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Biomolecules Oct 2022The treatment with finasteride (i.e., an inhibitor of 5α-reductase) may be associated with different side effects (i.e., depression, anxiety, cognitive impairment and...
The treatment with finasteride (i.e., an inhibitor of 5α-reductase) may be associated with different side effects (i.e., depression, anxiety, cognitive impairment and sexual dysfunction) inducing the so-called post finasteride syndrome (PFS). Moreover, previous observations in PFS patients and an experimental model showed alterations in gut microbiota populations, suggesting an inflammatory environment. To confirm this hypothesis, we have explored the effect of chronic treatment with finasteride (i.e., for 20 days) and its withdrawal (i.e., for 1 month) on the levels of steroids, neurotransmitters, pro-inflammatory cytokines and gut permeability markers in the colon of adult male rat. The obtained data demonstrate that the levels of allopregnanolone (ALLO) decreased after finasteride treatment and after its withdrawal. Following the drug suspension, the decrease in ALLO levels correlates with an increase in IL-1β and TNF-α, serotonin and a decrease in dopamine. Importantly, ALLO treatment is able to counteract some of these alterations. The relation between ALLO and GABA-A receptors and/or pregnenolone (ALLO precursor) could be crucial in their mode of action. These observations provide an important background to explore further the protective effect of ALLO in the PFS experimental model and the possibility of its translation into clinical therapy.
Topics: Animals; Rats; Male; Finasteride; Pregnanolone; Pregnenolone; Receptors, GABA-A; Inflammation
PubMed: 36358917
DOI: 10.3390/biom12111567 -
Pharmacology & Therapeutics Dec 2022Alcohol Use Disorder (AUD) is a multifaceted relapsing disorder that is commonly comorbid with psychiatric disorders, including anxiety. Alcohol exposure produces a... (Review)
Review
Alcohol Use Disorder (AUD) is a multifaceted relapsing disorder that is commonly comorbid with psychiatric disorders, including anxiety. Alcohol exposure produces a plethora of effects on neurobiology. Currently, therapeutic strategies are limited, and only a few treatments - disulfiram, acamprosate, and naltrexone - are available. Given the complexity of this disorder, there is a great need for the identification of novel targets to develop new pharmacotherapy. The GABAergic system, the primary inhibitory system in the brain, is one of the well-known targets for alcohol and is responsible for the anxiolytic effects of alcohol. Interestingly, GABAergic neurotransmission is fine-tuned by neuroactive steroids that exert a regulatory role on several endocrine systems involved in neuropsychiatric disorders including AUD. Mounting evidence indicates that alcohol alters the biosynthesis of neurosteroids, whereas acute alcohol increases and chronic alcohol decreases allopregnanolone levels. Our recent work highlighted that chronic alcohol-induced changes in neurosteroid levels are mediated by epigenetic modifications, e.g., DNA methylation, affecting key enzymes involved in neurosteroid biosynthesis. These changes were associated with changes in GABA receptor subunit expression, suggesting an imbalance between excitatory and inhibitory signaling in AUD. This review will recapitulate the role of neurosteroids in the regulation of the neuroendocrine system, highlight their role in the observed allostatic load in AUD, and develop a framework from mechanisms to potential pharmacotherapy.
Topics: Humans; Pregnanolone; Neurosteroids; Alcoholism; Receptors, GABA-A; Anxiety; Ethanol
PubMed: 36323379
DOI: 10.1016/j.pharmthera.2022.108299 -
Frontiers in Endocrinology 2022Placental endocrine function is essential to fetal brain development. Placental hormones include neurosteroids such as allopregnanolone (ALLO), a regulator of...
Placental endocrine function is essential to fetal brain development. Placental hormones include neurosteroids such as allopregnanolone (ALLO), a regulator of neurodevelopmental processes positive allosteric modulation of the GABA receptor (GABA-R). Using a mouse model (plKO) in which the gene encoding the ALLO synthesis enzyme is specifically deleted in trophoblasts, we previously showed that placental ALLO insufficiency alters cerebellar white matter development and leads to male-specific autistic-like behavior. We now demonstrate that the lack of placental ALLO causes female-predominant alterations of cortical development and function. Placental ALLO insufficiency disrupts cell proliferation in the primary somatosensory cortex (S1) in a sex-linked manner. Early changes are seen in plKO embryos of both sexes, but persist primarily in female offspring after birth. Adolescent plKO females show significant reduction in pyramidal neuron density, as well as somatosensory behavioral deficits as compared with plKO males and control littermates. Assessment of layer-specific markers in human postmortem cortices suggests that preterm infants may also have female-biased abnormalities in cortical layer specification as compared with term infants. This study establishes a novel and fundamental link between placental function and sex-linked long-term neurological outcomes, emphasizing the importance of the growing field of neuroplacentology.
