Allopregnanolone: An overview on its synthesis and effects

Journal of Neuroendocrinology, Journal Year: 2021, Volume and Issue: 34(2)

Published: June 1, 2021

Allopregnanolone, a 3α,5α-progesterone metabolite, acts as potent allosteric modulator of the γ-aminobutyric acid type A receptor. In present review, synthesis this neuroactive steroid occurring in nervous system is discussed with respect to physiological and pathological conditions. addition, its neuroprotective effects are also reported. Interestingly, levels steroid, well effects, sex-dimorphic, suggesting possible gender medicine based on for neurological disorders. However, allopregnanolone presents low bioavailability extensive hepatic metabolism, limiting use drug. Therefore, synthetic analogues or different therapeutic strategy able increase have been proposed overcome any pharmacokinetic issues.

Language: Английский

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Prefrontal 5α-reductase 2 mediates male-specific acute stress response

Science Advances, Journal Year: 2025, Volume and Issue: 11(4)

Published: Jan. 22, 2025

A key response to acute stress is the increased brain synthesis of neurosteroid allopregnanolone (AP). Although rate-limiting step this reaction catalyzed by 5α-reductase (5αR), role its two primary isoenzymes, 5αR1 and 5αR2, in reactivity remains unclear. Here, we found that led levels but not 5αR1, medial prefrontal cortex (mPFC) male, female, rats. Down-regulation 5αR2 mPFC significantly reduced males, similar sexual dimorphic effects were observed a novel line knockout Notably, regulated baseline AP synthesis, whereas enabled production under stress. Acute administration restored knockdown Single-nucleus transcriptomics showed stress-induced protein translation neurons glia. These results highlight crucial mediating sex-specific differences reactivity.

Language: Английский

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Preclinical and clinical pharmacology of brexanolone (allopregnanolone) for postpartum depression: a landmark journey from concept to clinic in neurosteroid replacement therapy

Psychopharmacology, Journal Year: 2023, Volume and Issue: 240(9), P. 1841 - 1863

Published: Aug. 11, 2023

Abstract This article describes the critical role of neurosteroids in postpartum depression (PPD) and outlines landmark pharmacological journey brexanolone as a first-in-class neurosteroid antidepressant with significant advantages over traditional antidepressants. PPD is neuroendocrine disorder that affects about 20% mothers after childbirth characterized by symptoms including persistent sadness, fatigue, dysphoria, well disturbances cognition, emotion, appetite, sleep. The main pathology behind reduction neurosteroids, referred to withdrawal, concept pioneered our preclinical studies. We developed replacement therapy (NRT) rational approach for treating other conditions related deficiency, unveiling power novel anxiolytic-antidepressants. neurosteroid, (BX), progesterone-derived allopregnanolone rapidly relieves anxiety mood deficits activating GABA-A receptors, making it transformational treatment PPD. In 2019, FDA approved BX, an intravenous formulation allopregnanolone, NRT treat clinical studies, BX significantly improved within hours administration, tolerable side effects headache, dizziness, somnolence. identified molecular mechanism neuronal PPD-like milieu. involves activation both synaptic extrasynaptic which promote tonic inhibition serve key target conditions. Neurosteroids offer several antidepressants, rapid onset, unique mechanism, lack tolerance upon repeated use. Some limitations include aqueous solubility, limited accessibility, hospitalization treatment, oral product, serious adverse events at high doses. However, unmet need synthetic address this condition supersedes these limitations. Recently, we hydrophilic superior profile drug delivery. Overall, approval major milestone field neurotherapeutics, paving way development depression, epilepsy, status epilepticus. Graphical abstract

Language: Английский

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Progestogen-Mediated Neuroprotection in Central Nervous System Disorders

Neuroendocrinology, Journal Year: 2022, Volume and Issue: 113(1), P. 14 - 35

Published: June 27, 2022

Neuroactive steroids can be synthetic or endogenous molecules produced by neuronal and glial cells peripheral glands. Examples include estrogens, testosterone, progesterone its reduced metabolites such as 5α-dihydro­progesterone allopregnanolone. Steroids neurons glia target the nervous system are called neurosteroids. Progesterone analog molecules, known progestogens, have been shown to exhibit neurotrophic, neuroprotective, antioxidant, anti-inflammatory, modulatory, promyelinating, remyelinating effects in several experimental models of neurodegenerative injury conditions. Pleiotropic mechanisms progestogens may act synergistically prevent neuron degeneration, astrocyte microglial reactivity, reducing morbidity mortality. The aim this review is summarize significant findings related actions other epidemiological clinical trials some most prevalent debilitating chronic disorders, namely, Alzheimer’s disease, Parkinson’s Huntington’s amyotrophic lateral sclerosis, multiple sclerosis. We evaluated progestogen alterations under pathological conditions, how pathology modifies their levels, well intracellular interactions underlying neuroprotective effects. Furthermore, an analysis potential natural progestins regenerative agents, when administered hormone replacement therapy menopause, also discussed.

