Genetic and Molecular Regulation of Extrasynaptic GABA-A Receptors in the Brain: Therapeutic Insights for Epilepsy

Chuang, Shu-Hui; Reddy, Doodipala Samba

doi:10.1124/jpet.117.244673

Cited by 120 publications

(121 citation statements)

References 206 publications

(233 reference statements)

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“…Our results suggest that the sex differences in the protective potency of neurosteroids and their synthetic analogs could be related to GABA‐A receptor subunit plasticity. The δ‐subunit containing GABA‐A receptors, located perisynaptically/extrasynaptically, mediate tonic current activated by ambient GABA levels . Neurosteroids can activate most GABA‐A receptor isoforms, but the δ‐containing receptors are more sensitive to neurosteroids .…”

Section: Discussionmentioning

confidence: 99%

“…The δ-subunit containing GABA-A receptors, located perisynaptically/extrasynaptically, mediate tonic current activated by ambient GABA levels. 19,39 Neurosteroids can activate most GABA-A receptor isoforms, but the δ-containing receptors are more sensitive to neurosteroids. 40,41 The δ-subunit undergoes dynamic plasticity during the ovarian cycle in females, with high expression at late diestrus and low expression at other stages.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to endogenous AD and AP, we investigated the protective efficacy of the synthetic neurosteroid ganaxolone in a kindling model of perimenstrual catamenial epilepsy in female mice. 16,19 We investigated the efficacy of ganaxolone in female mice undergoing perimenstrual-like NSW, which is linked to catamenial seizure exacerbation. 28,31 NSW is associated with up-regulation of δGABA-A receptors in the hippocampus 26 that may contribute to enhanced seizure protection by ganaxolone.…”

Section: Enhanced Antiseizure Sensitivity Of Ganaxolone In Catamenimentioning

confidence: 99%

“…Neurosteroids act on both synaptic (γ 2 ‐containing) and extrasynaptic (δ‐containing) GABA‐A receptors to regulate neuronal excitability . Neurosteroids exhibit relatively lower sensitivities at synaptic receptors than at extrasynaptic receptors, which are localized extrasynaptically in the dentate gyrus and contribute to tonic inhibition, promoting network shunting and reducing seizure susceptibility .…”

Section: Introductionmentioning

confidence: 99%

“…16,17 Neurosteroids act on both synaptic (γ 2 -containing) and extrasynaptic (δ-containing) GABA-A receptors to regulate neuronal excitability. 18,19 Neurosteroids exhibit relatively lower sensitivities at synaptic receptors than at extrasynaptic receptors, which are localized extrasynaptically in the dentate gyrus and contribute to tonic inhibition, promoting network shunting and reducing seizure susceptibility. 18 Neurosteroids are robust anticonvulsants in a variety of animal seizure models, including status epilepticus (SE), 4 with the exception of certain genetic conditions such as absence models, where they are shown to cause seizure exacerbations.…”

Section: Introductionmentioning

confidence: 99%

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Extrasynaptic γ‐aminobutyric acid type A receptor–mediated sex differences in the antiseizure activity of neurosteroids in status epilepticus and complex partial seizures

et al. 2019

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Summary Objective Sex differences are evident in the antiseizure activity of neurosteroids; however, the potential mechanisms remain unclear. In this study, we sought to determine whether differences in target extrasynaptic δ‐subunit γ‐aminobutyric acid type A (GABA‐A) receptor expression and function underlie the sex differences in seizure susceptibility and the antiseizure activity of neurosteroids. Methods Sex differences in seizure susceptibility and protective activity of three distinct neurosteroids—allopregnanolone (AP), androstanediol (AD), and ganaxolone—were evaluated in the pilocarpine model of status epilepticus (SE) and kindling seizure test in mice. Immunocytochemistry was used for δGABA‐A receptor expression analysis, and patch‐clamp recordings in brain slices evaluated its functional currents. Results Sex differences were apparent in kindling epileptogenic seizures, with males exhibiting a faster progression to a fully kindled state. Neurosteroids AP, AD, or ganaxolone produced dose‐dependent protection against SE and acute partial seizures. However, female mice exhibited strikingly enhanced sensitivity to the antiseizure activity of neurosteroids compared to males. Sex differences in neurosteroid protection were unrelated to pharmacokinetic factors, as plasma levels of neurosteroids associated with seizure protection were similar between sexes. Mice lacking extrasynaptic δGABA‐A receptors did not exhibit sex differences in neurosteroid protection. Consistent with a greater abundance of extrasynaptic δGABA‐A receptors, AP produced a significantly greater potentiation of tonic currents in dentate gyrus granule cells in females than males; however, such enhanced AP sensitivity was diminished in δGABA‐A receptor knockout female mice. Significance Neurosteroids exhibit greater antiseizure potency in females than males, likely due to a greater abundance of extrasynaptic δGABA‐A receptors that mediate neurosteroid‐sensitive tonic currents and seizure protection. These findings indicate the potential to develop personalized gender‐specific neurosteroid treatments for SE and epilepsy in men and women, including catamenial epilepsy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Enhanced Antiseizure Sensitivity Of Ganaxolone In Catamenimentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Extrasynaptic γ‐aminobutyric acid type A receptor–mediated sex differences in the antiseizure activity of neurosteroids in status epilepticus and complex partial seizures

