Phospholipid breakdown and choline release under hypoxic conditions: inhibition by bilobalide, a constituent of Ginkgo biloba

Klein, Jochen; Chatterjee, Shyam Sunder; Löffelholz, K.

doi:10.1016/s0006-8993(97)00239-4

Cited by 88 publications

(58 citation statements)

References 22 publications

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“…Hippocampal slices (400 µm) were prepared from male rats as previously described (Klein et al, 1997;Weichel et al, 1999) and superfused (0.7ml/min) at 35°C with Tyrode solution of the following composition: 142 mM NaCl, 2.7 mM KCl, 1.8 mM CaCl 2 , 1.2 mM MgCl 2 , 11.9 mM NaHCO3, 5.6 mM glucose. All superfusion solutions were continuously gassed with carbogen (95% O2, 5% CO2).…”

Section: Choline Release From Rat Hippocampal Slicesmentioning

confidence: 99%

“…Choline was determined by a chemoluminescence assay (Klein et al, 1997;Weichel et al, 1999). Briefly, 10 μl aliquots of the superfusates were given to a reaction mixture consisting of 20 mM Tris buffer pH 8.6, 1 μg luminol, 10 μg peroxidase, and 1.25 U choline oxidase, and the chemiluminescence resulting from oxidation of choline to betaine was measured at 425 nm in a LKB-Wallac luminometer.…”

Section: Choline Release From Rat Hippocampal Slicesmentioning

confidence: 99%

“…In an experimental model of hypoxia-induced phospholipid breakdown, we found that bilobalide, a sesquiterpene lactone which constitutes ca. 3 % of EGb761, was the active constituent of the extract (Klein et al, 1997) acting in the submicromolar range (IC 50 =0.38 μM). In further work, we described the antagonistic effect of bilobalide on NMDA receptor-induced choline release in the low micromolar range (IC 50 =2.3 μM) (Weichel et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

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Role of GABAergic antagonism in the neuroprotective effects of bilobalide

et al. 2007

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Bilobalide, a constituent of Ginkgo biloba, has neuroprotective properties. Its mechanism of action is unknown but it was recently found to block GABA A receptors. The goal of this study was to test the potential role of a GABAergic mechanism for the neuroprotective activity of bilobalide. In rat hippocampal slices exposed to NMDA, release of choline indicates breakdown of membrane phospholipids. NMDA-induced choline release was almost completely blocked in the presence of bilobalide (10 μM) and under low-chloride conditions. Bicuculline (100 μM), a competitive antagonist at GABA A receptors, reduced NMDA-induced choline release to a small extent (−23%). GABA (100 μM) partially antagonized the inhibitory action of bilobalide. Exposure of hippocampal slices to NMDA also caused edema formation as measured by increases of tissue water content. NMDA-induced edema formation was suppressed by bilobalide and by low-chloride conditions. Bicuculline exerted partial protection (by 30%) while GABA reduced bilobalide's effect by about one third.To investigate bilobalide's interaction with GABA A receptors directly, we measured binding of [ 35 S-TBPS] to rat cortical membranes. TBPS binding was competitively inhibited by bilobalide in the low micromolar range (IC 50 =3.7 μM). As a functional test, we determined 36 chloride flux in rat corticohippocampal synaptoneurosomes. GABA (100μM) significantly increased 36 chloride flux (+65 %), and this increase was blocked by bilobalide, but with low potency (IC 50 : 39 μM). We conclude that, while antagonism of GABA A receptors may contribute to bilobalide's neuroprotective effects, additional mechanisms must be postulated to fully explain bilobalide's actions.

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Section: Choline Release From Rat Hippocampal Slicesmentioning

confidence: 99%

Section: Choline Release From Rat Hippocampal Slicesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Role of GABAergic antagonism in the neuroprotective effects of bilobalide

et al. 2007

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“…EGb 761 contains two groups of bioactive constituents, the flavonoids (24%) and the terpenoids (6%), which have been actively investigated for their neuroprotective and neuromodulatory activities (5). It has been reported that the effectiveness of the Ginkgo biloba extract EGb 761 in a middle cerebral artery occlusion (MCAO) model was exclusively due to the presence of bilobalide (BB), a sesquiterpene lactone that constitutes 2.9-3.2% of the extract (6,7). Accumulating evidence suggest that BB has neuroprotective effects (2,8,9).…”

Section: Introductionmentioning

confidence: 99%

Protective effect of bilobalide on learning and memory impairment in rats with vascular dementia

