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Dialogues in Clinical Neuroscience Dec 2023Postpartum depression has deleterious effects on childbearing persons globally. Existing treatments have been largely extrapolated from those for other forms of... (Review)
Review
Postpartum depression has deleterious effects on childbearing persons globally. Existing treatments have been largely extrapolated from those for other forms of depression and have included pharmacotherapy, psychotherapy, and neuromodulation. Hormonal treatments with oestrogen and progestogens, thought to be a rational approach to treatment in response to an emerging literature on the pathophysiology of postpartum depression, have only limited evidence for efficacy to date. Novel antidepressant development with allopregnanolone analogues, in contrast, has proven a promising avenue for the development of rationally designed and efficacious treatments. This state-of-the-art review presents the evidence for the current standard-of-care pharmacotherapy, hormonal treatment, and emerging allopregnanolone analogues for the treatment of postpartum depression along with a discussion of the current understanding of its neuroactive steroid-driven pathophysiology.
Topics: Female; Humans; Depression, Postpartum; Pregnanolone; Antidepressive Agents; Psychotherapy
PubMed: 37796239
DOI: 10.1080/19585969.2023.2262464 -
Frontiers in Psychiatry 2023Benzodiazepines (BZs) are prescribed as anxiolytics, but their use is limited by side effects including abuse liability and daytime drowsiness. Neuroactive steroids are...
INTRODUCTION
Benzodiazepines (BZs) are prescribed as anxiolytics, but their use is limited by side effects including abuse liability and daytime drowsiness. Neuroactive steroids are compounds that, like BZs, modulate the effects of GABA at the GABA receptor. In a previous study, combinations of the BZ triazolam and neuroactive steroid pregnanolone produced supra-additive (i.e., greater than expected effects based on the drugs alone) anxiolytic effects but infra-additive (i.e., lower than expected effects based on the drugs alone) reinforcing effects in male rhesus monkeys, suggestive of an improved therapeutic window.
METHODS
Female rhesus monkeys (=4) self-administered triazolam, pregnanolone, and triazolam-pregnanolone combinations intravenously under a progressive-ratio schedule. In order to assess characteristic sedative-motor effects of BZ-neuroactive steroid combinations, female rhesus monkeys (n=4) were administered triazolam, pregnanolone, and triazolam-pregnanolone combinations. Trained observers, blinded to condition, scored the occurrence of species-typical and drug-induced behaviors.
RESULTS
In contrast to our previous study with males, triazolam-pregnanolone combinations had primarily supra-additive reinforcing effects in three monkeys but infra-additive reinforcing effects in one monkey. Scores for deep sedation (i.e., defined as atypical loose-limbed posture, eyes closed, does not respond to external stimuli) and observable ataxia (any slip, trip, fall, or loss of balance) were significantly increased by both triazolam and pregnanolone. When combined, triazolam-pregnanolone combinations had supra-additive effects for inducing deep sedation, whereas observable ataxia was attenuated, likely due to the occurrence of robust sedative effects.
DISCUSSION
These results suggest that significant sex differences exist in self-administration of BZ-neuroactive steroid combinations, with females likely to show enhanced sensitivity to reinforcing effects compared with males. Moreover, supra-additive sedative effects occurred for females, demonstrating a higher likelihood of this adverse effect when these drug classes are combined.
PubMed: 37252149
DOI: 10.3389/fpsyt.2023.1142531 -
Revista de Neurologia May 2022Catamenial pattern epilepsy is defined as an increase in the frequency of seizures during a specific stage of the menstrual cycle compared to baseline. It has been... (Review)
Review
Catamenial pattern epilepsy is defined as an increase in the frequency of seizures during a specific stage of the menstrual cycle compared to baseline. It has been described that around a third of women with epilepsy have a catamenial pattern. The changes in the seizure pattern would be explained by the influence of catamenial fluctuations, of female gonadal hormones on neuronal excitability. Progesterone through its metabolite allopregnanolone plays a protective role by increasing GABAergic transmission; however, its effect on brain progesterone receptors can increase neuronal excitability. The effects of estrogens are complex, they tend to increase neuronal excitability, although their effects depend on their concentration and exposure time. Three catamenial patterns of seizure exacerbation have been proposed: the perimenstrual pattern, the periovulatory pattern, and the luteal pattern. The diagnostic approach is carried out through a systematic process of 4 steps: a) clinical history of the pattern of the menstrual cycle and epileptic seizures; b) diagnostic methods to characterize the menstrual cycle and the pattern of seizures; c) check diagnostic criteria; and d) categorize the catamenial pattern. The treatment options studied require a higher level of evidence, and there is no specific treatment. Optimization of conventional antiseizure treatment is recommended as the first therapeutic option. Other therapeutic options, such as non-hormonal and hormonal treatments, could be useful in case the first therapeutic option proves to be ineffective.
