Steroid receptor-mediated effects of neuroactive steroids: characterization of structure-activity relationship

Rupprecht, Rainer; Berning, Barbara; Hauser, Charlotte; Holsboer, Florian; Reul, Johannes M. H. M.

doi:10.1016/0014-2999(96)00036-2

Cited by 57 publications

(33 citation statements)

References 34 publications

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“…The GABA A receptor is an important target for the neurosteroid allopregnanolone (14), but allopregnanolone is also capable of regulating gene expression via intracellular oxidation to dihydroprogesterone, which is a moderately potent PR agonist (22,23). In the present study, allopregnanolone has similar anesthetic activity in WT and PRKO mice, suggesting that PRs are not directly involved in the anesthetic activity of allopregnanolone.…”

Section: Discussionsupporting

confidence: 59%

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Differential anesthetic activity of ketamine and the GABAergic neurosteroid allopregnanolone in mice lacking progesterone receptor A and B subtypes

Reddy¹,

Zeng²

2007

Methods and Findings in Experimental and Clinical Pharmacology

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SUMMARY-Progesterone affects the function of the brain by multiple mechanisms. The physiological effects of progesterone are mediated by interaction of the hormone with progesterone receptors (PRs), which are widely expressed in the hypothalamus, hippocampus and limbic areas. The PR is composed of two protein isoforms, PR-A and PR-B, which are expressed from a single PR gene. In addition, progesterone influences neuronal activity through its conversion to allopregnanolone, a neurosteroid that acts as a positive allosteric modulator of GABA A receptors. However, the role of PRs in the sedative-hypnotic action of neurosteroids is unclear. In this study, PR knockout (PRKO) mice were used as model to study the sedative-anesthetic actions of the progesterone-derived neurosteroid allopregnanolone and the non-competitive NMDA receptor antagonist ketamine. Mice were confirmed to be PR deficient by genotyping and immunohistochemistry of PR expression in the brain. Anesthetic potency was evaluated by the loss of the righting reflex paradigm. Allopregnanolone induced anesthetic activity was similar in PRKO mice and their wild-type littermates, suggesting that PRs are not involved in the anesthetic response to allopregnanolone. However, the non-competitive NMDA receptor antagonist ketamine has significantly reduced anesthetic potency in PRKO mice, suggesting a possible developmental plasticity of glutamate receptors. There was no marked gender-related difference to ketamine response in both genotypes. In conclusion, these results suggest that the neurosteroid allopregnanolone and ketamine produce differential anesthetic response in mice lacking PRs.

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Section: Discussionsupporting

confidence: 59%

“…Consistent with its allosteric activity at GABA A receptors, allopregnanolone induces sleep in a benzodiazepinelike fashion (20,21). Although allopregnanolone binds to PRs with very low affinity, it may indirectly affect PRs by intracellular oxidation to 5α-dihydroprogesterone, a moderately potent PR agonist (22,23).…”

Section: Introductionmentioning

confidence: 99%

Differential anesthetic activity of ketamine and the GABAergic neurosteroid allopregnanolone in mice lacking progesterone receptor A and B subtypes

Reddy¹,

Zeng²

2007

Methods and Findings in Experimental and Clinical Pharmacology

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“…In contrast, 17-OHP, an additional progesterone metabolite with a low affinity for the progesterone receptor (Botella et al, 1990), did not show significant suppression at any of the concentrations used. Pregnenolone, a precursor of progesterone with little affinity for the receptor (Rupprecht et al, 1996), exerted no significant suppression. The PBMNC responses were significantly enhanced by Estradiol-17b.…”

Section: Effect Of Ovarian Hormones On the Responses Of Pbmncs To E mentioning

confidence: 92%

Effect of ovarian hormones on periodical changes in immune resistance associated with estrous cycle in the beagle bitch

et al. 2004

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“…For the steroid anaesthetics, structure-activity studies comparing in vivo and in vitro potencies support a role for GABA A receptors in the actions of these compounds [32,33,[247][248][249]. For example, the nonanaesthetic isomer structural betaxalone does not modulate the GABA A receptor [250,251].…”

Section: Intravenous Agentsmentioning

confidence: 98%

General anaesthetic actions on ligand-gated ion channels

Krasowski

Harrison

1999

Cellular and Molecular Life Sciences (CMLS)

358

275

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The molecular mechanisms of general anaesthetics have remained largely obscure since their introduction into clinical practice just over 150 years ago. This review describes the actions of general anaesthetics on mammalian neurotransmitter-gated ion channels. As a result of research during the last several decades, ligand-gated ion channels have emerged as promising molecular targets for the central nervous system effects of general anaesthetics. The last 10 years have witnessed an explosion of studies of anaesthetic modulation of recombinant ligand-gated ion channels, including recent studies which utilize chimeric and mutated receptors to identify regions of ligand-gated ion channels important for the actions of general anaesthetics. Exciting future directions include structural biology and gene-targeting approaches to further the understanding of general anaesthetic molecular mechanisms.

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Steroid receptor-mediated effects of neuroactive steroids: characterization of structure-activity relationship

Cited by 57 publications

References 34 publications

Differential anesthetic activity of ketamine and the GABAergic neurosteroid allopregnanolone in mice lacking progesterone receptor A and B subtypes

Differential anesthetic activity of ketamine and the GABAergic neurosteroid allopregnanolone in mice lacking progesterone receptor A and B subtypes

Effect of ovarian hormones on periodical changes in immune resistance associated with estrous cycle in the beagle bitch

General anaesthetic actions on ligand-gated ion channels

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