Modulation of native and recombinant GABAA receptors by endogenous and synthetic neuroactive steroids

Lambert, Jeremy J.; Belelli, Delia; Harney, Sarah C.; Peters, John A.; Frenguelli, Bruno G.

doi:10.1016/s0165-0173(01)00124-2

Cited by 145 publications

(101 citation statements)

References 67 publications

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“…Some GABA-potentiating steroids, including endogenous GABA-potentiating steroids, were reported to be largely inactive at glycine receptors Belelli et al, 1999b;Harrison et al, 1987;Pistis et al, 1997). On the other hand, some synthetic GABA-potentiating steroids augment glycine responses generated by recombinant glycine receptors (Lambert et al, 2001). Recent papers, however, reported significant antagonistic effects of 3α5βP on native and recombinant glycine receptors (Jiang et al, 2006;Weir et al, 2004).…”

Section: C Actions Of Neurosteroids Not Involving Gaba a Receptorsmentioning

confidence: 99%

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Mechanisms of neurosteroid interactions with GABAA receptors

Akk¹,

Covey²,

Evers³

et al. 2007

Pharmacology & Therapeutics

149

166

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Neuroactive steroids have some of their most potent actions by augmenting the function of GABA A receptors. Endogenous steroid actions on GABA A receptors may underlie important effects on mood and behavior. Exogenous neuroactive steroids have potential as anesthetics, anticonvulsants, and neuroprotectants. We have taken multiple approaches to understand more completely the interaction of neuroactive steroids with GABA A receptors. We have developed many novel steroid analogues in this effort. Recent work has resulted in synthesis of new enantiomer analogue pairs, novel ligands that probe various properties of the steroid pharmacophore, fluorescent neuroactive steroid analogues, and photoaffinity labels. Using these tools, combined with receptor binding and electrophysiological assays, we have begun to untangle the complexity of steroid actions at this important class of ligand-gated ion channel.

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Section: C Actions Of Neurosteroids Not Involving Gaba a Receptorsmentioning

confidence: 99%

“…Comprehensive recent reviews of many aspects of steroid/GABA A receptor interactions are available Brussaard & Koksma, 2003;Lambert et al, 2001;Lambert et al, 2003;Matsumoto et al, 2005;Reddy, 2004). Here we focus on several aspects of this interaction that have not been the primary focus of recent reviews.…”

Section: Steroid Interaction With the Gaba A Receptormentioning

confidence: 99%

Mechanisms of neurosteroid interactions with GABAA receptors

Akk¹,

Covey²,

Evers³

et al. 2007

Pharmacology & Therapeutics

149

166

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“…Additionally, following ethanol activation of the hypothalamicpituitary-adrenal (HPA) axis (denoted by the darkened arrows), ethanol increases neurosteroid precursors from the adrenal, which in turn results in increased neurosteroids in brain (Barbaccia et al, 1999;Khisti et al, 2003;O'Dell et al, 2004). Since neuroactive steroids enhance GABA responsiveness (Lambert et al, 2001(Lambert et al, , 2003Paul and Purdy, 1992), it is proposed that the ethanol-induced enhancement of neurosteroid presence in brain synergizes the effect of GABA released by ethanol (Criswell and Breese, 2005). Finally, other possible means by which ethanol is capable of enhancing the effect of GABA is by reducing excitatory drive or by influencing phosphorylation of GABA A receptors (see these topics in Additional Considerations).…”

Section: Proposed Role For Bzd-insensitive Gaba a Receptors In Ethanomentioning

confidence: 99%

“…These combined actions are proposed to be the primary contributors to the GABAmimetic profile of ethanol (Figure 4). Further, the specificity of neurosteroids on differing GABA A receptor subtypes (see Belelli et al, 2002;Bianchi and Macdonald, 2003;Lambert et al, 2001Lambert et al, , 2003Spigelman et al, 2003;Stell et al, 2003;Wallner et al, 2003) could conceivably contribute to the regional specificity of ethanol on GABA function.…”

Section: Neurosteroid Involvement In the Gabamimetic Profile Of Ethanmentioning

confidence: 99%

A Conceptualization of Integrated Actions of Ethanol Contributing to its GABAmimetic Profile: A Commentary

