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1.
Brain Behav ; 14(9): e70009, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39236116

RESUMO

BACKGROUND: Preterm birth is associated with brain injury and long-term behavioral abnormalities, for which there are limited prevention options. When born preterm, infants prematurely lose placental neurosteroid (allopregnanolone) support. This increases the risk of excitotoxic damage to the brain, which increases the risk of injury, causing long-term deficits in behavior, myelination, and alterations to neurotransmitter pathways. We propose that postnatal restoration of neurosteroid action through zuranolone therapy will reduce neurological impairments following preterm birth. METHODS: Guinea pig dams underwent survival cesarean section surgery to deliver pups prematurely (GA64) or at term (GA69). Between birth and term equivalence age, preterm pups received vehicle (15% ß-cyclodextrin) or the allopregnanolone analogue zuranolone (1 mg/kg/day). Behavioral analysis was performed at postnatal day (PND) 7 and 40, before tissue collection at PND 42. Immunostaining for myelin basic protein (MBP), as well as real-time polymerase chain reaction to characterize oligodendrocyte lineage and neurotransmitter pathways, was performed in frontal cortex tissues. RESULTS: Zuranolone treatment prevented the hyperactive phenotype in preterm-born offspring, most markedly in males. Additionally, preterm-related reductions in MBP were ameliorated. Several preterm-related alterations in mRNA expression of dopaminergic, glutamatergic, and GABAergic pathways were also restored back to that of a term control level. CONCLUSION: This is the first study to assess zuranolone treatment as a neuroprotective therapy following preterm birth. Zuranolone treatment improved behavioral outcomes and structural changes in the preterm offspring, which continued long term until at least a late childhood timepoint. Clinical studies are warranted for further exploring the neuroprotective possibilities of this treatment following preterm birth.


Assuntos
Lobo Frontal , Pregnanolona , Nascimento Prematuro , Animais , Pregnanolona/farmacologia , Feminino , Cobaias , Masculino , Nascimento Prematuro/prevenção & controle , Nascimento Prematuro/tratamento farmacológico , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Animais Recém-Nascidos , Gravidez , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/administração & dosagem , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/metabolismo , Proteína Básica da Mielina/metabolismo
2.
Biomolecules ; 14(9)2024 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-39334843

RESUMO

Produced by the mitochondria and endoplasmic reticulum, neurosteroids such as allopregnanolone are neuroprotective molecules that influence various neuronal functions and regulate neuroinflammation. They are reduced in neurodegenerative diseases, while in the Wobbler mouse model, allopregnanolone and its precursor progesterone showed protective effects on motor neuron degeneration. This single-center case-control study included 37 patients with amyotrophic lateral sclerosis (ALS) and 28 healthy controls. Cerebrospinal fluid (CSF) neurosteroid levels were quantified using liquid chromatography-electrospray tandem mass spectrometry and compared between the two cohorts. Neurosteroid concentrations have been correlated with neuroinflammation and neurodegeneration biomarkers detected through an automated immunoassay, along with disease features and progression. Pregnenolone, progesterone, allopregnanolone, pregnanolone, and testosterone levels were significantly lower in ALS patients' CSF compared to healthy controls. A significant inverse correlation was found between neurofilament and neurosteroid levels. Neurosteroid concentrations did not correlate with disease progression, phenotype, genotype, or survival prediction. Our study suggests the independence of the disease features and its progression, from the dysregulation of neurosteroids in ALS patients' CSF. This neurosteroid reduction may relate to disease pathogenesis or be a consequence of disease-related processes, warranting further research. The inverse correlation between neurosteroids and neurofilament levels may indicate a failure of compensatory neuroprotective mechanisms against neurodegeneration.


Assuntos
Esclerose Lateral Amiotrófica , Neuroesteroides , Esclerose Lateral Amiotrófica/líquido cefalorraquidiano , Humanos , Pessoa de Meia-Idade , Masculino , Feminino , Neuroesteroides/líquido cefalorraquidiano , Estudos de Casos e Controles , Idoso , Biomarcadores/líquido cefalorraquidiano , Pregnanolona/líquido cefalorraquidiano , Adulto , Pregnenolona/líquido cefalorraquidiano , Progesterona/líquido cefalorraquidiano , Testosterona/líquido cefalorraquidiano , Cromatografia Líquida , Espectrometria de Massas em Tandem
3.
Neurotox Res ; 42(4): 37, 2024 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-39102123

