Propofol and flurazepam act synergistically to potentiate GABAA receptor activation in human recombinant receptors

Reynolds, James N.; Maitra, Rajatavo

doi:10.1016/s0014-2999(96)00527-4

Cited by 21 publications

(7 citation statements)

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“…Richards and White () found that the steroid alphaxalone enhanced the anaesthetic effect of etomidate in rats. Synergistic interactions (loosely defined as more than additive effects of combinations of drugs) in electrophysiological assays have previously been noted for benzodiazepines and barbiturates (DeLorey et al ., ), or benzodiazepines and propofol (Reynolds and Maitra, ), and benzodiazepines show synergy with propofol with respect to some anaesthetic end points (Reynolds and Maitra, ; Wilder‐Smith et al ., ). An additive effect of the actions of propofol and sevoflurane was found using recombinant GABA A receptors (Sebel et al ., ).…”

Section: Discussionmentioning

confidence: 99%

The neurosteroid 5β‐pregnan‐3α‐ol‐20‐one enhances actions of etomidate as a positive allosteric modulator of α1β2γ2L GABA_A receptors

Bracamontes

Manion

et al. 2014

British J Pharmacology

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BACKGROUND AND PURPOSENeurosteroids potentiate responses of the GABAA receptor to the endogenous agonist GABA. Here, we examined the ability of neurosteroids to potentiate responses to the allosteric activators etomidate, pentobarbital and propofol. EXPERIMENTAL APPROACHElectrophysiological assays were conducted on rat α1β2γ2L GABAA receptors expressed in HEK 293 cells. The sedative activity of etomidate was studied in Xenopus tadpoles and mice. Effects of neurosteroids on etomidate-elicited inhibition of cortisol synthesis were determined in human adrenocortical cells. KEY RESULTSThe neurosteroid 5β-pregnan-3α-ol-20-one (3α5βP) potentiated activation of GABAA receptors by GABA and allosteric activators. Co-application of 1 μM 3α5βP induced a leftward shift (almost 100-fold) of the whole-cell macroscopic concentration-response relationship for gating by etomidate. Co-application of 100 nM 3α5βP reduced the EC50 for potentiation by etomidate of currents elicited by 0.5 μM GABA by about three-fold. In vivo, 3α5βP (1mg kg -1 ) reduced the dose of etomidate required to produce loss of righting in mice (ED50) by almost 10-fold. In tadpoles, the presence of 50 or 100 nM 3α5βP shifted the EC50 for loss of righting about three-or ten-fold respectively. Exposure to 3α5βP did not influence inhibition of cortisol synthesis by etomidate. CONCLUSIONS AND IMPLICATIONSPotentiating neurosteroids act similarly on orthosterically and allosterically activated GABAA receptors. Co-application of neurosteroids with etomidate can significantly reduce dosage requirements for the anaesthetic, and is a potentially beneficial combination to reduce undesired side effects. Abbreviations3α5αP, 5α-pregnan-3α-ol-20-one; 3α5βP, 5β-pregnan-3α-ol-20-one (pregnanolone); LRR, loss of righting reflex BJP British Journal of Pharmacology

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Section: Discussionmentioning

confidence: 99%

The neurosteroid 5β‐pregnan‐3α‐ol‐20‐one enhances actions of etomidate as a positive allosteric modulator of α1β2γ2L GABA_A receptors

Bracamontes

Manion

et al. 2014

British J Pharmacology

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“…They show different subunit dependence (Fisher, 2009) and the action of stiripentol is not blocked by benzodiazepine-site antagonists (Quilichini et al 2006). However, other positive modulators of GABA A receptors acting at distinct sites have been shown to interact to enhance (Reynolds and Maitra, 1996) or to inhibit (Zhong and Simmonds, 1997) one another. We co-applied a maximally effective concentration of stiripentol with the benzodiazepines diazepam, clonazepam, clobazam and norclobazam to recombinant α3β3γ2L or α3β3δ receptors.…”

Section: Discussionmentioning

confidence: 99%

Interactions between modulators of the GABAA receptor: Stiripentol and benzodiazepines

Fisher

2011

European Journal of Pharmacology

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Many patients with refractory epilepsy are treated with polytherapy, and nearly 15% of epilepsy patients receive two or more anti-convulsant agents. The anti-convulsant stiripentol is used as an add-on treatment for the childhood epilepsy syndrome known as severe myoclonic epilepsy in infancy (Dravet Syndrome). Stiripentol has multiple mechanisms of action, both enhancing GABAA receptors and reducing activity of metabolic enzymes that break down other drugs. Stiripentol is typically co-administered with other anti-convulsants such as benzodiazepines which also act through GABAA receptor modulation. Stiripentol slows the metabolism of some of these drugs through inhibition of a variety of cytochrome P450 enzymes, but could also influence their effects on GABAergic neurotransmission. Is it rational to co-administer drugs which can act through the same target? To examine the potential interaction between these modulators, we transiently transfected HEK-293T cells to produce α3β3γ2L or α3β3δ recombinant GABAA receptors. Using whole-cell patch clamp recordings, we measured the response to each benzodiazepine alone and in combination with a maximally effective concentration of stiripentol. We compared the responses to four different benzodiazepines: diazepam, clonazepam, clobazam and norclobazam. In all cases we found that these modulators were equally effective in the presence and absence of stiripentol. The δ-containing receptors were insensitive to modulation by the benzodiazepines, which did not affect potentiation by stiripentol. These data suggest that stiripentol and the benzodiazepines act independently at GABAA receptors and that polytherapy could be expected to increase the maximum effect beyond either drug alone, even without consideration of changes in metabolism.

