Progesterone receptor-mediated effects of neuroactive steroids

Rupprecht, Rainer; Reul, Johannes M. H. M.; Trapp, Thorsten; Steensel, Bas van; Wetzel, Christian H.; Damm, Klaus; Zieglgänsberger, W.; Holsboer, Florian

doi:10.1016/0896-6273(93)90156-l

Cited by 288 publications

(157 citation statements)

References 39 publications

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“…These results indicate that neuroactive steroids may be able to compensate for the loss of corticosterone (or cortisol in humans) following metyrapone. In this context it is of interest that these neuroactive steroids may exert both genomic and nongenomic effects (Rupprecht et al 1993) and that the concentration of these steroids is modulated by antidepressants in animals and humans (Romeo et al 1998;Uzunova et al 1998;Ströhle et al 2000).…”

Section: Cortisol Synthesis Inhibitorsmentioning

confidence: 99%

The Corticosteroid Receptor Hypothesis of Depression

Holsboer

2000

Neuropsychopharmacology

1,958

1,228

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Clinical EvidenceUntil now, the serendipitous discovery of antidepressants in the 1950s has profoundly inspired hypotheses of the pathogenesis of depression. The well-known pharmacological effects of antidepressants on presynaptic uptake transporters and degradating enzymes (i.e., MAO) of serotonin and norepinephrine has focused research on causality and treatment of depression on the metabolism of functional biogenic amines and the capacity of their respective receptors to alter intracellular signaling pathways that ultimately induce changes in gene activity. Elevated circulating levels of stress hormones among depressives were recognized even before antidepressants were discovered, but these changes were seen as epiphenomena, reflecting the stressful experience of depression, although M. Bleuler (1919) already demonstrated that hormones have diverse psychotropic effects and suggested hormone treatments as potential antidepressants. A vast amount of evidence has accumulated, that reject the view that altered stress hormone secretions in depression are epiphenomenal. During the past decade, several research groups formulated a hypothesis relating aberrant stress hormone dysregulation to causality of depression and submitted that antidepressants may act through normalisation of these HPA changes (

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Section: Cortisol Synthesis Inhibitorsmentioning

confidence: 99%

The Corticosteroid Receptor Hypothesis of Depression

Holsboer

2000

Neuropsychopharmacology

1,958

1,228

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“…5α-dihydroprogesterone binds to and activates the cytosolic progesterone receptor (18) and is therefore able to regulate gene expression. Genomic effects, however, are slow to develop.…”

Section: Figmentioning

confidence: 99%

The Anticonvulsant Effects of Progesterone and 5α‐dihydroprogesterone on Amygdala‐kindled Seizures in Rats

Lonsdale

Burnham

2003

Epilepsia

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Summary:Purpose: Progesterone has been shown to be anticonvulsant in several animal seizure models. The purpose of the present study was to investigate the anticonvulsant actions of progesterone and its primary metabolite 5α-dihydroprogesterone in the amygdala kindling model.Methods: Female Wistar rats were implanted in the right basolateral amygdala with a long-term, bipolar electrode. The subjects were kindled to 30 stage 5 seizures and stability tested. Multiple doses of progesterone and 5α-dihydroprogesterone were then tested for anticonvulsant activity against focal electrographic and generalized convulsive kindled seizures. The time course of progesterone's anticonvulsant action also was examined.Results: Progesterone had a median effective dose (ED 50 ) of 103 mg/kg against generalized convulsions at 15 min after injection. Subjects were not sedated at the time of seizure testing, although sedation developed later (40-60 min after injection). In time-course experiments, it was found that 120 mg/kg of progesterone caused complete suppression of the generalized convulsion from 20 to 160 min after injection. Suppression of the focal discharge also was seen in some animals between 20 and 160 min. 5α-dihydroprogesterone had an ED 50 of 2.9 mg/kg against generalized kindled convulsions and an ED 50 of 4.3 mg/kg against focal afterdischarge 15 min after injection. 5α-dihydroprogesterone did not produce sedation 15 min after injection, or at any later time interval.Conclusions: Progesterone is anticonvulsant only at high doses when tested against amygdala kindled seizures. 5α-dihydroprogesterone is considerably more potent than progesterone. At low, nonsedative doses, it was effective against both the kindled amygdala focal afterdischarge and the generalized convulsion. Key Words: Progesterone-5α-dihydroprogesterone-Allopregnanolone-Kindling-Complex partial seizures.Treatment with anticonvulsant drugs (AEDs) is the most common therapy for epilepsy. Approximately 60% of patients are seizure free while taking AEDs, and a further 20% achieve partial control of their seizures (1). Twenty percent of patients, however, have intractable epilepsyepilepsy that is not responsive to any drug regimen (1). New drugs are needed to help the patients who are partially or completely resistant to the existing agents.Endogenous hormones, including progesterone, have been found to have anticonvulsant effects. In 1942, Selye (2) demonstrated that progesterone, at anesthetic doses, prevented the induction of seizures by pentylenetetrazol (PTZ) in rats. Craig (3) later determined that large doses of progesterone also protected mice against PTZ-induced seizures.The anticonvulsant effects of progesterone have been investigated by recent experimenters, who have addressed progesterone's mechanism of action. Kokate et al. (4) (5) showed progesterone to be effective against PTZ-induced seizures in mice. The same researchers found that progesterone's anticonvulsant actions are due, at least in part, to its metabolites. Progesterone is first m...

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“…Neurosteroids have a greater sensitivity for GABA-A receptors, which are highly expressed in the dentate gyrus (Brown et al, 2002;Bianchi and Macdonald, 2003;Carver and Reddy, 2013;. Natural neurosteroids, such as AP (also known as brexanolone), have several limitations for therapeutic use, including low bioavailability, ultra-short t1/2, and hormonal side effects due to their steroid metabolites (Rupprecht et al, 1993). Therefore, synthetic analogs have been prepared to surpass these limitations (Reddy and Estes, 2016).…”

Section: Introductionmentioning

confidence: 99%