Pharmacokinetic and behavioral effects of allopregnanolone in healthy women

Timby, Erika; Balgård, Matts; Nyberg, Sigrid; Spigset, Olav; Andersson, Agneta; Porankiewicz-Asplund, Joanna; Purdy, Robert H.; Zhu, Di; Bäckström, Torbjörn; Sundström‐Poromaa, Inger

doi:10.1007/s00213-005-0148-7

Cited by 108 publications

(105 citation statements)

References 68 publications

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“…36,37 The increased amygdala response might therefore be specific for this concentration change, while higher supraphysiological concentrations might eventually decrease amygdala activity, 15 in parallel with increased sedation in humans. 53 These results therefore show that changes in progesterone level that are within the physiological range can increase amygdala activity.…”

Section: Discussionmentioning

confidence: 64%

Progesterone selectively increases amygdala reactivity in women

et al. 2007

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The acute neural effects of progesterone are mediated by its neuroactive metabolites allopregnanolone and pregnanolone. These neurosteroids potentiate the inhibitory actions of c-aminobutyric acid (GABA). Progesterone is known to produce anxiolytic effects in animals, but recent animal studies suggest that pregnanolone increases anxiety after a period of low allopregnanolone concentration. This effect is potentially mediated by the amygdala and related to the negative mood symptoms in humans that are observed during increased allopregnanolone levels. Therefore, we investigated with functional magnetic resonance imaging (MRI) whether a single progesterone administration to healthy young women in their follicular phase modulates the amygdala response to salient, biologically relevant stimuli. The progesterone administration increased the plasma concentrations of progesterone and allopregnanolone to levels that are reached during the luteal phase and early pregnancy. The imaging results show that progesterone selectively increased amygdala reactivity. Furthermore, functional connectivity analyses indicate that progesterone modulated functional coupling of the amygdala with distant brain regions. These results reveal a neural mechanism by which progesterone may mediate adverse effects on anxiety and mood.

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Section: Discussionmentioning

confidence: 64%

Progesterone selectively increases amygdala reactivity in women

et al. 2007

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“…At this dose of treatment, we determined that the maximum concentration of allopregnanolone achieved in the brain is ∼25 μM (∼8 μg/g tissue). Allopregnanolone has a very short half life in the plasma of wild type and NP-C mice (t 1/2 ∼ 30 minutes) as well as in human beings (t 1/2 ∼ 45 minutes) (Timby, et al, 2006). In addition, allopregnanolone has a short half-life in the brain, its concentrations are maximal within 10 minutes, and has a mean retention time of less than one hour.…”

Section: Allopregnanolone Is a Ligand For The Nuclear Pregnane-x Recementioning

confidence: 99%

Endogenous and synthetic neurosteroids in treatment of Niemann–Pick Type C disease

Mellon

Gong

Schonemann

2008

Brain Research Reviews

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The functions for neurosteroids during development and in response to nervous system injury are beginning to be identified. We focused on a mouse model in which we believed neurosteroid production would be altered, and which had a neurodegenerative phenotype. Niemann Pick Type-C (NP-C) is an autosomal recessive neurodegenerative disease caused by mutations in NPC1 (95%) or NPC2 (5%), resulting in lysosomal accumulation of unesterified cholesterol and glycolipids. The NIH mouse model of NP-C has a mutation in the NPC1 gene, and exhibits several pathological features of the most severe NP-C patients. How lysosomal storage and trafficking defects lead to neurodegeneration is unknown. We found that these mice had normal neurosteroidogenic enzyme activity during development, but lost this activity in the early neonatal period, prior to onset of neurological symptoms. Neurons that expressed P450scc, 3ß HSD, as well as those that expressed 3α HSD and 5α reductase were lost in adult NP-C brains, resulting in diminished concentrations of allopregnanolone. We treated NP-C mice with allopregnanolone and found that a single dose in the neonatal period resulted in a doubling of lifespan, substantial delay in onset of neurological symptoms, survival of cerebellar Purkinje and granule cell neurons, and reduction in cholesterol and ganglioside accumulation. The mechanism by which allopregnanolone elicited these effects is unknown. Our in vitro studies showed that Purkinje cell survival promoted by allopregnanolone was lost by treatment with bicuculline, suggesting GABA A receptors may play a role. We treated NP-C mice with a synthetic GABA A neurosteroid, ganaxolone (3α-hydroxy-3β-methyl-5α -pregnan-20-one). Ganaxolone treatment of NP-C mice produced beneficial neurological effects, but these effects were not as robust as those obtained using allopregnanolone. Thus, allopregnanolone may elicit its effects through GABA A receptors and through other mechanisms. Additional studies also suggest that allopregnanolone may elicit its effects through pregnane-X receptors (PXR). Our data suggest that mouse models of neurodegeneration may be beneficial in establishing both physiologic and pharmacologic actions of neurosteroids. These animal models further establish the wide range of functions of these compounds, which may ultimately be useful for treatment of human diseases.

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“…Two adult patients with SRSE in therapeutic coma who had persistent seizures with repeated attempts to wean anesthetic agents were successfully weaned when allopregnanolone was added to their treatment regimen. Dose selection was based on pharmacokinetic modeling,11 with a target plasma allopregnanolone concentration of 150 nmol/L, the physiological maximum concentration seen in pregnant women and the maximum concentration permitted at the time by the Food and Drug Administration (FDA). Subsequent successful use of allopregnanolone in pediatric patients has been reported 12…”

Section: Introductionmentioning

confidence: 99%

First‐in‐man allopregnanolone use in super‐refractory status epilepticus

Vaitkevicius

Husain

Rosenthal

et al. 2017

Ann Clin Transl Neurol

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Super‐refractory status epilepticus (SRSE) is associated with high morbidity and mortality. Treatment of SRSE is complicated by progressive cortical hyperexcitability believed to result in part from synaptic GABA receptor internalization and desensitization. Allopregnanolone, a neurosteroid that positively modulates synaptic and extrasynaptic GABAA receptors, has been proposed as a novel treatment. We describe the first two patients with SRSE who were each successfully treated with a 120‐h continuous infusion of allopregnanolone. Both patients recovered from prolonged SRSE with good cognitive outcomes.

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Pharmacokinetic and behavioral effects of allopregnanolone in healthy women

Cited by 108 publications

References 68 publications

Progesterone selectively increases amygdala reactivity in women

Progesterone selectively increases amygdala reactivity in women

Endogenous and synthetic neurosteroids in treatment of Niemann–Pick Type C disease

First‐in‐man allopregnanolone use in super‐refractory status epilepticus

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