RESUMO

Amyloid-peptide (Aß) monomeric forms (ABM) occurring in presymptomatic Alzheimer's disease (AD) brain are thought to be devoid of neurotoxicity while the transition/aggregation of ABM into oligomers is determinant for Aß-induced toxicity since Aß is predominantly monomeric up to 3 µM and aggregates over this concentration. However, recent imaging and/or histopathological investigations revealed alterations of myelin in prodromal AD brain in absence of aggregated Aß oligomers, suggesting that ABM may induce toxicity in myelin-producing cells in early AD-stages. To check this hypothesis, here we studied ABM effects on the viability of the Human oligodendrocyte cell line (HOG), a reliable oligodendrocyte model producing myelin proteins. Furthermore, to mimic closely interactions between oligodendrocytes and other glial cells regulating myelination, we investigated also ABM effects on mouse brain primary mixed-glial cell cultures. Various methods were combined to show that ABM concentrations (600 nM-1 µM), extremely lower than 3 µM, significantly decreased HOG cell and mouse brain primary mixed-glial cell survival. Interestingly, flow-cytometry studies using specific cell-type markers demonstrated that oligodendrocytes represent the most vulnerable glial cell population affected by ABM toxicity. Our work also shows that the neurosteroid 3α-O-allyl-allopregnanolone BR351 (250 and 500 nM) efficiently prevented ABM-induced HOG and brain primary glial cell toxicity. Bicuculline (50-100 nM), the GABA-A-receptor antagonist, was unable to block/reduce BR351 effect against ABM-induced HOG and primary glial cell toxicity, suggesting that BR351-evoked neuroprotection of these cells may not depend on GABA-A-receptor allosterically modulated by neurosteroids. Altogether, our results suggest that further exploration of BR351 therapeutic potential may offer interesting perspectives to develop effective neuroprotective strategies.


Assuntos
Peptídeos beta-Amiloides , Fármacos Neuroprotetores , Oligodendroglia , Pregnanolona , Animais , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/metabolismo , Humanos , Peptídeos beta-Amiloides/toxicidade , Fármacos Neuroprotetores/farmacologia , Pregnanolona/farmacologia , Camundongos , Linhagem Celular , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Camundongos Endogâmicos C57BL , Fragmentos de Peptídeos/toxicidade , Células Cultivadas , Relação Dose-Resposta a Droga
4.
Eur J Paediatr Neurol ; 51: 140-146, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38959712

RESUMO

CDKL5 deficiency disorder (CDD) is a rare developmental and epileptic encephalopathy. Ganaxolone, a neuroactive steroid, reduces the frequency of major motor seizures in children with CDD. This analysis explored the effect of ganaxolone on non-seizure outcomes. Children (2-19 years) with genetically confirmed CDD and ≥ 16 major motor seizures per month were enrolled in a double-blind randomized placebo-controlled trial. Ganaxolone or placebo was administered three times daily for 17 weeks. Behaviour was measured with the Anxiety, Depression and Mood Scale (ADAMS), daytime sleepiness with the Child Health Sleep Questionnaire, and quality of life with the Quality of Life Inventory-Disability (QI-Disability) scale. Scores were compared using ANOVA, adjusted for age, sex, number of anti-seizure mediations, baseline 28-day major motor seizure frequency, baseline developmental skills, and behaviour, sleep or quality of life scores. 101 children with CDD (39 clinical sites, 8 countries) were randomized. Median (IQR) age was 6 (3-10) years, 79.2 % were female, and 50 received ganaxolone. After 17 weeks of treatment, Manic/Hyperactive scores (mean difference 1.27, 95%CI -2.38,-0.16) and Compulsive Behaviour scores (mean difference 0.58, 95%CI -1.14,-0.01) were lower (improved) in the ganaxolone group compared with the placebo group. Daytime sleepiness scores were similar between groups. The total change in QOL score for children in the ganaxolone group was 2.6 points (95%CI -1.74,7.02) higher (improved) than in the placebo group but without statistical significance. Along with better seizure control, children who received ganaxolone had improved behavioural scores in select domains compared to placebo.


Assuntos
Qualidade de Vida , Humanos , Feminino , Masculino , Método Duplo-Cego , Criança , Pré-Escolar , Adolescente , Adulto Jovem , Resultado do Tratamento , Síndromes Epilépticas/tratamento farmacológico , Convulsões/tratamento farmacológico , Convulsões/etiologia , Pregnanolona/análogos & derivados , Espasmos Infantis
5.
Pharmacol Biochem Behav ; 244: 173842, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39069097

RESUMO

The gut microbiome is a vast, variable, and largely unexplored component of human biology that sits at the intersection of heritable and environmental factors, and represents a rich source of novel chemistry that is already known to be compatible with the human body. This alone would make it a promising place to search for new therapeutics, but recent work has also identified gut microbiome abnormalities in patients with a number of psychiatric disorders, including anxiety disorders-suggesting that not only treatments, but cures may lie therein. Here, we'll discuss two known "para-endogenous" anxiolytics-γ-hydroxybutyrate and the neurosteroid allopregnanolone-which have recently been discovered to be produced by the microbiome.


