Effects of single intraperitoneal injections of an extract of Ginkgo biloba (EGb 761) and its terpene trilactone constituents on barbital-induced narcosis in the mouse

Brochet, Denis; Chermat, R; DeFeudis, F.V.; Drieu, Katy

doi:10.1016/s0306-3623(99)00018-x

Cited by 25 publications

(19 citation statements)

References 15 publications

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“…The activity of the cytochrome P450 system can also be assessed by measuring the sleeping time of animals exposed to barbiturate drugs, the length of sleep reflecting the rate of P450-mediated metabolism (11). In order to establish the role of hepatic P450s in the disposition of pentobarbital, wild-type and hepatic CPR-null mice were administered an intraperitoneal dose of 20 mg/kg of body weight.…”

Section: Table I Testosterone Hydroxylation By Hepatic Microsomes Fromentioning

confidence: 99%

Inactivation of the Hepatic Cytochrome P450 System by Conditional Deletion of Hepatic Cytochrome P450 Reductase

Henderson¹,

Otto²,

Carrié

et al. 2003

Journal of Biological Chemistry

237

259

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Cytochrome P450 (CYP) monooxygenases catalyze the oxidation of a large number of endogenous compounds and the majority of ingested environmental chemicals, leading to their elimination and often to their metabolic activation to toxic products. This enzyme system therefore provides our primary defense against xenobiotics and is a major determinant in the therapeutic efficacy of pharmacological agents. To evaluate the importance of hepatic P450s in normal homeostasis, drug pharmacology, and chemical toxicity, we have conditionally deleted the essential electron transfer protein, NADH:ferrihemoprotein reductase (EC 1.6.2.4, cytochrome P450 reductase, CPR) in the liver, resulting in essentially complete ablation of hepatic microsomal P450 activity. Hepatic CPR-null mice could no longer break down cholesterol because of their inability to produce bile acids, and whereas hepatic lipid levels were significantly increased, circulating levels of cholesterol and triglycerides were severely reduced. Loss of hepatic P450 activity resulted in a 5-fold increase in P450 protein, indicating the existence of a negative feedback pathway regulating P450 expression. Profound changes in the in vivo metabolism of pentobarbital and acetaminophen indicated that extrahepatic metabolism does not play a major role in the disposition of these compounds. Hepatic CPR-null mice developed normally and were able to breed, indicating that hepatic microsomal P450-mediated steroid hormone metabolism is not essential for fertility, demonstrating that a major evolutionary role for hepatic P450s is to protect mammals from their environment. The hepatic cytochrome P450 (CYP)1 -dependent monoxygenase system plays a central role in mammalian defense against harmful environmental chemicals (1); it is also a major determinant of the half-life and pharmacological properties of therapeutic drugs and in certain cases, mediates the activation of drugs, toxins, and carcinogens to their ultimate toxic species (2, 3). Several other functions have been ascribed to hepatic P450s, including control of cholesterol and steroid hormone metabolism and bile acid biosynthesis (4). However, for certain of these pathways, the exact role of P450s in normal homeostasis is unknown.Over the last four decades, there have been significant advances in understanding the functions, genetics, and regulation of these enzymes and more recently their structure (5). However, a great deal remains to be learned about the expression and regulation of P450s, and their endogenous function(s), particularly in individual tissues. The size and diversity of the P450 multigene family results in great difficulties in dissecting out the function(s) of individual enzymes, particularly as many of those involved in foreign compound metabolism exhibit overlapping substrate specificities and may be expressed to a greater or lesser extent in almost every cell and tissue. The contribution that P450s in any particular tissue make to the overall pharmacokinetics of a drug is still, in the majority of cases,...

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Section: Table I Testosterone Hydroxylation By Hepatic Microsomes Fromentioning

confidence: 99%

Inactivation of the Hepatic Cytochrome P450 System by Conditional Deletion of Hepatic Cytochrome P450 Reductase

Henderson¹,

Otto²,

Carrié

et al. 2003

Journal of Biological Chemistry

237

259

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“…The best available evidence, however, points to an interference with GABAergic neurotransmission. Electrophysiological data in hippocampal slices as well as antagonistic effects of bilobalide on barbital-induced sleeping time (Brochet et al, 1999) gave the first indirect evidence for an interference of bilobalide with GABAergic actions. Further data on GABAergic actions of bilobalide were reported by us in neurochemical models (Klein et al, 2003) and by others in electrophysiological studies .…”

Section: Introductionmentioning

confidence: 99%

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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“…Evidence for vigilance-enhancing properties was also given in another recent report [5] describing the effects of acute intraperitoneal doses of EGb 761 and several of its components on barbital-induced narcosis in mice. Single doses of the extract (25 and 50 mg/kg) administered 60 min prior to a narcotic dose of barbital significantly shortened sleeping time, with similar observations after ginkgolide B (1 mg/kg) or bilobalide (2 and 5 mg/ kg) pretreatment.…”

Section: Other Cns Effectsmentioning

confidence: 80%

Cognitive and Other Behavioral Effects of EGb 761® in Animal Models

Müller

Chatterjee²

2003

Pharmacopsychiatry

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Extensive pre-clinical and clinical studies conducted over more than three decades have established that EGb 761 (definition see editorial) represents a polyvalent therapeutic principle that is useful in the therapy of mildly to moderately severe dementia and other cognitive disorders. Besides cognition, other emotional and affective aspects of brain function also seem to benefit from EGb 761 treatment. Extensive behavioural studies in experimental animals are generally in line with clinical data since cognition improvement, stress protection, and antidepressive effects have been identified with this extract in proper animal models. While individual effects in all areas have been reported for adult animals and acute dosing, more pronounced effects are usually seen in aged animals and after subchronic treatment. Specifically, for the cognition improving properties pronounced beneficial effects are mainly present in those situations where cognition was impaired by aging or other noxious stimuli. Since all these conditions are associated with mitochondrial dysfunction, the stabilizing or even protecting effect of EGb 761 on mitochondrial function seems to be a major mechanism associated with many of EGb 761's behavioural effects. Bilobalide is most important in this respect. Moreover, bilobalide and the ginkgolides have recently been shown to affect chloride conductance by interfering with the function of membrane proteins related to receptor-gated chloride channels. These mechanisms are probably associated with behavioural effects requiring acute changes of neuronal activity, but might indirectly also improve mitochondrial function.

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Effects of single intraperitoneal injections of an extract of Ginkgo biloba (EGb 761) and its terpene trilactone constituents on barbital-induced narcosis in the mouse

Cited by 25 publications

References 15 publications

Inactivation of the Hepatic Cytochrome P450 System by Conditional Deletion of Hepatic Cytochrome P450 Reductase

Inactivation of the Hepatic Cytochrome P450 System by Conditional Deletion of Hepatic Cytochrome P450 Reductase

Role of GABAergic antagonism in the neuroprotective effects of bilobalide

Cognitive and Other Behavioral Effects of EGb 761® in Animal Models

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