Topics: Epilepsy, Reflex; Female; Humans; Menstrual Cycle; Pregnanolone; Progesterone; Seizures
PubMed: 35484702
DOI: 10.33588/rn.7409.2022041 -
ACS Chemical Neuroscience May 2023Multiple molecular targets have been identified to mediate membrane-delimited and nongenomic effects of natural and synthetic steroids, but the influence of steroid...
Multiple molecular targets have been identified to mediate membrane-delimited and nongenomic effects of natural and synthetic steroids, but the influence of steroid metabolism on neuroactive steroid signaling is not well understood. To begin to address this question, we set out to identify major metabolites of a neuroprotective synthetic steroid 20-oxo-5β-pregnan-3α-yl l-glutamyl 1-ester (pregnanolone glutamate, PAG) and characterize their effects on GABA and NMDA receptors (GABARs, NMDARs) and their influence on zebrafish behavior. Gas chromatography-mass spectrometry was used to assess concentrations of PAG and its metabolites in the hippocampal tissue of juvenile rats following intraperitoneal PAG injection. PAG is metabolized in the peripheral organs and nervous tissue to 20-oxo-17α-hydroxy-5β-pregnan-3α-yl l-glutamyl 1-ester (17-hydroxypregnanolone glutamate, 17-OH-PAG), 3α-hydroxy-5β-pregnan-20-one (pregnanolone, PA), and 3α,17α-dihydroxy-5β-pregnan-20-one (17-hydroxypregnanolone, 17-OH-PA). Patch-clamp electrophysiology experiments in cultured hippocampal neurons demonstrate that PA and 17-OH-PA are potent positive modulators of GABARs, while PAG and 17-OH-PA have a moderate inhibitory effect at NMDARs. PAG, 17-OH-PA, and PA diminished the locomotor activity of zebrafish larvae in a dose-dependent manner. Our results show that PAG and its metabolites are potent modulators of neurotransmitter receptors with behavioral consequences and indicate that neurosteroid-based ligands may have therapeutic potential.
Topics: Rats; Animals; Pregnanolone; Receptors, N-Methyl-D-Aspartate; Zebrafish; Glutamic Acid; Esters; gamma-Aminobutyric Acid; Receptors, GABA-A
PubMed: 37126803
DOI: 10.1021/acschemneuro.3c00131 -
Nature Communications Aug 2023γ-Aminobutyric acid type A (GABA) receptors mediate fast inhibitory signaling in the brain and are targets of numerous drugs and endogenous neurosteroids. A subset of...
γ-Aminobutyric acid type A (GABA) receptors mediate fast inhibitory signaling in the brain and are targets of numerous drugs and endogenous neurosteroids. A subset of neurosteroids are GABA receptor positive allosteric modulators; one of these, allopregnanolone, is the only drug approved specifically for treating postpartum depression. There is a consensus emerging from structural, physiological and photolabeling studies as to where positive modulators bind, but how they potentiate GABA activation remains unclear. Other neurosteroids are negative modulators of GABA receptors, but their binding sites remain debated. Here we present structures of a synaptic GABA receptor bound to allopregnanolone and two inhibitory sulfated neurosteroids. Allopregnanolone binds at the receptor-bilayer interface, in the consensus potentiator site. In contrast, inhibitory neurosteroids bind in the pore. MD simulations and electrophysiology support a mechanism by which allopregnanolone potentiates channel activity and suggest the dominant mechanism for sulfated neurosteroid inhibition is through pore block.
