Protection against β-amyloid induced abnormal synaptic function and cell death by Ginkgolide J

Vitolo, Ottavio V.; Gong, Bing; Cao, Zhonglin; Ishii, Hideki; Jaracz, Stanislav; Nakanishi, Koji; Arancio, Ottavio; Dzyuba, Sergei V.; Lefort, Roger; Shelanski, Michael L.

doi:10.1016/j.neurobiolaging.2007.05.025

Cited by 42 publications

(26 citation statements)

References 54 publications

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“…These features of ginkgolides fit the proposed pharmacophore of hPXR ligands, which includes a molecular mass Ͼ300 Da, an ability to form hydrophobic interactions (e.g., aromatic -interactions), and the presence of hydrogen bond acceptors (one or two) and hydrogen bond donors (Xiao et al, 2011). Although molecular docking analysis predicts that ginkgolide J, which is bioactive (Vitolo et al, 2009), binds very weakly to the ligand-binding domain of the receptor, it does not activate hPXR, as shown in the various assays conducted in the present study. However, it is possible that ginkgolide J is capable of acting as an antagonist of hPXR, but future studies are needed to address this issue.…”

Section: Discussionmentioning

confidence: 68%

“…For example, ginkgolide B and ginkgolide C are more efficacious than ginkgolide A and ginkgolide J in antagonizing the glycine-gated chloride channel (Ivic et al, 2003). Ginkgolide B (Xiao et al, 2010) and ginkgolide J (Vitolo et al, 2009) also inhibit ␤-amyloid-induced cell death in rodent hippocampal neurons. Other actions of ginkgolide B include antagonism of platelet-activating factor receptor and antiapoptotic, anti-inflammatory, antioxidant, and antiproliferative activities (Xia and Fang, 2007).…”

Section: Introductionmentioning

confidence: 99%

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Selective Agonism of Human Pregnane X Receptor by Individual Ginkgolides

Lau¹,

Yang²,

Yap³

et al. 2012

Drug Metab Dispos

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ABSTRACT:Ginkgolide A, ginkgolide B, ginkgolide C, and ginkgolide J are structurally related terpene trilactones present in Ginkgo biloba extract. Pregnane X receptor (PXR), glucocorticoid receptor (GR), and constitutive androstane receptor (CAR) regulate the expression of genes involved in diverse biological functions. In the present study, we investigated the effects of individual ginkgolides as single chemical entities on the function of human PXR (hPXR), human GR (hGR), and human CAR (hCAR). In cell-based reporter gene assays, none of the ginkgolides activated hGR or hCAR (wild-type and its SV23, SV24, and SV25 splice variants). Concentration-response experiments showed that ginkgolide A and ginkgolide B activated hPXR and rat PXR to a greater extent than ginkgolide C, whereas ginkgolide J had no effect. As determined by a time-resolved fluorescence resonance energy transfer competitive binding assay, ginkgolide A and ginkgolide B, but not ginkgolide C or ginkgolide J, were shown to bind to the ligandbinding domain of hPXR, consistent with molecular docking data. Compared with tetraethyl 2-(3,5-di-tert-butyl-4-hydroxyphenyl)ethenyl-1,1-bisphosphonate (SR12813) (a known agonist of hPXR), ginkgolide A and ginkgolide B were considerably less potent in binding to hPXR. These two ginkgolides recruited steroid receptor coactivator-1 to hPXR and increased hPXR target gene (CYP3A4) expression, as assessed by a mammalian two-hybrid assay and real-time polymerase chain reaction, respectively. In conclusion, the individual ginkgolides regulate the function of nuclear receptors in a receptor-selective and chemical-dependent manner. This study identifies ginkgolide A and ginkgolide B as naturally occurring agonists of hPXR and provides mechanistic insight into the structure-activity relationship in ligand activation of hPXR.

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Section: Discussionmentioning

confidence: 68%

Section: Introductionmentioning

confidence: 99%

Selective Agonism of Human Pregnane X Receptor by Individual Ginkgolides

Lau¹,

Yang²,

Yap³

et al. 2012

Drug Metab Dispos

View full text Add to dashboard Cite

show abstract

“…Many recent reports confirm that ginkgolide compounds, the most important constituents of Ginkgo biloba, have free radical-scavenging activity against hydroxyl radicals and superoxide anions [13,14]. Recently, Vitolo et al [15] found that the activity of natural ginkgolides was determined by their cage-like structure and hydroxyl group location in cell death of rodent hippocampal neurons caused by amyloid beta 1-42. As we know, platelet-activating factor (PAF) is a bioactive phospholipid that accumulates during I/R and is involved in the activation of platelets, neutrophils and pro-inflammatory signaling, which is suggested to enhance brain I/R damage.…”

Section: Introductionmentioning

confidence: 99%

Neuroprotective effect of ginkgolide K against acute ischemic stroke on middle cerebral ischemia occlusion in rats

Yin

Chen

et al. 2011

J Nat Med

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Ginkgolide K, a natural platelet-activating factor receptor antagonist, was isolated from the leaves of Ginkgo biloba. However, little is known about its neuroprotective effect in ischemia-reperfusion (I/R)-induced cerebral injury. Hence, the present study was carried out to investigate the effect of ginkgolide K on neuroprotection and the potential mechanisms in the rat I/R model induced by middle cerebral artery occlusion (MCAO). The rats were pretreated with ginkgolide K 2, 4 and 8 mg/kg (i.v.) once a day for 5 days before MCAO. Neurological deficit score (NDS), brain water content, 2,3,5-triphenyltetrazolium chloride (TTC) staining and pathology of brain tissue, as well as indexes of oxidative stress [superoxide dismutase (SOD), malondialdehyde (MDA), nitric oxide (NO) and nitric oxide synthase (NOS)] were measured at 24 h after ischemia. The results indicated that pretreatment with ginkgolide K significantly diminished the volume of infarction and brain water content, and improved NDS. Moreover, ginkgolide K markedly reversed the level of MDA, NO, NOS and SOD to their normal state in serum or cerebral ischemic section. In addition, hematoxylin and eosin staining showed the neuronal injury was significantly improved after being pretreated with ginkgolide K. These findings demonstrate that ginkgolide K exhibits neuroprotective properties through its antioxidative action in MCAO rats.

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“…Up to now, flavones glycosides, terpene lactones and other chemical components have been separated from and identified in Ginkgo biloba extracts Dew et al, 2013). Previous studies have shown that ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide J, and ginkgolide K all have neuroprotective effects and antioxidative properties, especially on neuron injuries induced by cerebral ischemia Qin et al, 2014;Ma et al, 2012a,b;Numa et al, 2007;Vitolo et al, 2009). Interestingly, ginkgolide activities, particularly in protecting against cerebral ischemia injury, were found to be affected by the chemical structure of ginkgolide (Ma et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Transport of ginkgolides with different lipophilicities based on an hCMEC/D3 cell monolayer as a blood–brain barrier cell model

Liu

et al. 2014

Life Sciences

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Protection against β-amyloid induced abnormal synaptic function and cell death by Ginkgolide J

Cited by 42 publications

References 54 publications

Selective Agonism of Human Pregnane X Receptor by Individual Ginkgolides

Selective Agonism of Human Pregnane X Receptor by Individual Ginkgolides

Neuroprotective effect of ginkgolide K against acute ischemic stroke on middle cerebral ischemia occlusion in rats

Transport of ginkgolides with different lipophilicities based on an hCMEC/D3 cell monolayer as a blood–brain barrier cell model

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