Topics: Female; Male; Infant, Newborn; Humans; Pregnancy; Adolescent; Neurosteroids; Placenta; Infant, Premature; Pregnanolone; Receptors, GABA-A
PubMed: 36313771
DOI: 10.3389/fendo.2022.972033 -
Biomolecules Sep 2022Enzyme-linked immunosorbent assays (ELISAs) for saliva are simple, non-invasive methods for hormone detection. Allopregnanolone (ALLO) is a neuroactive steroid hormone...
Enzyme-linked immunosorbent assays (ELISAs) for saliva are simple, non-invasive methods for hormone detection. Allopregnanolone (ALLO) is a neuroactive steroid hormone that plays a crucial role in the aetiology of reproductive mood disorders. To better understand the relationship between ALLO and mood, a validated method to measure peripheral hormone levels is required. Currently, there is no commercially available ELISA with which to measure ALLO in saliva. We validated two ELISAs, developed for use with blood, with the saliva samples of 25 pregnant women, examining the range and sensitivity, intra- and inter-assay precision, parallelism, linearity of dilution, and recovery. The samples were simultaneously analysed using the liquid-chromatography-mass-spectrometry (LC-MS) method. The kits differed in range (31.2-2000 pg/mL vs. 1.6-100 ng/mL) and sensitivity (<9.5 pg/mL vs. 0.9 ng/mL), with the latter showing significant matrix effects and the former fulfilling the acceptance criteria of all the parameters. The concentrations measured with LC-MS were below the lower limit of quantification (<1.0 ng/mL) and no signal was detected. One of the tested ELISAs is a valid method for detecting ALLO in the saliva of pregnant women. It has a suitable measurement range and higher sensitivity than the conventional LC-MS method.
Topics: Humans; Female; Pregnancy; Saliva; Tandem Mass Spectrometry; Pregnanolone; Pregnant Women; Neurosteroids; Enzyme-Linked Immunosorbent Assay; Hormones
PubMed: 36291590
DOI: 10.3390/biom12101381 -
Aging Oct 2022Premenstrual dysphoric disorder (PMDD) is a severe mood disorder with pathological changes rooted in copy number variation. Here, we aimed to elucidate the gene dose...
BACKGROUND
Premenstrual dysphoric disorder (PMDD) is a severe mood disorder with pathological changes rooted in copy number variation. Here, we aimed to elucidate the gene dose effect and allopregnanolone binding mechanism of Gabrb2 on possible PMDD-like and comorbid phenotypes in knockout mice.
METHODS
PMDD-like behaviors of -knockout mice were measured through various tests. Western Blot and ELISA were used to detect changes in the subunits and related neurotransmitter changes in mice respectively for the internal mechanism. The response of mice to allopregnanolone (ALLO) was examined through an exogenous ALLO injection, then validated by the patch-clamp technique to elaborate the potential mechanism of ALLO-mediated .
RESULTS
-knockout mice displayed changes in anxiety-like and depression-like emotions opposite to PMDD symptoms, changes in social, learning, and memory capacities similar to PMDD symptoms, and pain threshold changes opposite to PMDD symptoms. subunit expression in the brains of the -knockout mice was significantly higher than that of Wild-type mice (P<0.05). -knockout mice demonstrated neurotransmitter metabolism disturbance of GABA, Glu, acetylcholine, DA, norepinephrine, and epinephrine. Moreover, -knockout mice did not display the expected phenotypic effect after ALLO injection. Relative to WT mice, the knockout of the β2 subunit gene enhanced the agonistic effect of ALLO on GABAA receptors in cortical neuronal cells.
CONCLUSIONS
regulates PMDD-like behaviors. The ALLO binding site may not be located on subunits, abnormal δ and ε subunit expression in the mouse brain and the disturbance of neurotransmitters may result in ALLO sensitivity.
Topics: Humans; Female; Animals; Mice; Premenstrual Dysphoric Disorder; Pregnanolone; Receptors, GABA-A; Mice, Knockout; DNA Copy Number Variations
PubMed: 36287173
DOI: 10.18632/aging.204351 -
Biology of Sex Differences Oct 2022Progesterone administration has therapeutic effects in tobacco use disorder (TUD), with females benefiting more than males. Conversion of progesterone to the... (Randomized Controlled Trial)
Randomized Controlled Trial
Effect of progesterone administration in male and female smokers on nicotine withdrawal and neural response to smoking cues: role of progesterone conversion to allopregnanolone.