Topics: Female; Humans; Neurosteroids; Pregnanolone; Receptors, GABA-A; Binding Sites; Sulfates; gamma-Aminobutyric Acid
PubMed: 37607940
DOI: 10.1038/s41467-023-40800-1 -
Chronic Stress (Thousand Oaks, Calif.) 2018Allopregnanolone and pregnanolone-neurosteroids synthesized from progesterone in the brain, adrenal gland, ovary and testis-have been implicated in a range of... (Review)
Review
Allopregnanolone and pregnanolone-neurosteroids synthesized from progesterone in the brain, adrenal gland, ovary and testis-have been implicated in a range of neuropsychiatric conditions including seizure disorders, post-traumatic stress disorder, major depression, post-partum depression, pre-menstrual dysphoric disorder, chronic pain, Parkinson's disease, Alzheimer's disease, neurotrauma, and stroke. Allopregnanolone and pregnanolone equipotently facilitate the effects of gamma-amino-butyric acid (GABA) at GABA receptors, and when sulfated, antagonize N-methyl-D-aspartate receptors. They play myriad roles in neurophysiological homeostasis and adaptation to stress while exerting anxiolytic, antidepressant, anti-nociceptive, anticonvulsant, anti-inflammatory, sleep promoting, memory stabilizing, neuroprotective, pro-myelinating, and neurogenic effects. Given that these neurosteroids are synthesized de novo on demand, this review details the molecular steps involved in the biochemical conversion of cholesterol to allopregnanolone and pregnanolone within steroidogenic cells. Although much is known about the early steps in neurosteroidogenesis, less is known about transcriptional, translational, and post-translational processes in allopregnanolone- and pregnanolone-specific synthesis. Further research to elucidate these mechanisms as well as to optimize the timing and dose of interventions aimed at altering the synthesis or levels of these neurosteroids is much needed. This should include the development of novel therapeutics for the many neuropsychiatric conditions to which dysregulation of these neurosteroids contributes.
PubMed: 32440589
DOI: 10.1177/2470547018818555 -
International Review of Psychiatry... May 2019Psychiatric symptoms that coincide with reproductive transitions are related to changes in sex steroids, but studies show that this relationship is governed by... (Review)
Review
Psychiatric symptoms that coincide with reproductive transitions are related to changes in sex steroids, but studies show that this relationship is governed by individual women's vulnerability to change rather than by differences in level. There is growing interest in the role of allopregnanolone (ALLO), a 3- reduced metabolite of progesterone and a strong allosteric modulator of the GABA receptor, in such symptoms, with enough evidence now across various times of reproductive transition to offer an overview of the role of this hormone in reproductive psychiatry. This review offers a brief overview, focusing on literature of the last 3 years, of the relationship between allopregnanolone and mood at menarche; in the menstrual cycle; in the peripartum; and in the menopausal transition. ALLO dysregulation is identified in all of these transitions and found to be associated with mood symptoms, although evidence of its exact role; its relationship to other systems; and directionality is not consistent.
Topics: Affect; Anxiety; Female; Humans; Menarche; Menstrual Cycle; Perimenopause; Pregnanolone; Psychiatry; Receptors, GABA-A; Reproductive Health
PubMed: 30701996
DOI: 10.1080/09540261.2018.1553775 -
The Journal of Headache and Pain Mar 2021Neurosteroids affect the balance between neuroexcitation and neuroinhibition but have been little studied in migraine. We compared the serum levels of pregnenolone...
BACKGROUND
Neurosteroids affect the balance between neuroexcitation and neuroinhibition but have been little studied in migraine. We compared the serum levels of pregnenolone sulfate, pregnanolone and estradiol in women with menstrually-related migraine and controls and analysed if a correlation existed between the levels of the three hormones and history of migraine and age.
METHODS
Thirty women (mean age ± SD: 33.5 ± 7.1) with menstrually-related migraine (MM group) and 30 aged- matched controls (mean age ± SD: 30.9 ± 7.9) participated in the exploratory study. Pregnenolone sulfate and pregnanolone serum levels were analysed by liquid chromatography-tandem mass spectrometry, while estradiol levels by enzyme-linked immunosorbent assay.
RESULTS
Serum levels of pregnenolone sulfate and pregnanolone were significantly lower in the MM group than in controls (pregnenolone sulfate: P = 0.0328; pregnanolone: P = 0.0271, Student's t-test), while estradiol levels were similar. In MM group, pregnenolone sulfate serum levels were negatively correlated with history of migraine (R = 0.1369; P = 0.0482) and age (R = 0.2826, P = 0.0025) while pregnenolone sulfate levels were not age-related in the control group (R = 0.04436, P = 0.4337, linear regression analysis).
CONCLUSION
Low levels of both pregnanolone, a positive allosteric modulator of the GABAA receptor, and pregnenolone sulfate, a positive allosteric modulator of the NMDA receptor, involved in memory and learning, could contribute either to headache pain or the cognitive dysfunctions reported in migraine patients. Overall, our results agree with the hypothesis that migraine is a disorder associated with a loss of neurohormonal integrity, thus supporting the therapeutic potential of restoring low neurosteroid levels in migraine treatment.