et al. 2019

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A Comprehensive and Advanced Mouse Model of Post‐Traumatic Epilepsy with Robust Spontaneous Recurrent Seizures

et al. 2022

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Traumatic brain injury (TBI) is a leading cause of epilepsy in military persons and civilians. Spontaneous recurrent seizures (SRSs) occur in the months or years following the injury, which is commonly referred to as post-traumatic epilepsy (PTE). Currently, there is no effective treatment or cure for PTE; therefore, there is a critical need to develop animal models to help further understand and assess mechanisms and interventions related to TBI-induced epilepsy. Despite many attempts to induce PTE in animals, success has been limited due to a lack of consistent SRSs after TBI. We present a comprehensive protocol to induce PTE after contusion brain injury in mice, which exhibit robust SRSs along with neurodegeneration and neuroinflammation. This article provides a complete set of protocols for injury, outcomes, troubleshooting, and data analysis. Our broad profiling of a TBI mouse reveals features of progressive, long-lasting epileptic activity, hippocampal sclerosis, and comorbid mood and memory deficits. Overall, the PTE mouse shows striking consistency in recapitulating major hallmark features of human PTE. This mouse model will be helpful in assessing mechanisms of and interventions for TBI-induced epileptogenesis, epilepsy, and neuropsychiatric dysfunction.

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Comparative pharmacodynamic and pharmacokinetic study of MIDD0301 and its (S) enantiomer

Roni

Zahn

Yocum

et al. 2022

Drug Development Research

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MIDD0301 is being developed as an oral drug to relax airway smooth muscle (ASM) and reduce lung inflammation in asthma. We report a comparative study of MIDD0301 and its S isomer (MIDD0301S), and found that the compounds have equivalent affinity for γ-aminobutyric acid type A receptor (GABA A R) expressed in rat brain, with half maximal inhibitory concentration values of 25.1 and 26.3 nM for the S and R enantiomers, respectively. Both compounds relaxed substance P contracted ASM within 30 min and neither enantiomer revealed affinity to 48 receptors in an off-target screen. Both enantiomers reduced airway hyperresponsiveness (AHR) with nebulized and oral dosing in two mouse models of bronchoconstriction.In A/J mice, which are very sensitive to methacholine-induced bronchoconstriction, we observed reduction of AHR at 10.8 mg/kg MIDD0301 and 15 mg/kg MIDD0301S. Using oral administration, 100 mg/kg/day for 3 days of either enantiomer was sufficient to reduce AHR. In a model of severe airway inflammation induced by interferon-γ and lipopolysaccharide (LPS), we observed reduction of AHR at 7.2 mg/kg for both enantiomers using nebulized administration, and at 100 mg/kg for oral administration. MIDD0301 and MIDD0301S did not undergo Phase I metabolism. Glucuronidation was observed for both compounds, whereas only MIDD0301 formed the corresponding glucoside in the presence of kidney microsomes. Pharmacokinetic analysis identified glucuronides as the major metabolite with concentrations up to 20-fold more than the parent compound. MIDD0301 glucuronide and MIDD0301 taurine bind GABA A Rs, although 10-fold weaker than MIDD0301. In mouse blood, the taurine adduct was only observed for MIDD0301.Overall, both compounds exhibited similar receptor binding and pharmacodynamic properties with subtle differences in metabolism and greater oral availability and blood concentrations of MIDD0301S.

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Genetic and Molecular Regulation of Extrasynaptic GABA-A Receptors in the Brain: Therapeutic Insights for Epilepsy

Cited by 120 publications

References 206 publications

Extrasynaptic γ‐aminobutyric acid type A receptor–mediated sex differences in the antiseizure activity of neurosteroids in status epilepticus and complex partial seizures

Extrasynaptic γ‐aminobutyric acid type A receptor–mediated sex differences in the antiseizure activity of neurosteroids in status epilepticus and complex partial seizures

A Comprehensive and Advanced Mouse Model of Post‐Traumatic Epilepsy with Robust Spontaneous Recurrent Seizures

Comparative pharmacodynamic and pharmacokinetic study of MIDD0301 and its (S) enantiomer

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