BACKGROUND
Progesterone administration has therapeutic effects in tobacco use disorder (TUD), with females benefiting more than males. Conversion of progesterone to the neurosteroid allopregnanolone is hypothesized to partly underlie the therapeutic effects of progesterone; however, this has not been investigated clinically.
METHODS
Smokers (n = 18 males, n = 21 females) participated in a randomized, double-blind, placebo-controlled crossover study of 200 mg progesterone daily across 4 days of abstinence. The ratio of allopregnanolone:progesterone was analyzed in relationship to nicotine withdrawal, smoking urges, mood states, subjective nicotine effects, and neural response to smoking cues.
RESULTS
Allopregnanolone:progesterone ratio interacted with sex to predict withdrawal symptoms (p = 0.047), such that females with higher allopregnanolone:progesterone ratios reported lower withdrawal severity (b = - 0.98 [- 1.95, - 0.01]; p = 0.048). In addition, allopregnanolone:progesterone ratio interacted with sex to predict confusion (p = 0.014) and fatigue (p = 0.034), such that females with higher allopregnanolone:progesterone ratios reported less confusion (b = - 0.45 [- 0.78, - 0.12]; p = 0.008) and marginally lower fatigue (b = - 0.50 [- 1.03, 0.02]; p = 0.062. Irrespective of sex, higher ratios of allopregnanolone:progesterone were associated with stronger "good effects" of nicotine (b = 8.39 [2.58, 14.20]); p = 0.005) and weaker "bad effects" of nicotine (b = - 7.13 [- 13.53, - 0.73]; p = 0.029).
CONCLUSIONS
Conversion of progesterone to allopregnanolone correlated with smoking-related outcomes in both sex-dependent and sex-independent ways. Sex-dependent effects suggest that conversion of progesterone to allopregnanolone may contribute to greater therapeutic benefits in females but not males with TUD. Trial registration Clinicaltrials.gov registration, retrospectively registered: NCT01954966; https://clinicaltrials.gov/ct2/show/NCT01954966 \.
Topics: Female; Humans; Nicotine; Progesterone; Pregnanolone; Smokers; Cues; Cross-Over Studies; Neurosteroids; Substance Withdrawal Syndrome; Smoking; Fatigue
PubMed: 36274158
DOI: 10.1186/s13293-022-00472-w -
Cell Reports Oct 2022The pyrin inflammasome acts as a guard of RhoA GTPases and is central to immune defenses against RhoA-manipulating pathogens. Pyrin activation proceeds in two steps....
The pyrin inflammasome acts as a guard of RhoA GTPases and is central to immune defenses against RhoA-manipulating pathogens. Pyrin activation proceeds in two steps. Yet, the second step is still poorly understood. Using cells constitutively activated for the pyrin step 1, a chemical screen identifies etiocholanolone and pregnanolone, two catabolites of testosterone and progesterone, acting at low concentrations as specific step 2 activators. High concentrations of these metabolites fully and rapidly activate pyrin, in a human specific, B30.2 domain-dependent manner and without inhibiting RhoA. Mutations in MEFV, encoding pyrin, cause two distinct autoinflammatory diseases pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND) and familial Mediterranean fever (FMF). Monocytes from PAAND patients, and to a lower extent from FMF patients, display increased responses to these metabolites. This study identifies an unconventional pyrin activation mechanism, indicates that endogenous steroid catabolites can drive autoinflammation, through the pyrin inflammasome, and explains the "steroid fever" described in the late 1950s upon steroid injection in humans.
Topics: Etiocholanolone; Familial Mediterranean Fever; Humans; Inflammasomes; Mutation; Pregnanolone; Progesterone; Pyrin; Testosterone
PubMed: 36223753
DOI: 10.1016/j.celrep.2022.111472 -
Acta Neurobiologiae Experimentalis 2022Postpartum depression (PPD) is the most common type of puerperal mental syndrome and affects maternal physical and mental health and even the growth and development of...
Postpartum depression (PPD) is the most common type of puerperal mental syndrome and affects maternal physical and mental health and even the growth and development of infants. Paeoniflorin exerts a potential antidepressive effect; however, the functional roles and potential mechanisms of paeoniflorin in PPD are still largely unknown. PPD rat models were prepared by withdrawing hormone‑simulated pregnancy (HSP), and subjects were treated with paeoniflorin and fluoxetine or plasmids. The sucrose preference test (SPT), forced swimming test (FST) and tail suspension test (TST) were used to monitor depression‑like behavior in rats. A radioimmunoassay was utilized for estradiol (E2) and progesterone (P) measurements. ELISA was performed to detect serum corticosterone (Cor), hippocampal allopregnanolone (Allo), IL‑1β and TNF‑α levels. Expression of the E2 receptors ERα and ERβ was detected by qPCR. Western blotting was used to detect TSPO, BDNF and mTOR phosphorylation. Paeoniflorin drastically increased the sucrose preference of rats while decreasing the immobility time in the FST and TST in PPD models. Moreover, paeoniflorin intervention upregulated serum E2, hippocampal Allo, ERα, and ERβ levels but degraded P, serum Cor, IL‑1β, TNF‑α and ERα/ERβ levels. Mechanistically, paeoniflorin promoted TSPO and BDNF‑mTOR pathway activation in PPD rats. Furthermore, suppression of TSPO or the BDNF‑mTOR pathway partially reversed the effects of paeoniflorin on depression‑like behaviors, hormone levels, and inflammatory cytokine release. Paeoniflorin may improve symptoms of PPD by regulating the TSPO and BDNF‑mTOR pathways, indicating that paeoniflorin may be an effective anti‑PPD and antidepressant drug, providing evidence for the future treatment of PPD.