Topics: Aged; Estradiol; Female; Humans; Migraine Disorders; Pregnanolone; Pregnenolone
PubMed: 33757421
DOI: 10.1186/s10194-021-01231-9 -
Psychoneuroendocrinology Sep 2021Progesterone (P4) can be metabolized to two general classes of neuroactive steroids (NAS) -those like allopregnanolone (ALLO) and pregnanolone (PA) which are positive...
Progesterone (P4) can be metabolized to two general classes of neuroactive steroids (NAS) -those like allopregnanolone (ALLO) and pregnanolone (PA) which are positive allosteric modulators of the Gamma Aminobutyric Acid type A (GABA) receptor and those like isoallopregnanolone (ISOALLO) and epipregnanolone (EPI) which are negative allosteric modulators of the GABA receptor. While exogenous administration of ALLO is effective in treating postpartum depression, knowledge gaps remain in the dynamic interplay of NAS across the perinatal period. In particular little is known about ALLO and PA in relation to depression earlier in pregnancy, and the role of ISOALLO and EPI in relation to depression at any point in the perinatal period. In a prospective, nested case/control study in low-income women of color, we compared the metabolism of P4 to four NAS (i.e., ratios ALLO:P4, PA:P4, ISOALLO:P4, EPI:P4) in pregnant women with depression at either or both of the first and second trimesters (cases) and women without depression at either time point (controls). Fifty women (36% depressed, 56% Black, 28% Latina) completed depression screening using a computerized adaptive test of mental health (CAT-MH™) and provided blood serum samples in both trimesters. In longitudinal mixed effects models of both trimesters, PND cases showed higher ratios of ALLO:P4 (p = .002) and PA:P4 (p = .03) compared to controls. In regression models of only first trimester data, there was no significant difference in NAS ratios between cases and controls (p > .05). Conversely, in models of the second trimester, ratios of PA:P4 (p = .002) and ISOALLO:P4 (p = .01) were significantly higher in cases compared to controls, and ratios of ALLO:P4 (p = .08) and EPI:P4 (p = .1) also trended higher in cases. The most severe cases, those with depression at both trimesters, showed an increase in ALLO:P4 (p = .06) and EPI:P4 (p < .001) ratios from the first to the second trimester, whereas controls showed a decrease in these ratios. Secondary analyses confirmed higher levels of ALLO (p = .04) and PA (p = .07) overall in cases compared to controls, along with higher levels of PA (p = .005) and ISOALLO (p = .02) in the second trimester alone. This work suggests a dynamic relationship between NAS and PND; whereas low ALLO levels have been previously associated with postpartum depression, earlier in pregnancy a higher metabolism of P4 to ALLO (and higher ALLO levels) is associated with depression. Some women may show a hormone-sensitive depressive response to acute increases in NAS metabolism in early pregnancy.
PubMed: 34607173
DOI: 10.1016/j.psyneuen.2021.105424 -
Biomolecules Aug 2023The pathological consequences of type 2 diabetes mellitus (T2DM) also involve the central nervous system; indeed, T2DM patients suffer from learning and memory...
The pathological consequences of type 2 diabetes mellitus (T2DM) also involve the central nervous system; indeed, T2DM patients suffer from learning and memory disabilities with a higher risk of developing dementia. Although several factors have been proposed as possible contributors, how neuroactive steroids and the gut microbiome impact brain pathophysiology in T2DM remain unexplored. On this basis, in male Zucker diabetic fatty (ZDF) rats, we studied whether T2DM alters memory abilities using the novel object recognition test, neuroactive steroid levels by liquid chromatography-tandem mass spectrometry, hippocampal parameters using molecular assessments, and gut microbiome composition using 16S next-generation sequencing. Results obtained reveal that T2DM worsens memory abilities and that these are correlated with increased levels of corticosterone in plasma and with a decrease in allopregnanolone in the hippocampus, where neuroinflammation, oxidative stress, and mitochondrial dysfunction were reported. Interestingly, our analysis highlighted a small group of taxa strictly related to both memory impairment and neuroactive steroid levels. Overall, the data underline an interesting role for allopregnanolone and microbiota that may represent candidates for the development of therapeutic strategies.
Topics: Humans; Rats; Animals; Male; Rats, Zucker; Gastrointestinal Microbiome; Diabetes Mellitus, Type 2; Neurosteroids; Pregnanolone
PubMed: 37759725
DOI: 10.3390/biom13091325