manner. （2） Pretreatment with L-glutamate （L-Glu, 0.2 mmol/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 （1 μmol/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 （0.1 μmol/L）, induced a significant increase in the discharge rates of 8 （8/8, 100%） neurons, while ginkgolide b （1μmol/L） applied into the perfusate, could inhibit the discharges of 8 （100%） neurons. （4） In 8 neurons, the broad potassium channels blocker, tetraethylammonium （TEA, 1 mmol/L） completely blocked the inhibitory effect of ginkgolide b （1 μmol/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 potentially concerned with delayed rectifier potassium channel （KDR）.

关键词： paraventricular hypothalamic nucleus ginkgolide b L-glutamate bay K 8644 TEA

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Therapeutic neuroprotective effects of ginkgolide b on cortex and basal ganglia in a rat model of transient focal ischemia

Therapeutic neuroprotective effects of Ginkgolide B on corte...

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中国药理学会第十一次全国学术会议

作者： LV Peng (China Pharmaceutical University,Nanjing 210009,China) China Pharmaceutical University Nanjing 210009 China

Cerebral ischemia and reperfusion is one of the leading causes for death and severe disabilities in the world and often lead to irreversible brain damage over later *** aim of this study was to investigate the evolution of pathological damage in cerebral cortex and basal ganglia following ischemia and to evaluate the therapeutic neuroprotective effect of ginkgolide b in a rat model of stroke induced by middle cerebral artery occlusion(MCAO).TTC stain,brain water content and Evans-blue extravagation were used to quantify brain *** results demonstrated that basal ganglia undergo progressive pathological damage earlier following MCAO,and injury was stable and irreversible after 5 h following ***,onset of ischemia injury in cerebral cortex appeared later than basal ganglia and became evident about 3 h following MCAO,and injury was stable and irreversible after 6 h following *** brain barrier opened progressively,and it seemed to be significantly destroyed after 4 h following MCAO comparing with 0 ***-ischemic treatment with ginkgolide b improved neurological function and reduced infarct size in basal ganglia within 3h and cerebral cortex within 5 h following *** therapeutic effect of ginkgolide b on extenuate brain edema and decrease blood brain barrier permeability were extended for 5 h after ischemia,and more evident reversal effect were observed when administrated at earlier time.

关键词： cerebral ischemia MCAO pathological damage blood brain barrier ginkgolide b

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银杏内酯b（ginkgolide b）抑制小鼠脑缺血再灌注损伤炎症反应及细胞凋亡与NF-κb的关系

银杏内酯B（Ginkgolide B）抑制小鼠脑缺血再灌注损伤炎症反应及...

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作者：葛建彬苏州大学

学位级别：硕士

目的：观察银杏内酯b(ginkgolide b, Gb)对小鼠短暂性局灶性脑缺血的保护作用及其对脑缺血再灌注损伤后NF-κb的激活以及炎症反应、细胞凋亡的影响方法：采用小鼠短暂性大脑中动脉阻塞(transient middle cerebral artery occlusion, tM... 详细信息