Topics: Animals; Antidepressive Agents; Brain-Derived Neurotrophic Factor; Carrier Proteins; Corticosterone; Depression; Depression, Postpartum; Disease Models, Animal; Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Female; Fluoxetine; Glucosides; Hippocampus; Humans; Monoterpenes; Pregnancy; Pregnanolone; Progesterone; Rats; Receptors, GABA-A; Stress, Psychological; Sucrose; TOR Serine-Threonine Kinases; Tumor Necrosis Factor-alpha
PubMed: 36214717
DOI: 10.55782/ane-2022-033 -
Neuropsychopharmacology : Official... Jan 2023Neurosteroids that positively modulate GABA receptors are among a growing list of rapidly acting antidepressants, including ketamine and psychedelics. To develop...
Neurosteroids that positively modulate GABA receptors are among a growing list of rapidly acting antidepressants, including ketamine and psychedelics. To develop increasingly specific treatments with fewer side effects, we explored the possibility of EEG signatures in mice, which could serve as a cross-species screening tool. There are few studies of the impact of non-sedative doses of rapid antidepressants on EEG in either rodents or humans. Here we hypothesize that EEG features may separate a rapid antidepressant neurosteroid, allopregnanolone, from other GABA positive modulators, pentobarbital and diazepam. Further, we compared the actions GABA modulators with those of ketamine, an NMDA antagonist and prototype rapid antidepressant. We examined EEG spectra during active exploration at two cortical locations and examined cross-regional and cross-frequency interactions. We found that at comparable doses, the effects of allopregnanolone, despite purported selectivity for certain GABAR subtypes, was indistinguishable from pentobarbital during active waking exploration. The actions of diazepam had recognizable common features with allopregnanolone and pentobarbital but was also distinct, consistent with subunit selectivity of benzodiazepines. Finally, ketamine exhibited no distinguishing overlap with allopregnanolone in the parameters examined. Our results suggest that rapid antidepressants with different molecular substrates may remain separated at the level of large-scale ensemble activity, but the studies leave open the possibility of commonalities in more discrete circuits and/or in the context of a dysfunctional brain.
Topics: Humans; Mice; Animals; Pregnanolone; Ketamine; Pentobarbital; Receptors, GABA-A; Diazepam; Neurosteroids; Antidepressive Agents; gamma-Aminobutyric Acid; Electroencephalography
PubMed: 36168047
DOI: 10.1038/s41386-022-01450-x -
Biomolecules Sep 2022The neuroactive steroid allopregnanolone ((3α,5α)-3-hydroxypregnan-20-one or 3α,5α-THP) plays a key role in the response to stress, by normalizing... (Review)
Review
The neuroactive steroid allopregnanolone ((3α,5α)-3-hydroxypregnan-20-one or 3α,5α-THP) plays a key role in the response to stress, by normalizing hypothalamic-pituitary-adrenal (HPA) axis function to restore homeostasis. Most studies have been conducted on male rats, and little is known about the allopregnanolone response to stress in females, despite that women are more susceptible than men to develop emotional and stress-related disorders. Here, we provide an overview of animal and human studies examining the allopregnanolone responses to acute stress in females in the context of stress-related neuropsychiatric diseases and under the different conditions that characterize the female lifespan associated with the reproductive function. The blunted allopregnanolone response to acute stress, often observed in female rats and women, may represent one of the mechanisms that contribute to the increased vulnerability to stress and affective disorders in women under the different hormonal fluctuations that occur throughout their lifespan. These studies highlight the importance of targeting neuroactive steroids as a therapeutic approach for stress-related disorders in women.
Topics: Animals; Female; Humans; Hypothalamo-Hypophyseal System; Male; Neurosteroids; Pituitary-Adrenal System; Pregnanolone; Rats
PubMed: 36139100
DOI: 10.3390/biom12091262