Huang

et al. 2013

Molecular Medicine Reports

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Abstract. Vascular dementia (VD) is the second most common type of dementia in the elderly. Currently, there are no effective drugs for preventing or decreasing the progression of dementia. Bilobalide (BB) is a monomer extracted from Ginkgo biloba leaves. The present study investigated the neuroprotective effects of BB in a two-vessel occlusion (2-VO)-induced VD rat model. The results showed that BB (4 and 8 mg/kg) significantly protected VD rats against cognitive deficits in the Morris water maze. Biochemical assessment showed that BB (4 and 8 mg/kg) increased superoxide dismutase (SOD) activity and glutathione (GSH) content, and decreased nitric oxide synthase (NOS) activity and malondialdehyde (MDA) content. Additionally, BB (4 and 8 mg/kg) was found to alleviate neuronal apoptosis and to reduce the expression of tumor necrosis factor-α (TNF-α) in the brain cortex and the hippocampal CA1 region in VD rats. These results suggest that BB provides protection against learning and memory impairment by reducing free radical injury and inhibiting neuronal apoptosis in the brain cortex and hippocampal CA1 region in VD rats.

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“…10) Actually, these effects have been recognized clinically using many double-blind studies with GBE versus placebo. [11][12][13] The mechanisms for thebeneficial effects of GBE are considered to be due to the improvements of (a) haemodynamic disorders 14,15) ; (b) PAF-associated abnormalities [16][17][18] ; (c) cell damages induced by free radicals [16][17][18] ; and (d) decrease in ATP level during anoxia. 19) GBE modulates cytochrome (CYP) P450.…”

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Pharmacokintics of the Ginkgo Bfollowing Intravenous Administration of Ginkgo B Emulsion in Rats

Chen

Liang

Xie

et al. 2007

Biological & Pharmaceutical Bulletin

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GBE has been used worldwide as a herbal medicine. 1) GBE possesses many constituents, and is mainly composed of flavonoids such as quercetin andrutin, and terpenoids such as bilobalide and ginkgolides A, B and C. 2) In German pharmaceutical analysis, the quality of GBE has been standardized ascontaining 22-27% flavonoid glycosides and 6% terpenoids. 3) In recent clinical and experimental experiments, GBE has been reported to be effective against ischemic brain injury, 4,5) cerebral (or cerebrovascular) insufficiency, 6) cognitive speed, 7) dementia and Alzheimer's disease, 8) peripheral vascular disease such as arterial occlusive disease 9) and aging damages. 10) Actually, these effects have been recognized clinically using many double-blind studies with GBE versus placebo. [11][12][13] The mechanisms for thebeneficial effects of GBE are considered to be due to the improvements of (a) haemodynamic disorders 14,15) ; (b) PAF-associated abnormalities [16][17][18] ; (c) cell damages induced by free radicals [16][17][18] ; and (d) decrease in ATP level during anoxia. 19) GBE modulates cytochrome (CYP) P450. GBE induced markedly the activity of CYP2B, CYP3A1 and CYP3A2 in the rat liver. 20,21) These results suggest that GBE attenuates the therapeutic potency of nicardipine due to the induction of the CYP3A2 level. It is still unknown whether GBE can pass through the blood-brain barrier. The endothelial productions (i.e., NO) induced by GBE application might pass through the blood-brain barrier and then would cause the vasodilation in cerebral arteries. The concentrations used in our studies are relatively higher, because the concentrations in in vitro experiments are generally higher than actual clinical serum concentrations. The pharmacological activities of GBE mainly was attributed to ginkgolides ( Fig. 1).Accumulating evidence suggested that ginkgolide B(GB) shows the strongest pharmacological activity among the ginkgolides. Now, GB is being developed for treating cerebrovascular accident, but no information is available on systemic and comprehensive pharmacokinetics of GB. In this study, we report for the first time a thorough characterization of the pharmacokinetics of GB and providing large data sets that can be used to predict biological events related to pharmacokinetic behavior of GB through determining the concentrations in biological samples after intravenous administration of GB emulsion to rats. MATERIALS AND METHODS Chemicals and ReagentsGinkgolide B was supplied by National Institute for the Control of Pharmaceutical and Biological Produces (Beijing, China). 23-OH betulic acid (internal standard) was obtained from Chemistry Institute of China Pharmaceutical University. GB emulsion was presented by Beijing 303 Hospital. All other reagents were commercially available. Water was purified using Milli-Q Labo (Millipore, U.S.A.). Sprague-Dawley rats, weighing 180-220 g, were supplied by Experimental Animal Center of China Pharmaceutical University. The rats were fasted but allowed free access to water 12 h ...

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Phospholipid breakdown and choline release under hypoxic conditions: inhibition by bilobalide, a constituent of Ginkgo biloba

Cited by 88 publications

References 22 publications

Role of GABAergic antagonism in the neuroprotective effects of bilobalide

Role of GABAergic antagonism in the neuroprotective effects of bilobalide

Protective effect of bilobalide on learning and memory impairment in rats with vascular dementia

Pharmacokintics of the Ginkgo Bfollowing Intravenous Administration of Ginkgo B Emulsion in Rats

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