Ginkgolide A

Ginkgolide A is an extract from in Ginkgo biloba and a g-aminobutyric acid (GABA) antagonist. Target: GABA Receptor Ginkgolide A is a highly active PAF antagonist cage molecule that is isolated from the leaves of the Ginkgo biloba tree. Shows potential in a wide variety of inflammatory and immunological disorders. Ginkgolide A significantly shortened the sleeping time induced by anesthetics in mice [1]. Ginkgolide A failed to affect apoptotic damage neither in serum-deprived nor in staurosporine-treated neurons [2].

References:
[1]. Wada, K., et al., Isolation of bilobalide and ginkgolide A from Ginkgo biloba L. shorten the sleeping time induced in mice by anesthetics. Biol Pharm Bull, 1993. 16(2): p. 210-2. [2]. Ahlemeyer, B. and J. Krieglstein, Pharmacological studies supporting the therapeutic use of Ginkgo biloba extract for Alzheimer's disease. Pharmacopsychiatry, 2003. 36(S 1): p. 8-14.

Ginkgolide A reduces inflammatory response in high-glucose-stimulated human umbilical vein endothelial cells through STAT3-mediated pathway.[Pubmed:25681539]

Int Immunopharmacol. 2015 Apr;25(2):242-8.

High-glucose-induced low-grade inflammation has been regarded as a key event in the onset and progression of endothelial dysfunction in diabetic vascular complications. Ginkgolide A (GA), a major compound from Ginkgo biloba extract, is widely used for the treatment of cardiovascular diseases and diabetic vascular complications. Here, its effect on high-glucose-stimulated vascular inflammation in human umbilical vein endothelial cells (HUVECs) was investigated. In the present study, the optimal stimulation conditions for HUVECs were screened for inducing endothelial inflammation, namely, high glucose at the concentration of 30mM for continuous 8h. The endothelial production of high-glucose-induced interleukin (IL)-4, IL-6, IL-13 and signal transducer and activator of transcription-3 (STAT-3) phosphorylation were significantly inhibited by the pretreatment with GA at concentrations of 10, 15 and 20muM based on enzyme-linked immunosorbent assay (ELISA), western blot or/and RT-PCR experiments. These senescent alterations induced by high glucose were significantly attenuated by the specific STAT3 inhibitor S3I-201 at the concentration of 20muM. Furthermore, the phosphorylation of STAT3, IL-4, IL-6, IL-13 and intercellular cell adhesion molecule-1 (ICAM-1) protein as well as mRNA levels were attenuated by the pretreatment of cells with STAT3 siRNA. Our results demonstrated that GA improved high-glucose-caused low-grade vascular inflammation, which might be achieved through regulating the STAT3-mediated pathway. These findings indicated that GA might be a promising candidate for attenuating vascular inflammation in diabetic vascular complications.

An anxiolytic-like effect of Ginkgo biloba extract and its constituent, ginkgolide-A, in mice.[Pubmed:14575433]

J Nat Prod. 2003 Oct;66(10):1333-7.

The anxiolytic-like effects of Ginkgo biloba extract (GBE) and its four terpenoid components (ginkgolide-A, ginkgolide-B, ginkgolide-C, and bilobalide) were assessed using the elevated plus-maze test in mice. Administration of GBE as a single oral dose (0.5 or 1 g/kg, po) caused a state of suppressed motor activity and, thus, shortened the time spent in the open-sided arms. However, when GBE (0.063-1 g/kg, po) was administered daily for 7 days and the plus-maze test was carried out 24 h after the final administration, the time spent in the open-sided arms was prolonged, with the peak anxiolytic-like effect at 0.125 g/kg. A combination of seven-day administration of GBE (0.125 g/kg) and a single dose of diazepam (1 mg/ kg, po, 10 min before testing) enhanced the anxiolytic-like effect. Flumazenil (0.3 mg/kg, ip, 10 min before testing) blocked the effect of diazepam, but not of GBE. Daily administration of ginkgolide-A (1 or 2 mg/kg, po) resulted in an anxiolytic-like effect by the third treatment, with the maximal effect observed after the fifth administration. Neither ginkgolide-B, ginkgolide-C, nor bilobalide produced any anxiolytic-like effects. At doses higher than 0.5 g/kg, GBE not only inhibited motor activity but also suppressed active avoidance behavior, reduced caffeine-induced stimulation, and enhanced pentobarbital-induced sleep, while ginkgolide-A (up to 20 mg/kg) did not exhibit these effects. Diazepam (1 mg/kg) is known to enhance pentobarbital-induced sleep. These results suggest that GBE produces a significant anxiolytic-like effect following repeated administration and that ginkgolide-A is most likely responsible for this effect. There are also indications that although GBE exerts a sedative effect at comparatively higher doses, ginkgolide-A has a relatively weak tendency to produce benzodiazepine-like side effects.

Effects of ginkgolide A on okadaic acid-induced tau hyperphosphorylation and the PI3K-Akt signaling pathway in N2a cells.[Pubmed:22700047]

Planta Med. 2012 Aug;78(12):1337-41.

