Pregnanolone glutamate (PA-G) is a neuroactive steroid that has been previously demonstrated to be a potent neuroprotective compound in several biological models in vivo. Our in vitro experiments identified PA-G as an inhibitor of N-methyl-D-aspartate receptors and a potentiator of γ-aminobutyric acid receptors (GABAARs).
Many hormones display distinct circadian rhythms, driven by central regulators, hormonal bioavailability, and half-life. A set of 11-oxygenated C19 steroids (11-oxyandrogens) and pregnenolone sulfate (PregS) are elevated in congenital adrenal hyperplasia and other disorders, but their circadian patterns have not been characterized.
Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men Read More »
The fundamental framework of steroidogenesis is similar across steroidogenic cells, especially in initial mitochondrial steps.
The Expanding Role of Mitochondria, Autophagy and Lipophagy in Steroidogenesis Read More »
Pregnenolone (P5) promotes prostate cancer cell growth, and de novo synthesis of intratumoural P5 is a potential cause of development of castration resistance. Immune cells can also synthesize P5 de novo.
CLICK-enabled analogues reveal pregnenolone interactomes in cancer and immune cells Read More »
This article provides a succinct overview of sex differences in epilepsy and putative molecular mechanisms underlying sex differences in seizure susceptibility in chemical, genetic, and acquired epileptogenesis.
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.
Subclinical hypothyroidism is related with increased risk of cardiovascular diseases. The decreased levels of dehydroepiandrosterone sulphate (DHEA-S) are associated with hyperlipidemia, atherosclerosis and obesity. The lower levels of DHEA‑S might be an important factor in development of atherosclerosis in subclinical hypothyroidism.
Neuroactive steroids are potent modulators of microglial functions and are capable of counteracting their excessive reactivity. This action has mainly been ascribed to neuroactive steroids released from other sources, as microglia have been defined unable to produce neurosteroids de novo.
Already for centuries, humankind is driven to understand the physiological and pathological mechanisms that occur in our brains. Today, we know that ion channels play an essential role in the regulation of neural processes and control many functions of the central nervous system.
TRPM3 in brain (patho)physiology Read More »
Alcohol use disorder (AUD) is a chronic relapsing brain disorder. GABAA receptor (GABAAR) subunits are a target for the pharmacological effects of alcohol. Neurosteroids play an important role in the fine-tuning of GABAAR function in the brain. Recently, we have shown that AUD is associated with changes in DNA methylation mechanisms. However, the role of DNA methylation in the regulation of neurosteroid biosynthesis and GABAergic neurotransmission in AUD patients remains under-investigated.
Evidence shows coronavirus disease 2019 (COVID-19)-induced symptom severity and mortality is more frequent in men than in women, suggesting sex steroids may play a protective role.
Sex and COVID-19: a protective role for reproductive steroids Read More »
Neurosteroids modulate epileptic activity by interacting with the γ-aminobutyric acid type A receptor, but their brain levels are still undetermined.
Neurosteroids are a family of compounds that are synthesized in principal excitatory neurons and glial cells, and derive from the transformation of cholesterol into pregnenolone. The most studied neurosteroids-allopregnanolone and allotetrahydrodeoxycorticosterone (THDOC)-are known to modulate GABAΑ receptor-mediated transmission, thus playing a role in controlling neuronal network excitability.
Neurosteroids and focal epileptic disorders Read More »
Lower dehydroepiandrosterone-sulfate (DHEA-S) levels have been inconsistently associated with coronary heart disease (CHD) and mortality. Data are limited for heart failure (HF) and association between DHEA-S change and events.
Neuroactive steroids (NAS) are derivatives of cholesterol or steroidal precursors made in the gonads, adrenal gland, placenta and brain. We characterized longitudinal plasma proneuroactive and NAS in healthy perinatal comparison women (HPCW), women at-risk for perinatal depression (AR-PND), and women with PND with/without comorbid anxiety. We hypothesized that AR-PND women who either did or did not go on to develop PND would have elevated NAS concentrations as compared to HPCW and that NAS would be correlated to depressive and anxiety symptoms.