Language: Английский

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Role of allopregnanolone-mediated γ-aminobutyric acid A receptor sensitivity in the pathogenesis of premenstrual dysphoric disorder: Toward precise targets for translational medicine and drug development

Frontiers in Psychiatry, Journal Year: 2023, Volume and Issue: 14

Published: March 2, 2023

Premenstrual dysphoric disorder (PMDD) can be conceptualized as a of suboptimal sensitivity to neuroactive steroid hormones. Its core symptoms (emotional instability, irritability, depression, and anxiety) are related the increase stress due fluctuation hormone level in luteal phase menstrual cycle. In this review, we describe emotional regulatory effect allopregnanolone (ALLO), summarize relationship between ALLO γ-aminobutyric acid A (GABA ) receptor subunits based on rodent experiments clinical observations. rapid decrease reduces GABA receptor, chloride influx, hindered inhibitory GABAergic neurons pyramidal neurons, then increased excitability resulting PMDD-like behavior. Finally, discuss depth treatment PMDD with targeted receptors, hoping find precise target for drug development subsequent application. conclusion, pathophysiology is rooted changes caused by levels. Targeting receptors may alleviate occurrence PMDD.

Language: Английский

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The emergence of antidepressant drugs targeting GABAA receptors: A concise review

Biochemical Pharmacology, Journal Year: 2024, Volume and Issue: 228, P. 116481 - 116481

Published: Aug. 13, 2024

Depression is among the most common psychiatric illnesses, which imposes a major socioeconomic burden on patients, caregivers, and public health system. Treatment with classical antidepressants (e.g. tricyclic selective serotonine reuptake inhibitors), primarily affect monoaminergic systems has several limitations, such as delayed onset of action moderate efficacy in relatively large proportion depressed patients. Furthermore, depression highly heterogeneus, its different subtypes, including post-partum depression, involve distinct neurobiology, warranting differential approach to pharmacotherapy. Given these shortcomings, need for novel that are superior faster fully justified. The development market introduction rapid-acting accelerated recent years. Some new act through GABAergic In this review, we discuss discovery, efficacy, limitations treatment classic antidepressants. We provide detailed discussion neurotransmission, special focus GABA

Language: Английский

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Diabetic Encephalopathy in a Preclinical Experimental Model of Type 1 Diabetes Mellitus: Observations in Adult Female Rat

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(2), P. 1196 - 1196

Published: Jan. 7, 2023

Patients affected by diabetes mellitus (DM) show diabetic encephalopathy with an increased risk of cognitive deficits, dementia and Alzheimer's disease, but the mechanisms are not fully explored. In male animal models DM, development impairment seems to be result concomitance different processes such as neuroinflammation, oxidative stress, mitochondrial dysfunction, aberrant synaptogenesis. However, even if shows some sex-dimorphic features, no observations in female rats have been so far reported on these aspects. Therefore, experimental model type 1 DM (T1DM), we explored impact one month pathology memory abilities novel object recognition test synaptogenesis functionality. Moreover, given that steroids involved learning, also analysed their levels receptors. We dysfunction can associated features hippocampus cerebral cortex. Indeed, hippocampus, observed neuroinflammation possibly due results locally progesterone metabolites (i.e., dihydroprogesterone allopregnanolone). These suggest specific brain-area effects T1DM since alterations

Language: Английский

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Cholesterol metabolites modulate ionotropic P2X4 and P2X7 receptor current in microglia cells.

Neuropharmacology, Journal Year: 2025, Volume and Issue: unknown, P. 110294 - 110294

Published: Jan. 1, 2025

The central nervous system is a well-known steroidogenic tissue producing, among others, cholesterol metabolites such as neuroactive steroids, oxysterols and steroid hormones. It well known that these endogenous molecules affect several receptor classes, including ionotropic GABAergic NMDA glutamatergic receptors in neurons. has been shown also purinergic (P2X) are metabolites' targets. Among P2X receptors, P2X4 P2X7 expressed microglia, the innate immune cells involved brain inflammatory response. In this study, we explore modulation by microglia. Patch-clamp experiments were performed BV2 cells, murine microglia cell line, to evaluate effects of using micro- nanomolar concentrations. About receptor, found testosterone butyrate (20 μM 200 nM) allopregnanolone (10 100 both potentiated its current, while neither 25-hydroxycholesterol nor 17β-estradiol (1 μM) showed any effects. On other hand, current was nM). Taken together, our data show either affected differently metabolites, suggesting structure-activity relationship players. Identifying possible link between transmission, will allow define new targets for drug development treat neuroinflammation.

Language: Английский

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Neuroactive steroid exposure impacts neurodevelopment: Comparison of human and rodent placental contribution

Journal of Neuroendocrinology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 9, 2025

Abstract The placenta is a fetal endocrine organ that secretes many neuroactive factors, including steroids, play critical roles in brain development. study of the placenta‐brain axis and links between placental function development represents an emerging research area dubbed “neuroplacentology.” drives circulating steroids to very high levels during gestation. Recent studies have highlighted role shaping specific structures behaviors. This review uses cross‐species framework discuss genomic in‐utero environmental changes, conditions alter steroidogenesis, leading changes early developmental trajectories relevant for psychiatric such as autism, sex‐linked manner.

Language: Английский

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Allopregnanolone in the Pathogenesis of the Psychiatric Comorbidities of Polycystic Ovarian Syndrome

The Journal of Steroid Biochemistry and Molecular Biology, Journal Year: 2025, Volume and Issue: unknown, P. 106719 - 106719

Published: March 1, 2025

Language: Английский

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