Alzheimer's disease is the most common form of dementia leading to the irreversible loss of neurons, and Tau hyperphosphorylation has an important role in the pathology of Alzheimer's disease. Ginkgolide A is one of the active components of Ginkgo biloba extracts which has been proven to have neuroprotective effects, but the effect of Ginkgolide A on Tau hyperphosphorylation has not yet been reported. In this study, the effects of Ginkgolide A on cell viability, Tau hyperphosphorylation, and the PI3K-Akt signaling pathway in N2a cell lines were explored, and methods such as the MTT assay, ELISA, and Western blots techniques were used. The results showed that Ginkgolide A could increase cell viability and suppress the phosphorylation level of Tau in cell lysates, meanwhile, GSK3beta was inhibited with phosphorylation at Ser9. Moreover, treatment of the cells with Ginkgolide A promoted phosphorylation of PI3K and Akt, suggesting that the activation of the PI3K-Akt signaling pathway may be the mechanism for Ginkgolide A to prevent the intracellular accumulation of p-Tau induced by okadaic acid and to protect the cells from Tau hyperphosphorylation-related toxicity.

Ginkgolide B inhibits the neurotoxicity of prions or amyloid-beta1-42.[Pubmed:15285798]

J Neuroinflammation. 2004 May 11;1(1):4.

BACKGROUND: Neuronal loss in Alzheimer's or prion diseases is preceded by the accumulation of fibrillar aggregates of toxic proteins (amyloid-beta1-42 or the prion protein). Since some epidemiological studies have demonstrated that the EGb 761 extract, from the leaves of the Ginkgo biloba tree, has a beneficial effect on Alzheimer's disease, the effect of some of the major components of the EGb 761 extract on neuronal responses to amyloid-beta1-42, or to a synthetic miniprion (sPrP106), were investigated. METHODS: Components of the EGb 761 extract were tested in 2 models of neurodegeneration. SH-SY5Y neuroblastoma cells were pre-treated with ginkgolides A or B, quercetin or myricetin, and incubated with amyloid-beta1-42, sPrP106, or other neurotoxins. After 24 hours neuronal survival and the production of prostaglandin E2 that is closely associated with neuronal death was measured. In primary cortical neurons apoptosis (caspase-3) in response to amyloid-beta1-42 or sPrP106 was measured, and in co-cultures the effects of the ginkgolides on the killing of amyloid-beta1-42 or sPrP106 damaged neurons by microglia was tested. RESULTS: Neurons treated with ginkgolides A or B were resistant to amyloid-beta1-42 or sPrP106. Ginkgolide-treated cells were also resistant to platelet activating factor or arachidonic acid, but remained susceptible to hydrogen peroxide or staurosporine. The ginkgolides reduced the production of prostaglandin E2 in response to amyloid-beta1-42 or sPrP106. In primary cortical neurons, the ginkgolides reduced caspase-3 responses to amyloid-beta1-42 or sPrP106, and in co-culture studies the ginkgolides reduced the killing of amyloid-beta1-42 or sPrP106 damaged neurons by microglia. CONCLUSION: Nanomolar concentrations of the ginkgolides protect neurons against the otherwise toxic effects of amyloid-beta1-42 or sPrP106. The ginkgolides also prevented the neurotoxicity of platelet activating factor and reduced the production of prostaglandin E2 in response to platelet activating factor, amyloid-beta1-42 or sPrP106. These results are compatible with prior reports that ginkgolides inhibit platelet-activating factor, and that platelet-activating factor antagonists block the toxicity of amyloid-beta1-42 or sPrP106. The results presented here suggest that platelet-activating factor antagonists such as the ginkgolides may be relevant treatments for prion or Alzheimer's diseases.

Ginkgolide A contributes to the potentiation of acetaminophen toxicity by Ginkgo biloba extract in primary cultures of rat hepatocytes.[Pubmed:17045319]

Toxicol Appl Pharmacol. 2006 Dec 1;217(2):225-33.

The present cell culture study investigated the effect of Ginkgo biloba extract pretreatment on acetaminophen toxicity and assessed the role of Ginkgolide A and cytochrome P450 3A (CYP3A) in hepatocytes isolated from adult male Long-Evans rats provided ad libitum with a standard diet. Acetaminophen (7.5-25 mM for 24 h) conferred hepatocyte toxicity, as determined by the lactate dehydrogenase (LDH) assay. G. biloba extract alone increased LDH leakage in hepatocytes at concentrations > or =75 mug/ml and > or =750 mug/ml after a 72 h and 24 h treatment period, respectively. G. biloba extract (25 or 50 mug/ml once every 24 h for 72 h) potentiated LDH leakage by acetaminophen (10 mM for 24 h; added at 48 h after initiation of extract pretreatment). The effect was confirmed by a decrease in [(14)C]-leucine incorporation. At the level present in a modulating concentration (50 mug/ml) of the extract, Ginkgolide A (0.55 mug/ml), which increased CYP3A23 mRNA levels and CYP3A-mediated enzyme activity, accounted for part but not all of the potentiating effect of the extract on acetaminophen toxicity. This occurred as a result of CYP3A induction by Ginkgolide A because triacetyloleandomycin (TAO), a specific inhibitor of CYP3A catalytic activity, completely blocked the effect of Ginkgolide A. Ginkgolide B, ginkgolide C, ginkgolide J, quercetin, kaempferol, isorhamnetin, and isorhamnetin-3-O-rutinoside did not alter the extent of LDH leakage by acetaminophen. In summary, G. biloba pretreatment potentiated acetaminophen toxicity in cultured rat hepatocytes and Ginkgolide A contributed to this novel effect of the extract by inducing CYP3A.