Criswell

Breese

2005

Neuropsychopharmacol

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Early behavioral investigations supported the contention that systemic ethanol displays a GABAmimetic profile. Microinjection of GABA agonists into brain and in vivo electrophysiological studies implicated a regionally specific action of ethanol on GABA function. While selectivity of ethanol to enhance the effect of GABA was initially attributed an effect on type-1-benzodiazepine (BZD)-GABA A receptors, a lack of ethanol's effect on GABA responsiveness from isolated neurons with this receptor subtype discounted this contention. Nonetheless, subsequent work identified GABA A receptor subtypes, with limited distribution in brain, sensitive to enhancement of GABA at relevant ethanol concentrations. In view of these data, it is hypothesized that the GABAmimetic profile for ethanol is due to activation of mechanisms associated with GABA function, distinct from a direct action on the majority of postsynaptic GABA A receptors. The primary action proposed to account for ethanol's regional specificity on GABA transmission is its ability to release GABA from some, but not all, presynaptic GABAergic terminals. As systemic administration of ethanol increases neuroactive steroids, which can enhance GABA responsiveness, this elevated level of neurosteroids is proposed to magnify the effect of GABA released by ethanol. Additional factors contributing to the degree to which ethanol interacts with GABA function include an involvement of GABA B and other receptors that influence ethanol-induced GABA release, an effect of phosphorylation on GABA responsiveness, and a regional reduction of glutamatergic tone. Thus, an integration of these consequences induced by ethanol is proposed to provide a logical basis for its in vivo GABAmimetic profile.

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“…Allopregnanolone is a potent, endogenously produced neuroactive steroid that acts as a positive allosteric modulator (PAM) on a broad range of γ‐aminobutyric acid type A receptor (GABA A R) isoforms12, 13, 14, 15, 16 expressed throughout the brain, including those that mediate either phasic or tonic inhibition 17, 18, 19. Extrasynaptic receptors containing the δ‐subunit that mediate tonic inhibition are particularly sensitive to modulation by neurosteroids 18.…”

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confidence: 99%

Brexanolone as adjunctive therapy in super‐refractory status epilepticus

Rosenthal

Claassen

Wainwright

et al. 2017

Annals of Neurology

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ObjectiveSuper‐refractory status epilepticus (SRSE) is a life‐threatening form of status epilepticus that continues or recurs despite 24 hours or more of anesthetic treatment. We conducted a multicenter, phase 1/2 study in SRSE patients to evaluate the safety and tolerability of brexanolone (USAN; formerly SAGE‐547 Injection), a proprietary, aqueous formulation of the neuroactive steroid, allopregnanolone. Secondary objectives included pharmacokinetic assessment and open‐label evaluation of brexanolone response during and after anesthetic third‐line agent (TLA) weaning.MethodsPatients receiving TLAs for SRSE control were eligible for open‐label, 1‐hour brexanolone loading infusions, followed by maintenance infusion. After 48 hours of brexanolone infusion, TLAs were weaned during brexanolone maintenance. After 4 days, the brexanolone dose was tapered. Safety and functional status were assessed over 3 weeks of follow‐up.ResultsTwenty‐five patients received open‐label study drug. No serious adverse events (SAEs) were attributable to study drug, as determined by the Safety Review Committee. Sixteen patients (64%) experienced ≥1 SAE. Six patient deaths occurred, all deemed related to underlying medical conditions. Twenty‐two patients underwent ≥1 TLA wean attempt. Seventeen (77%) met the response endpoint of weaning successfully off TLAs before tapering brexanolone. Sixteen (73%) were successfully weaned off TLAs within 5 days of initiating brexanolone infusion without anesthetic agent reinstatement in the following 24 hours.InterpretationIn an open‐label cohort of limited size, brexanolone demonstrated tolerability among SRSE patients of heterogeneous etiologies and was associated with a high rate of successful TLA weaning. The results suggest the possible development of brexanolone as an adjunctive therapy for SRSE requiring pharmacological coma for seizure control. Ann Neurol 2017;82:342–352

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Modulation of native and recombinant GABAA receptors by endogenous and synthetic neuroactive steroids

Cited by 145 publications

References 67 publications

Mechanisms of neurosteroid interactions with GABAA receptors

Mechanisms of neurosteroid interactions with GABAA receptors

A Conceptualization of Integrated Actions of Ethanol Contributing to its GABAmimetic Profile: A Commentary

Brexanolone as adjunctive therapy in super‐refractory status epilepticus

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