Assuntos
Ansiolíticos , Microbioma Gastrointestinal , Humanos , Ansiolíticos/farmacologia , Ansiolíticos/uso terapêutico , Microbioma Gastrointestinal/efeitos dos fármacos , Transtornos de Ansiedade/tratamento farmacológico , Transtornos de Ansiedade/microbiologia , Transtornos de Ansiedade/metabolismo , Pregnanolona/uso terapêutico , Pregnanolona/farmacologia , Animais , Ansiedade/tratamento farmacológico , Ansiedade/microbiologia
6.
Br J Pharmacol ; 181(21): 4229-4244, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-38978389

RESUMO

BACKGROUND AND PURPOSE: Neurosteroids are allosteric modulators of GABAA currents, acting through several functional binding sites although their affinity and specificity for each site are unknown. The goal of this study was to measure steady-state binding affinities of various neurosteroids for specific sites on the GABAA receptor. EXPERIMENTAL APPROACH: Two methods were developed to measure neurosteroid binding affinity: (1) quenching of specific tryptophan residues in neurosteroid binding sites by the neurosteroid 17-methylketone group, and (2) FRET between MQ290 (an intrinsically fluorescent neurosteroid) and tryptophan residues in the binding sites. The assays were developed using ELIC-α1GABAAR, a chimeric receptor containing transmembrane domains of the α1-GABAA receptor. Tryptophan mutagenesis was used to identify specific interactions. KEY RESULTS: Allopregnanolone (3α-OH neurosteroid) was shown to bind at intersubunit and intrasubunit sites with equal affinity, whereas epi-allopregnanolone (3ß-OH neurosteroid) binds at the intrasubunit site. MQ290 formed a strong FRET pair with W246, acting as a site-specific probe for the intersubunit site. The affinity and site-specificity of several neurosteroid agonists and inverse agonists was measured using the MQ290 binding assay. The FRET assay distinguishes between competitive and allosteric inhibition of MQ290 binding and demonstrated an allosteric interaction between the two neurosteroid binding sites. CONCLUSIONS AND IMPLICATIONS: The affinity and specificity of neurosteroid binding to two sites in the ELIC-α1GABAAR were directly measured and an allosteric interaction between the sites was revealed. Adaptation of the MQ290 FRET assay to a plate-reader format will enable screening for high affinity agonists and antagonists for neurosteroid binding sites.


Assuntos
Neuroesteroides , Receptores de GABA-A , Receptores de GABA-A/metabolismo , Receptores de GABA-A/química , Receptores de GABA-A/genética , Sítios de Ligação , Neuroesteroides/metabolismo , Animais , Pregnanolona/farmacologia , Pregnanolona/metabolismo , Humanos , Transferência Ressonante de Energia de Fluorescência , Xenopus laevis , Ligação Proteica
7.
Expert Rev Neurother ; 24(10): 945-951, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39082513

RESUMO

INTRODUCTION: Cyclin-dependent kinase-Like 5 (CDKL5) deficiency disorder (CDD) is a rare neurodevelopmental condition commonly characterized by drug-resistant, refractory epilepsy, and seizures beginning in infancy. Most patients use multiple drugs, yet seizures remain difficult to control. So far, no conventional anti-seizure medications have been proven to be effective in individuals with CDD, in well-conducted studies. AREAS COVERED: In this review, the authors assess the pharmacokinetics, early studies and appraise a recent study investigating the efficacy and safety of the oral suspension of ganaxolone (3α-hydroxy-3ß-methyl-5α-pregnan-20-one) as an adjunctive therapy to treat seizures in CDD. The authors also discuss the impact of this drug on non-seizure outcomes. EXPERT OPINION: Ganaxolone is a neuroactive 3ß-methylated synthetic analogue of the potent agonist of gamma-aminobutyric acid type A receptors, allopregnanolone. Ganaxolone is the only drug that has been studied in a robust randomized controlled trial and been proven to be effective in this population.


Assuntos
Pregnanolona , Convulsões , Humanos , Convulsões/tratamento farmacológico , Pregnanolona/análogos & derivados , Pregnanolona/uso terapêutico , Pregnanolona/farmacologia , Anticonvulsivantes/uso terapêutico , Anticonvulsivantes/farmacologia
8.
Ideggyogy Sz ; 77(7-8): 227-235, 2024 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-39082257

RESUMO

Depression, anxiety and psychotic disorders are common perinatal mental health disorders in the postpartum period. Depressive symptoms that occur postpartum are also present in the prenatal period in 50% of patients. Risk factors for the development of postpartum depression include poor relationship with the partner, lack of social support, mother’s low socioeconomic status and multiparity. It has been determined that reproductive hormones change significantly during peripartum. Progesterone is one of these hormones and acts on the central nervous system starting from the fetal period; neurogenesis, neuromodulation, sedation are some of these effects. It has also been observed that progesterone has positive effects on learning, memory and mood. Progesterone exerts its effects on the central nervous system by converting into its metabolite allopregnanolone. Allopregnanolone is one of the neuroactive steroids, and found in similar amounts in the circulation of pregnant women and fetuses. It acts on synaptic and extrasynaptic γ-aminobutyric acid type A (GABAA) receptors and is a positive allosteric modulator of the GABAA receptor. Allopregnanolone increases both the receptor’s opening frequency and its open duration and improves GABAergic current. Low serum allopregnanolone levels in the second trimester are predictive of postpartum depression. Each 1 ng/mL increase in serum allopregnanolone level reduces the risk of development of postpartum depression by 63%. Brexanolone and zuranolone are synthetic allopregnanolone preparations approved by the FDA for use in female patients with postpartum depression. They act via positive allosteric modulation on the GABAA receptor. Brexanolone is administered via intravenous infusion at varying infusion rates in a healthcare facility over 60 hours. Its effect starts immediately after treatment and continues until the 30th day of follow-up, and depressive mood does not recur. Zuranolone was developed for oral use, and administered as a single dose of 50 mg after a fatty meal. Their effectiveness has been demonstrated in patients with treatment-resistant depression. The development of other novel agents that act on the GABAA receptor and other pathways for the treatment of postpartum depression is in progress.