目的：观察银杏内酯b(ginkgolide b, Gb)对小鼠短暂性局灶性脑缺血的保护作用及其对脑缺血再灌注损伤后NF-κb的激活以及炎症反应、细胞凋亡的影响方法：采用小鼠短暂性大脑中动脉阻塞(transient middle cerebral artery occlusion, tMCAO)模型观察Gb10、20、40mg/kg对脑梗死体积、脑水肿及行为学症状的影响,小鼠脑缺血再灌注后即时尾静脉注射给药。应用免疫荧光法分析NF-κb的核转位及小胶质细胞的活化;采用RT-PCR技术检测TNF-α,IL-1β及iNOS mRNA的表达;采用Western-blot法检测小鼠大脑皮层Iκbα, p-Iκbα, p-IKKα,p53,bcl-2,bax及Caspase3蛋白含量。结果：Gb10、20、40mg/kg静脉注射呈剂量依赖性减少tMCAO小鼠脑梗死体积,降低脑含水量和改善行为学症状(Pblot显示：小鼠缺血再灌注3小时后大脑皮层缺血区Iκbα的含量显著降低(Pb能显著提高Iκbα的含量(Pbα的含量(Pbp65主要表达在神经细胞胞浆中;缺血再灌注3小时后,模型组小鼠大脑皮层大量p65蛋白表达于神经细胞胞核,说明缺血使NF-κb从细胞浆移位至细胞核;Gb20mg/kg能明显抑制NF-κb的核转位。免疫荧光亦证明：假手术组小鼠大脑皮层小胶质细胞处于静息状态,缺血再灌注2天后,模型组小鼠大脑皮层小胶质细胞被激活,Gb20mg/kg能明显抑制小胶质细胞的活化。RT-PCR结果表明：小鼠缺血再灌注2天后大脑皮层缺血区TNF-α,IL-1β,iNOS mRNA的表达明显增高,Gb能明显下调TNF-α,IL-1β,iNOS mRNA的表达(Pblot结果亦证明：缺血再灌注12小时后小鼠大脑皮层缺血区p53的水平明显增高(Pb能明显降低小鼠大脑皮层缺血区的p53,bax及Caspase3水平(Pbcl-2水平(Pb对小鼠脑缺血再灌注损伤具有保护作用,其作用机制可能与抑制NF-κb信号通路激活,进而抑制炎症反应及神经细胞凋亡有关。

关键词： ginkgolide b 脑缺血再灌注神经保护 NF-κb 炎症反应细胞凋亡

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Neuroprotective effects of Ginkgo biloba extract and GinkgoUde b against oxygen-glucose deprivation/reoxygenation and glucose injury in a new in vitro multicellular network model

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Frontiers of Medicine 2018年第3期12卷 307-318页

作者： Xiaohan Yang Tiezheng Zheng Hao Hong Nan Cai Xiaofeng Zhou Changkai Sun Liying Wu Shuhong Liu Yongqi Zhao Lingling Zhu Ming Fan Xuezhong Zhou Fengxie Jin Department of biomedical Engineering Faculty of Electronic Information and Electrical Engineering Dalian University of Technology Dalian 116024 China Research Center for the Control Engineering of Translational Precision Medicine Dalian University of Technology Dalian 116024 China State Key Laboratory of Fine Chemicals Dalian R&D Center for Stem Cell and Tissue Engineering Dalian University of Technology Dalian 116024 China Liaoning Provincial Key Laboratory of Cerebral Diseases Institute for Brain Disorders Dalian Medical University Dalian 116044 China Institute of basic Medical Sciences Academy of Military Medical Sciences Beijing 100850 China School of Computer and Information Technology and beijing Key Lab of Traffic Data Analysis and Mining Beijing Jiaotong University Beijing 100044 China College of biotecknology Dalian Polytechnic University Dalian 116034 China

Acute ischemic stroke （AIS）, as the third leading cause of death worldwide, is characterized by its high incidence, mortality rate, high incurred disability rate, and frequent reoccurrence. The neuroprotective effects of Ginkgo biloba extract （GbE） against several cerebral diseases have been reported in previous studies, but the underlying mechanisms of action are still unclear. Using a novel in vitro rat cortical capillary endothelial cell- astrocyte-neuron network model, we investigated the neuroprotective effects of GbE and one of its important constituents, ginkgolide b （Gb）, against oxygenglucose deprivation/reoxygenation and glucose （OGD/R） injury. In this model, rat cortical capillary endothelial cells, astrocytes, and neurons were cocultured so that they could be synchronously observed in the same system. Pretreatment with GbE or Gb increased the neuron cell viability, ameliorated cell injury, and inhibited the cell apoptotic rate through bax and bcl-2 expression regulation after OGD/R injury. Furthermore, GbE or Gb pretreatment enhanced the transendothelial electrical resistance of capillary endothelial monolayers, reduced the endothelial permeability coefficients for sodium fluorescein （Na-F）, and increased the expression levels of tight junction proteins, namely, ZO-1 and occludin, in endothelial cells. Results demonstrated the preventive effects of GbE on neuronal cell death and enhancement of the function of brain capillary endothelial monolayers after OGD/R injury in vitro; thus, GbE could be used as an effective neuroprotective agent for AIS/reperfusion, with Gb as one of its significant constituents.

关键词： acute ischemic stroke Ginkgo biloba extract ginkgolide b network model neuroprotection

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