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“…However, in relating drug affinities in vitro to effective doses in vivo, one should like to know something about the bioavailability, plasma concentrations, and brain penetration of the drugs in question. In this regard, zopiclone is rapidly absorbed, distributed in various tissues, including brain, and achieves plasma concentrations of 30 to 90 ng ml Ϫ1 (100 -300 nM) after therapeutic doses (Gaillot et al, 1983), which is comparable with its effective concentration at GABA A receptors in vitro (Table 2; Reynolds and Maitra, 1996;Davies et al, 2000). There are as yet no comparable pharmacokinetic data on SEP-174559, but it may be important to consider that SEP-174559 is far more soluble in aqueous solution than zopiclone or benzodiazepines and so might differ dramatically in its ability to act at central GABA A receptors.…”

Section: Discussionmentioning

confidence: 99%

“…Racemic zopiclone, which consists of (R)-and (S)-enantiomers, acts at the benzodiazepine site to enhance GABA A receptor binding and function (Im et al, 1993;Davies et al, 2000). Although the selectivity of zopiclone is not fully characterized, it is known to act at ␥2-bearing GABA A receptors, including ␣1␤2␥2 (Im et al, 1993;Reynolds and Maitra, 1996;Davies et al, 2000). Recent behavioral studies in rodents suggest that the sedative and anxiolytic activities of (R,S)-zopiclone are produced mainly by the (S)-enantiomer (Carlson et al, 2001), which is metabolized in vivo to (S)-desmethylzopiclone (SEP-174559).…”

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confidence: 99%

Molecular Actions of (S)-Desmethylzopiclone (SEP-174559), an Anxiolytic Metabolite of Zopiclone

Fleck

2002

J Pharmacol Exp Ther

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This study set out to profile the activity of (S)-desmethylzopiclone (SEP-174559) at subtypes of the ␥-aminobutyric acid type-A (GABA A ) receptor and other neurotransmitter receptor ion channels. Recombinant receptors were expressed in human embryonic kidney 293 cells and examined functionally by patch-clamp recording with fast perfusion of agonist and drug solutions. Micromolar concentrations of SEP-174559 potentiated GABA A receptor currents evoked by subsaturating concentrations of GABA. The potentiation was related to a leftward shift in the GABA dose-response curves, suggesting the drug acts to increase GABA binding affinity. The potentiation strictly required the presence of the ␥2 subunit; no enhancement was seen for receptors containing instead the ␥1 subunit or lacking a ␥ subunit altogether. SEP-174559 and its parent compound, racemic zopiclone, were not selective between ␣1-, ␣2-, or ␣3-bearing GABA A receptors. Within the nicotinic receptor superfamily, SEP-174559 did not affect serotonin type-3 receptor function but was found to inhibit nicotinic acetylcholine (nACh) receptors. The inhibition of nACh receptors was noncompetitive and was mimicked by zopiclone, alprazolam, and diazepam. In the glutamate receptor superfamily, SEP-174559 inhibited N-methyl-D-aspartate (NMDA) receptor currents but did not affect non-NMDA receptors. These data confirm that SEP-174559 has benzodiazepine-like actions at ␥2-bearing subtypes of the GABA A receptor and suggest additional actions of benzodiazepine-site ligands at nACh and NMDA receptors.

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Propofol and flurazepam act synergistically to potentiate GABAA receptor activation in human recombinant receptors

Cited by 21 publications

References 17 publications

The neurosteroid 5β‐pregnan‐3α‐ol‐20‐one enhances actions of etomidate as a positive allosteric modulator of α1β2γ2L GABA_A receptors

The neurosteroid 5β‐pregnan‐3α‐ol‐20‐one enhances actions of etomidate as a positive allosteric modulator of α1β2γ2L GABA_A receptors

Interactions between modulators of the GABAA receptor: Stiripentol and benzodiazepines

Molecular Actions of (S)-Desmethylzopiclone (SEP-174559), an Anxiolytic Metabolite of Zopiclone

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Propofol and flurazepam act synergistically to potentiate GABAA receptor activation in human recombinant receptors

Cited by 21 publications

References 17 publications

The neurosteroid 5β‐pregnan‐3α‐ol‐20‐one enhances actions of etomidate as a positive allosteric modulator of α1β2γ2L GABAA receptors

The neurosteroid 5β‐pregnan‐3α‐ol‐20‐one enhances actions of etomidate as a positive allosteric modulator of α1β2γ2L GABAA receptors

Interactions between modulators of the GABAA receptor: Stiripentol and benzodiazepines

Molecular Actions of (S)-Desmethylzopiclone (SEP-174559), an Anxiolytic Metabolite of Zopiclone

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Product

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The neurosteroid 5β‐pregnan‐3α‐ol‐20‐one enhances actions of etomidate as a positive allosteric modulator of α1β2γ2L GABA_A receptors

The neurosteroid 5β‐pregnan‐3α‐ol‐20‐one enhances actions of etomidate as a positive allosteric modulator of α1β2γ2L GABA_A receptors