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Assuntos
Depressão Pós-Parto , Pregnanolona , Humanos , Depressão Pós-Parto/tratamento farmacológico , Feminino , Pregnanolona/uso terapêutico , Gravidez , Antidepressivos/uso terapêutico , Progesterona/uso terapêutico , Combinação de Medicamentos , beta-Ciclodextrinas
9.
Eur J Med Chem ; 276: 116602, 2024 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-38971049

RESUMO

Zuranolone (SAGE-217) is a neuroactive steroid (γ-aminobutyric acid)A (GABAA) receptor positive allosteric modulator (PAM) as the first oral drug approved by the FDA in 2023, which is used to treat patients with postpartum depression (PPD). SAGE-217 has a "black box" warning with impairing ability to drive or engage in other potentially hazardous activities. In addition, SAGE-217 can cause CNS depressant effects such as somnolence and confusion, suicidal thoughts and behavior and embryo-fetal toxicity. Based on the structure-activity relationship (SAR) of SAGE-217, a total of 28 neuroactive steroids with novel pharmacophore at C-21 modulated SAGE-217 derivatives were designed and synthesized. The biological activities were evaluated by both synaptic α1ß2γ2 GABAA receptor and extrasynaptic α4ß3δ GABAA receptor cell assays. The optimal compound S28 exhibited much more potent potency and similar efficacy at extrasynaptic GABAA receptor than SAGE-217. Different from above, compound S28 exhibited similar potency and lower efficacy at synaptic GABAA receptor than SAGE-217, which were consistent with the analysis of molecular docking and dynamics simulation results. The appropriate lower efficacy at synaptic GABAA receptor of compound S28 might contribute to reduce the side effects of excessive sedation. Furthermore, compound S28 was demonstrated to have excellent in vivo pharmacokinetic (PK) parameters, robust in vivo pharmacodynamic (PD) effects and good safety profiles. Therefore, compound S28 represents a potentially promising treatment of PPD candidate that warrants further investigation.


Assuntos
Receptores de GABA-A , Receptores de GABA-A/metabolismo , Relação Estrutura-Atividade , Humanos , Animais , Estrutura Molecular , Relação Dose-Resposta a Droga , Camundongos , Neuroesteroides/farmacologia , Neuroesteroides/metabolismo , Neuroesteroides/síntese química , Neuroesteroides/química , Simulação de Acoplamento Molecular , Regulação Alostérica/efeitos dos fármacos , Masculino , Moduladores GABAérgicos/farmacologia , Moduladores GABAérgicos/síntese química , Moduladores GABAérgicos/química , Farmacóforo , Pregnanolona , Pirazóis
10.
PLoS One ; 19(6): e0304481, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38875235

RESUMO

Pro-inflammatory changes contribute to multiple neuropsychiatric illnesses. Understanding how these changes are involved in illnesses and identifying strategies to alter inflammatory responses offer paths to potentially novel treatments. We previously found that acute pro-inflammatory stimulation with high (µg/ml) lipopolysaccharide (LPS) for 10-15 min dampens long-term potentiation (LTP) in the hippocampus and impairs learning. Effects of LPS involved non-canonical inflammasome signaling but were independent of toll-like receptor 4 (TLR4), a known LPS receptor. Low (ng/ml) LPS also inhibits LTP when administered for 2-4 h, and here we report that this LPS exposure requires TLR4. We also found that effects of low LPS on LTP involve the oxysterol, 25-hydroxycholesterol, akin to high LPS. Effects of high LPS on LTP are blocked by inhibiting synthesis of 5α-reduced neurosteroids, indicating that neurosteroids mediate LTP inhibition. 5α-Neurosteroids also have anti-inflammatory effects, and we found that exogenous allopregnanolone (AlloP), a key 5α-reduced steroid, prevented effects of low but not high LPS on LTP. We also found that activation of TLR2, TLR3 and TLR7 inhibited LTP and that AlloP prevented the effects of TLR2 and TLR7, but not TLR3. The enantiomer of AlloP, a steroid that has anti-inflammatory actions but low activity at GABAA receptors, prevented LTP inhibition by TLR2, TLR3 and TLR7. In vivo, both AlloP enantiomers prevented LPS-induced learning defects. These studies indicate that neurosteroids play complex roles in network effects of acute neuroinflammation and have potential importance for development of AlloP analogues as therapeutic agents.


