Neurosteroids and their role in sex-specific epilepsies

Reddy, Doodipala Samba

doi:10.1016/j.nbd.2014.06.010

Cited by 54 publications

(44 citation statements)

References 124 publications

(185 reference statements)

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“…Higher concentrations represent direct activation of GABA A receptors in the ability to achieve full anticonvulsant protection by AP. This pharmacokinetics/pharmacodynamics relationship is consistent with the anticonvulsant profile of neurosteroids (Reddy and Rogawski, 2002;Reddy, 2004Reddy, , 2011Reddy, , 2014Reddy and Woodward, 2004).…”

Section: Tablesupporting

confidence: 74%

Neurosteroid Structure-Activity Relationships for Functional Activation of Extrasynaptic GABAA Receptors

Carver

Reddy

2016

Journal of Pharmacology and Experimental Therapeutics

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Synaptic GABA A receptors are primary mediators of rapid inhibition in the brain and play a key role in the pathophysiology of epilepsy and other neurologic disorders. The d-subunit GABA A receptors are expressed extrasynaptically in the dentate gyrus and contribute to tonic inhibition, promoting network shunting as well as reducing seizure susceptibility. However, the neurosteroid structure-function relationship at dGABA A receptors within the native hippocampus neurons remains unclear. Here we report a structure-activity relationship for neurosteroid modulation of extrasynaptic GABA A receptor-mediated tonic inhibition in the murine dentate gyrus granule cells. We recorded neurosteroid allosteric potentiation of GABA as well as direct activation of tonic currents using a wide array of natural and synthetic neurosteroids. Our results shows that, for all neurosteroids, the C3a-OH group remains obligatory for extrasynaptic receptor functional activity, as C3b-OH epimers were inactive in activating tonic currents. Allopregnanolone and related pregnane analogs exhibited the highest potency and maximal efficacy in promoting tonic currents. Alterations at the C17 or C20 region of the neurosteroid molecule drastically altered the transduction kinetics of tonic current activation. The androstane analogs had the weakest modulatory response among the analogs tested. Neurosteroid potentiation of tonic currents was completely (approximately 95%) diminished in granule cells from d-knockout mice, suggesting that d-subunit receptors are essential for neurosteroid activity. The neurosteroid sensitivity of dGABA A receptors was confirmed at the systems level using a 6-Hz seizure test. A consensus neurosteroid pharmacophore model at extrasynaptic dGABA A receptors is proposed based on a structure-activity relationship for activation of tonic current and seizure protection.

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Section: Tablesupporting

confidence: 74%

Neurosteroid Structure-Activity Relationships for Functional Activation of Extrasynaptic GABAA Receptors

Carver

Reddy

2016

Journal of Pharmacology and Experimental Therapeutics

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confidence: 99%

The Perimenstrual Delta Force: A Trojan Horse for Neurosteroid Effects

Galanopoulou¹

2015

Epilepsy Curr

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CommentaryHormones influence neuronal excitability and seizure susceptibility in both adulthood and during development (1)(2)(3)(4)(5)(6)(7)(8). A paradigm illustrating these interactions is catamenial epilepsy, where seizures may cluster around specific periods of the menstrual cycle (3). The perimenstrual (C1) type of catamenial epilepsy is a type of epilepsy in which seizures cluster around the menstrual phase when estradiol, progesterone, as well as the neurosteroid allopregnanolone decline. Allopregnanolone is a progesterone metabolite known to act on GABA A receptors. Progesterone is converted to 5a-dihydroprogesterone (5a-DHP) by 5a-reductase, and then 5a-DHP is converted to allopregnanolone by 3b-hydroxysteroid dehydrogenase (3b-HSD).Reddy's team has been a pioneer in studies aiming to shed light in the molecular and pathophysiological mechanisms of increased seizure susceptibility in perimenstrual epilepsy. To recreate the hormonal and neurosteroid changes occurring during this perimenstrual period, they introduced a model of neurosteroid withdrawal (NSW) in adult female mice by administering high dose progesterone twice daily for 7 days followed by finasteride, a 5a-reductase inhibitor that blocks neurosteroid synthesis (8). This NSW model recreates high levels of allopregnanolone during the progesterone administration phase, which rapidly decline to normal levels during NSW. Interestingly, NSW mice demonstrate increased susceptibility to kindling associated with increased expression of the a4 GABA A receptor subunit in the dentate gyrus granule cells (8). The Carver et al. study completes these findings by showing a parallel increased expression of the d GABA A receptor subunit, a common partner of a4 in extrasynaptic GABA A receptors, as well as enhanced allopregnanolone potentiation of tonic but also phasic GABA A receptor currents in NSW mice. Such findings would be normally considered as capable of evoking antiseizure effects by increasing tonic inhibition. However, the authors found smaller tonic GABA current shifts in NSW granule cells compared to controls in the absence of added GABA, possibly suggesting the existence of silent GABA A receptors or low extracellular GABA in NSW hippocampus. In d knock-out Neurosteroids are endogenous regulators of neuronal excitability and seizure susceptibility. Neurosteroids, such as allopregnanolone (AP; 3α-hydroxy-5α-pregnan-20-one), exhibit enhanced anticonvulsant activity in perimenstrual catamenial epilepsy, a neuroendocrine condition in which seizures are clustered around the menstrual period associated with neurosteroid withdrawal (NSW). However, the molecular mechanisms underlying such enhanced neurosteroid sensitivity remain unclear. Neurosteroids are allosteric modulators of both synaptic (αβγ2-containing) and extrasynaptic (αβδ-containing) GABA A receptors, but they display greater sensitivity toward δ-subunit receptors in dentate gyrus granule cells (DGGCs). Here we report a novel plasticity of extrasynaptic δ-containing GABA A receptors in the den...

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“…In particular, estradiol, allopregnanolone and related endogenous neurosteroids serve to reduce intrinsic neuronal excitability through various mechanisms 204 .…”

Section: Psychosis As a Disorder Of Connectivitymentioning

confidence: 99%

Inefficient Neural Self-Stabilization: A theory of spontaneous resolutions and recurrent relapses in psychosis

Palaniyappan

2018

Preprint

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Neurosteroids and their role in sex-specific epilepsies

Cited by 54 publications

References 124 publications

Neurosteroid Structure-Activity Relationships for Functional Activation of Extrasynaptic GABAA Receptors

Neurosteroid Structure-Activity Relationships for Functional Activation of Extrasynaptic GABAA Receptors

The Perimenstrual Delta Force: A Trojan Horse for Neurosteroid Effects

Inefficient Neural Self-Stabilization: A theory of spontaneous resolutions and recurrent relapses in psychosis

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