Sex differences exist in heart failure (HF) phenotypes, but there is limited research on the role of sex hormones in HF and its subtypes.
Neurosteroids are steroids synthetized in the nervous system, with the first step of steroidogenesis taking place within mitochondria with the synthesis of pregnenolone. They exert important brain-specific functions by playing a role in neurotransmission, learning and memory processes, and neuroprotection.
Clock-controlled mitochondrial dynamics correlates with cyclic pregnenolone synthesis Read More »
Still circa 25% to 30% of patients with epilepsy cannot be efficiently controlled with available antiepileptic drugs so newer pharmacological treatment options have been continuously searched for. In this context, a group of endogenous or exogenous neurosteroids allosterically positively modulating GABA-A receptors may offer a promising approach.
Neurosteroids and seizure activity Read More »
Neurosteroids can modulate γ-aminobutyric acid type A receptor-mediated inhibitory currents. Recently, we discovered that the neurosteroids progesterone, 5α-dihydroprogesterone, allopregnanolone, and pregnanolone are reduced in the cerebrospinal fluid of patients with status epilepticus (SE). However, it is undetermined whether neurosteroids influence SE.
Neuroinflammation, whose distinctive sign is the activation of microglia, is supposed to play a key role in the development and progression of neurodegenerative diseases. The aim of this investigation was to determine levels of neurosteroids produced by resting and injured BV-2 microglial cells.
N-methyl-D-aspartate receptor (NMDAR) hypofunction has been implicated in several neurodevelopmental disorders. NMDAR function can be augmented by positive allosteric modulators, including endogenous compounds, such as cholesterol and neurosteroid pregnenolone sulfate (PES).
Endocannabinoids are suggested to play a role in energy balance regulation. We aimed to investigate associations of endocannabinoid concentrations during the day with energy balance and adiposity and interactions with 2 diets differing in protein content in participants in the postobese phase with prediabetes.
Alzheimer’s disease (AD) is a multifactorial age-related neurodegenerative disease that today has no effective treatment to prevent or slow its progression. Neuroactive steroids, including neurosteroids and sex steroids, have attracted attention as potential suitable candidates to alleviate AD pathology.
Glucocorticoid synthesis is a complex, multistep process that starts with cholesterol being delivered to the inner membrane of mitochondria by StAR and StAR-related proteins.
Transient receptor potential (TRP) channels are remarkable transmembrane protein complexes that are essential for the physiology of the tissues in which they are expressed. They function as non-selective cation channels allowing for the signal transduction of several chemical, physical and thermal stimuli and modifying cell function. These channels play pivotal roles in the nervous and reproductive systems, kidney, pancreas, lung, bone, intestine, among others.
Steroids and TRP channels: a close relationship Read More »
Neuroactive steroids, molecules produced from cholesterol in steroidogenic cells (i.e., peripheral glands and nervous system) are physiological modulators and protective agents of nervous function. A possible role for neuroactive steroids in the sex-dimorphic clinical manifestation, onset and progression of Multiple Sclerosis (MS) has been recently suggested.
Sex dimorphism in an animal model of multiple sclerosis: focus on pregnenolone synthesis Read More »
Most neonatal outcomes in neonates are related to normal adrenal gland function. Assessment of adrenal function in a sick preterm neonate remains a challenge, thus we hypothesized that adrenal steroid precursors to their product ratios have a direct relationship with neonatal outcomes.
Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene are responsible for the onset of CDKL5 Deficiency Disorder (CDD), a neurological pathology characterised by severe infantile seizures, intellectual disability, impairment of gross motor skills, sleep and gastrointestinal disturbances. CDKL5 is a serine/threonine kinase the molecular network of which is not yet fully understood.
Dehydroepiandrosterone (DHEA), mostly present as its sulfated ester (DHEA-S), is an anabolic hormone that naturally declines with age. Furthermore, it is the most abundant androgen and estrogen precursor in humans.