Assuntos
Hipocampo , Lipopolissacarídeos , Potenciação de Longa Duração , Neuroesteroides , Animais , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Neuroesteroides/metabolismo , Receptores Toll-Like/metabolismo , Aprendizagem/efeitos dos fármacos , Camundongos , Plasticidade Neuronal/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo , Inflamação/metabolismo , Camundongos Endogâmicos C57BL , Hidroxicolesteróis/farmacologia , Hidroxicolesteróis/metabolismo , Pregnanolona/farmacologia , Pregnanolona/metabolismo
11.
J Clin Psychopharmacol ; 44(4): 337-344, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38739007

RESUMO

PURPOSE/BACKGROUND: Zuranolone is a positive allosteric modulator of both synaptic and extrasynaptic γ-aminobutyric acid type A receptors and a neuroactive steroid approved as an oral, once-daily, 14-day treatment course for adults with postpartum depression in the United States. This study assessed zuranolone transfer into breast milk. METHODS/PROCEDURES: Healthy, nonpregnant, lactating adult female participants received once-daily 30 mg zuranolone from day (D)1 through D5 in this phase 1 open-label study. The relative infant dose (RID; weight-adjusted proportion of the maternal dose in breast milk over 24 hours) for 30 mg zuranolone was assessed at D5. An RID for 50 mg zuranolone was estimated using a simulation approach across a range of infant ages and weights. FINDINGS/RESULTS: Of 15 enrolled participants (mean age, 30.1 years), 14 completed the study. The mean RID for 30 mg zuranolone at D5 was 0.357%; the mean steady-state milk volume over D3 to D5 decreased from baseline by 8.3%. Overall unbound zuranolone in plasma was low (≤0.49%). Plasma concentrations peaked at D5 before decreasing in a biexponential manner. There was strong concordance between the temporal profiles of zuranolone concentrations in plasma and breast milk. The estimated mean RID for 50 mg zuranolone based on a milk intake of 200 mL/kg per day was 0.984%. All treatment-emergent adverse events reported by participants were mild, the most common being dizziness (n = 3). IMPLICATIONS/CONCLUSIONS: Zuranolone transfer into the breast milk of healthy, nonpregnant, lactating adult female participants was low; the estimated RID for 50 mg zuranolone was <1%, well below the <10% threshold generally considered compatible with breastfeeding.


Assuntos
Lactação , Leite Humano , Humanos , Feminino , Adulto , Leite Humano/metabolismo , Lactação/efeitos dos fármacos , Lactação/metabolismo , Adulto Jovem , Voluntários Saudáveis , Pregnanolona , Pirazóis
12.
Stress ; 27(1): 2357330, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38775373

RESUMO

Why individuals suffer negative consequences following stress is a complex phenomenon that is dictated by individual factors, the timing of stress within the lifespan, and when in the lifespan the consequences are measured. Women who undergo adverse childhood experiences are at risk for lasting biological consequences, including affective and stress dysregulation. We have shown that pubertal adversity is associated with a blunted hypothalamic-pituitary-adrenal axis glucocorticoid response in peripartum humans and mice. In mice, our prior examination of the paraventricular nucleus (PVN) of the hypothalamus showed that pubertal stress led to an upregulation of baseline mRNA expression of six immediate early genes (IEGs) in the PVN of adult, pregnant mice. Separately, we showed that the pregnancy-associated hormone allopregnanolone is necessary and sufficient to produce the blunted stress response phenotype in pubertally stressed mice. In the current study, we further examined a potential mechanistic role for the IEGs in the PVN. We found that in pubertally stressed adult female, but not male, mice, intra-PVN allopregnanolone was sufficient to recapitulate the baseline IEG mRNA expression profile previously observed in pubertally stressed, pregnant mice. We also examined baseline IEG mRNA expression during adolescence, where we found that IEGs have developmental trajectories that showed sex-specific disruption by pubertal stress. Altogether, these data establish that IEGs may act as a key molecular switch involved in increased vulnerability to negative outcomes in adult, pubertally stressed animals. How the factors that produce vulnerability combine throughout the lifespan is key to our understanding of the etiology of stress-related disorders.


Assuntos
Núcleo Hipotalâmico Paraventricular , Estresse Psicológico , Transcriptoma , Animais , Feminino , Masculino , Camundongos , Estresse Psicológico/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Pregnanolona , Hipotálamo/metabolismo , Hipotálamo/efeitos dos fármacos , Gravidez , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Maturidade Sexual , Genes Precoces
13.
Psychopharmacology (Berl) ; 241(7): 1299-1317, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38802705

RESUMO

RATIONALE: Zuranolone, a newly FDA-approved synthetic neurosteroid, shows promise in treating depression. OBJECTIVES: Our aim is to evaluate Zuranolone's efficacy and safety in treating depression. METHODS: Five databases were searched until September 2023 for relevant randomized clinical trials evaluating the efficacy and safety of zuranolone. The potential risk of bias in the included trials was evaluated by the Cochrane Risk of Bias II guideline Data were extracted and pooled using Review Manager Software (RevMan 5.3). RESULTS: An analysis of eight studies highlights Zuranolone's efficacy in treating depression compared to placebo across most of the outcomes. Notably, the 30mg and 50mg doses demonstrated significant improvements in reducing HAM-D scores by over 50% within a 15-day follow-up (RR) of 1.46 (95% CI [1.27, 1.68], p < 0.0001) and 1.14 (95% CI [1.01, 1.3], p = 0.04). Additionally, the HAM-D ≤ 7% score analysis revealed significant enhancements with the 30mg dose over both 15-day (RR = 1.82, 95% CI [1.44, 2.31], p < 0.0001) and 45-day (RR = 1.43, 95% CI [1.16, 1.77], p = 0.0008) durations. Adverse Events Drug Discontinuation demonstrated no overall significant difference (OR = 1.33, 95% CI: [0.79, 2.23], p = 0.282). Further, specific adverse events, such as headache, showed no significant overall difference between Zuranolone and placebo (OR = 1.11, 95% CI: [0.84, 1.47], p = 0.47), with dose-dependent analysis revealing less headache in the 30 mg group. CONCLUSION: Zuranolone demonstrates favorable tolerability and safety, particularly at 30mg and 50mg doses after 15 days, suggesting its potential and effective treatment for depression.


Assuntos
Ensaios Clínicos Controlados Aleatórios como Assunto , Humanos , Antidepressivos/administração & dosagem , Antidepressivos/efeitos adversos , Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Relação Dose-Resposta a Droga , Resultado do Tratamento , Pregnanolona , Pirazóis
14.
Psychoneuroendocrinology ; 166: 107081, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38759520

RESUMO

BACKGROUND: Allopregnanolone (ALLO) is a metabolite of progesterone and a neuroactive steroid hormone. As a positive allosteric modulator of gamma-aminobutyric acid (GABA) receptors, ALLO seems to have antidepressant and anxiolytic effects, and was therefore approved as a specific medication for the treatment of postpartum depression in 2019. Despite the growing number of publications investigating ALLO levels, results on the biological and psychological correlates in the peripartum period remain inconsistent, possibly due to methodological challenges regarding measurement. To date, however, there is no systematic review examining the correlates, concentrations, and challenges in measuring ALLO in peripartum women. METHOD: A systematic literature search of PubMed and PsycINFO was conducted in August 2023. Original research articles that measured ALLO concentrations in peripartum women were included. Reports were excluded if they were not original research, included non-human subjects, did not include peripartum women, did not include ALLO measurement as an outcome, included (pharmacological) interventions, constituted method validations, or used the same cohort as another study. RESULTS: The literature search yielded 234 articles, and two articles were identified from other sources. After full-text screening, 19 articles (N = 1401) met the inclusion criteria, of which seven focused on biological correlates of ALLO and 12 on mood correlates. Of the latter, six found no association between ALLO and mood, four found a negative association, and two found a positive association. Overall, the results show an increase in ALLO levels during pregnancy and a decrease after birth, with levels then remaining low until six months postpartum. ALLO was most commonly measured in blood plasma and by gas chromatography-mass spectrometry (GC-MS). A significant matrix effect was found for blood serum and a significant method effect for radioimmunoassays (RIAs). A significant effect of time of measurement was found. CONCLUSION: ALLO measurement shows method and matrix effects. ALLO levels are higher when measured in serum compared to in plasma, and when measured using RIA compared to other methods. Time of measurement, study design, and standardization of measurement also influence the reliability of measurement and the interpretation of results.


Assuntos
Depressão Pós-Parto , Período Periparto , Pregnanolona , Humanos , Pregnanolona/sangue , Pregnanolona/análise , Feminino , Gravidez , Depressão Pós-Parto/sangue , Depressão Pós-Parto/tratamento farmacológico , Depressão Pós-Parto/metabolismo , Adulto
15.
Phytomedicine ; 130: 155549, 2024 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-38810551

RESUMO

Premenstrual dysphoric disorder (PMDD) is a severe subtype of premenstrual syndrome in women of reproductive age, with its pathogenesis linked to the heightened sensitivity of type A γ -aminobutyric acid receptors (GABAAR) to neuroactive steroid hormone changes, particularly allopregnanolone (ALLO). While a low dose of fluoxetine, a classic selective serotonin reuptake inhibitor, is commonly used as a first-line drug to alleviate emotional disorders in PMDD in clinical settings, its mechanism of action is related to ALLO-GABAA receptor function. However, treating PMDD requires attention to both emotional and physical symptoms, such as pain sensitivity. This study aims to investigate the efficacy of ShuYu capsules, a traditional Chinese medicine, in simultaneously treating emotional and physical symptoms in a rat model of PMDD. Specifically, our focus centres on the midbrain periaqueductal grey (PAG), a region associated with emotion regulation and susceptibility to hyperalgesia. Considering the underlying mechanisms of ALLO-GABAA receptor function in the PAG region, we conducted a series of experiments to evaluate and define the effects of ShuYu capsules and uncover the relationship between the drug's efficacy and ALLO concentration fluctuations on GABAA receptor function in the PAG region. Our findings demonstrate that ShuYu capsules significantly improved oestrous cycle-dependant depression-like behaviour and reduced stress-induced hyperalgesia in rats with PMDD. Similar to the low dose of fluoxetine, ShuYu capsules targeted and mitigated the sharp decline in ALLO, rescued the upregulation of GABAAR subunit function, and activated PAG neurons in PMDD rats. The observed effects of ShuYu capsules suggest a central mechanism underlying PMDD symptoms, involving ALLO_GABAA receptor function in the PAG region. This study highlights the potential of traditional Chinese medicine in addressing both emotional and physical symptoms associated with PMDD, shedding light on novel therapeutic approaches for this condition.


Assuntos
Medicamentos de Ervas Chinesas , Pregnanolona , Transtorno Disfórico Pré-Menstrual , Ratos Sprague-Dawley , Receptores de GABA-A , Animais , Feminino , Medicamentos de Ervas Chinesas/farmacologia , Receptores de GABA-A/metabolismo , Pregnanolona/farmacologia , Transtorno Disfórico Pré-Menstrual/tratamento farmacológico , Ratos , Cápsulas , Modelos Animais de Doenças , Síndrome Pré-Menstrual/tratamento farmacológico , Fluoxetina/farmacologia
16.
Clin Ther ; 46(5): 433-438, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38697873

RESUMO

PURPOSE: Postpartum depression is a prevalent and overlooked mental disorder. Pathophysiology is thought to originate from a combination of biological and social factors, including hormones, and genetics. The consequences of untreated postpartum depression can be severe and negatively impact maternal and infant health. Zuranolone was approved as an oral agent in August 2023 for the treatment of postpartum depression in adults. The purpose of this article is evaluating the clinical aspects of zuranolone, including safety and efficacy pertaining to the drug and the clinical data that led to its approval. METHODS: A literature search was conducted using PubMed, Web of Science, and EMBASE with the terms postpartum depression, postpartum depression management, and zuranolone to locate relevant data for this narrative review. The prescribing information of zuranolone and clinicaltrials.gov were also utilized. FINDINGS: Two Phase III trials (Study 1-NCT04442503 and Study 2-NCT02978326) led to the approval of zuranolone by the Food and Drug Administration (FDA) based on clinically meaningful improvement in depressive symptoms. The trials met their primary endpoint, a change from baseline in HAM-D total score at day 15 (Study 1; 95% CI -6.3 to -1.7, P = 0.001: Study 2; 95% CI (-6.9 to -1.5, P = 0.003). IMPLICATIONS: Zuranolone, an oral and rapidly acting antidepressant, represents a promising new oral treatment option for individuals with postpartum depression.


Assuntos
Depressão Pós-Parto , Humanos , Depressão Pós-Parto/tratamento farmacológico , Feminino , Administração Oral , Antidepressivos/uso terapêutico , Antidepressivos/administração & dosagem , Resultado do Tratamento , Ensaios Clínicos Fase III como Assunto , Pregnanolona , Pirazóis
17.
Cell ; 187(12): 2952-2968.e13, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38795705

RESUMO

Recent studies suggest that human-associated bacteria interact with host-produced steroids, but the mechanisms and physiological impact of such interactions remain unclear. Here, we show that the human gut bacteria Gordonibacter pamelaeae and Eggerthella lenta convert abundant biliary corticoids into progestins through 21-dehydroxylation, thereby transforming a class of immuno- and metabo-regulatory steroids into a class of sex hormones and neurosteroids. Using comparative genomics, homologous expression, and heterologous expression, we identify a bacterial gene cluster that performs 21-dehydroxylation. We also uncover an unexpected role for hydrogen gas production by gut commensals in promoting 21-dehydroxylation, suggesting that hydrogen modulates secondary metabolism in the gut. Levels of certain bacterial progestins, including allopregnanolone, better known as brexanolone, an FDA-approved drug for postpartum depression, are substantially increased in feces from pregnant humans. Thus, bacterial conversion of corticoids into progestins may affect host physiology, particularly in the context of pregnancy and women's health.


Assuntos
Microbioma Gastrointestinal , Glucocorticoides , Hidrogênio , Progestinas , Humanos , Progestinas/metabolismo , Hidrogênio/metabolismo , Feminino , Glucocorticoides/metabolismo , Gravidez , Animais , Família Multigênica , Fezes/microbiologia , Pregnanolona/metabolismo , Camundongos
18.
Nurs Womens Health ; 28(4): 315-318, 2024 08.
Artigo em Inglês | MEDLINE | ID: mdl-38768648

RESUMO

Postpartum depression is one of the most common perinatal mood disorders. The U.S. Food and Drug Administration approved the first oral medication developed specifically for the treatment of postpartum depression in August 2023. Zuranolone, marketed under the brand name Zurzuvae (Sage Therapeutics, Inc. and Biogen), is thought to work similarly to other positive allosteric modulators of gamma-aminobutyric acid A receptors such as benzodiazepines. It can be used alone or as an adjunct to other oral antidepressant medication. Its 2-week regimen of once-daily oral administration provides women with postpartum depression the opportunity to maintain their daily routines in an outpatient setting. This article provides an overview of zuranolone, including indications, mechanism of action, potential adverse reactions, and implications for nursing practice.


Assuntos
Depressão Pós-Parto , Humanos , Depressão Pós-Parto/tratamento farmacológico , Feminino , Administração Oral , Antidepressivos/uso terapêutico , Pregnanolona , Pirazóis
19.
J Steroid Biochem Mol Biol ; 241: 106525, 2024 07.
Artigo em Inglês | MEDLINE | ID: mdl-38636682

RESUMO

Gamma-aminobutyric acid A (GABA-A) receptors in the cells of the immune system enhance anti-inflammatory responses by regulating cytokine secretion, cytotoxic responses, and cell activation. In the CNS, the formation of GABA-A subunits into a pentameric structure has been extensively studied; however, no such study has been conducted in the immune system. The objective of the present study was to examine associations between the levels of steroid hormones and GABA-A receptor δ subunit expression in the immune system. We focused on this subunit because GABA-A receptors that contain it become significantly more sensitive to steroid hormones. We collected 80 blood samples from reproductive age women for the purpose of analyzing dehydroepiandrosterone (DHEA), 17ß-estradiol, progesterone, and allopregnanolone using liquid chromatography-mass spectrometry (LC-MS). Furthermore, we extracted peripheral blood mononuclear cells (PBMCs) for determining mRNA expression levels of GABA-A receptor genes encoding the δ and ε subunits. We constructed linear mixed effect models for each GABA-A receptor subunit with all 4 steroid hormones, age, and age of menarche as predictors. Whereas DHEA was significantly associated with δ subunit expression (t-value = 2.981; p = 0.003), in line with our hypothesis, none of the steroid hormones were significantly associated with the expression of the ε subunit. Results of this study indicate that significant interactions between hormones from the steroid hormone biosynthesis pathway and GABAergic machinery from the immune cells may be utilized to expand models examining the molecular basis of inflammatory conditions.


Assuntos
Desidroepiandrosterona , Receptores de GABA-A , Humanos , Feminino , Receptores de GABA-A/genética , Receptores de GABA-A/metabolismo , Adulto , Progesterona/sangue , Adulto Jovem , Estradiol/sangue , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Pregnanolona/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Expressão Gênica/efeitos dos fármacos
20.
Biomolecules ; 14(4)2024 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-38672476

RESUMO

The recent approval of formulations of the endogenous neurosteroid allopregnanolone (brexanolone) and the synthetic neuroactive steroid SAGE-217 (zuranolone) to treat postpartum depression (PPD) has encouraged further research to elucidate why these potent enhancers of GABAAR function are clinically effective in this condition. Dopaminergic projections from the ventral tegmental area (VTA) to the nucleus accumbens are associated with reward/motivation and brain imaging studies report that individuals with PPD show reduced activity of this pathway in response to reward and infant engagement. However, the influence of neurosteroids on GABA-ergic transmission in the nucleus accumbens has received limited attention. Here, we investigate, in the medium spiny neurons (MSNs) of the mouse nucleus accumbens core, the effect of allopregnanolone, SAGE-217 and other endogenous and synthetic steroids of interest on fast phasic and tonic inhibition mediated by synaptic (α1/2ßγ2) and extrasynaptic (α4ßδ) GABAARs, respectively. We present evidence suggesting the resident tonic current results from the spontaneous opening of δ-GABAARs, where the steroid-enhanced tonic current is GABA-dependent. Furthermore, we demonstrate local neurosteroid synthesis in the accumbal slice preparation and reveal that GABA-ergic neurotransmission of MSNs is influenced by an endogenous neurosteroid tone. Given the dramatic fluctuations in allopregnanolone levels during pregnancy and postpartum, this neurosteroid-mediated local fine-tuning of GABAergic transmission in the MSNs will probably be perturbed.


Assuntos
Neuroesteroides , Núcleo Accumbens , Pregnanolona , Receptores de GABA-A , Animais , Núcleo Accumbens/metabolismo , Núcleo Accumbens/efeitos dos fármacos , Camundongos , Receptores de GABA-A/metabolismo , Neuroesteroides/metabolismo , Pregnanolona/farmacologia , Pregnanolona/metabolismo , Sinapses/metabolismo , Sinapses/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Feminino , Masculino , Transmissão Sináptica/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/efeitos dos fármacos
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