Sleep deprivation (SD) is associated with a broad spectrum of cognitive and behavioural complications, including emotional lability and enhanced stress reactivity, as well as deficits in executive functions, decision making and impulse control.
Cerebral ischemic stroke is a significant cause of morbidity and mortality. Sex differences exist following stroke in terms of incidence, symptoms, outcomes and response to some treatments. Importantly, molecular mechanisms of injury, activated following ischemia may differ between the sexes and if so may account, at least in part, for sex differences seen in treatment response.
miRNAs are endogenous noncoding single-stranded small RNAs of ~22 nucleotides in length that post-transcriptionally repress the expression of their various target genes. They contribute to the regulation of a variety of physiologic processes including embryonic development, differentiation and proliferation, apoptosis, metabolism, hemostasis and inflammation.
The role of miRNAs in regulating adrenal and gonadal steroidogenesis Read More »
The pregnenolone-progesterone-allopregnanolone pathway is receiving increasing attention in research on the role of neurosteroids in pathophysiology, particularly in stress-related and drug use disorders. These disorders involve an allostatic change that may result from deficiencies in allostasis or adaptive responses, and may be downregulated by adjustments in neurotransmission by neurosteroids.
Pregnenolone and dehydroepiandrosterone (DHEA) are hydroxysteroids that serve as biosynthetic precursors for steroid hormones in human body. SULT2B1b has been reported to be critically involved in the sulfation of pregnenolone and DHEA, particularly in the sex steroid-responsive tissues.
The nervous system is a target and a source of steroids. Neuroactive steroids are steroids that target neurons and glial cells. They include hormonal steroids originated in the peripheral glands, steroids locally synthesized by the neurons and glial cells (neurosteroids) and synthetic steroids, some of them used in clinical practice.
Neuroactive steroids, neurosteroidogenesis and sex Read More »
Pregnenolone is a steroid hormone precursor that is synthesized in various steroidogenic tissues, in the brain, and in lymphocytes. In addition to serving as the precursor for other steroid hormones, pregnenolone exerts its own effect as an anti-inflammatory molecule to maintain immune homeostasis in various inflammatory conditions.
Many steroid hormones such as estrogen (E2) bind to their receptors for the regulation of biological processes. Pregnenolone (P5) is the precursor form of almost all steroid hormones and is often used to treat skin disorders and neurological complications. However, the mechanism and physiological function of P5 in reproductive organs are not well established.
There are sex differences in sleep from a very early age till adulthood and older age. The changing hormone profile across the reproductive life of a woman, from puberty through the reproductive period to the postmenopausal years, has a significant influence on sleep.
Sleep and sleep-related disorders in women Read More »
Translocator protein 18 kDa (TSPO) is located in the mitochondrial outer membrane and plays an important role in steroidogenesis and cell survival. In the central nervous system (CNS), its expression is upregulated in neuropathologies such as Alzheimer’s disease (AD).
TSPO ligands boost mitochondrial function and pregnenolone synthesis Read More »
Obesity-related alterations in the circulating steroid hormone profile remain equivocal in women. Our objective was to identify circulating steroid levels that relate to increased adiposity and altered adipose phenotype in premenopausal women.
Four series of pregnenolone derivatives having one or two α,β-unsaturated carbonyls and an ester moiety at C-21 or C-3 were synthetized to compare their cytotoxicity effect.
The aim was to study the effects of flutamide on cell proliferation, in vivo tumour growth and steroid production in canine and human IBC cell lines.
Dehydroepiandrosterone sulfate (DHEAS) is the most abundant steroid in human circulation, and adrenocorticotropic hormone (ACTH) is considered the major regulator of its synthesis. Pregnenolone sulfate (PregS) and 5-androstenediol-3-sulfate (AdiolS) have recently emerged as biomarkers of adrenal disorders.
In animal models, levels of the neurosteroid pregnenolone increase after tetrahydrocannabinol (THC) administration and pregnenolone appears to attenuate the brain effects of THC. Given these interactions between pregnenolone and THC, we evaluated baseline neurosteroid levels in participants with a history of a cannabis use disorders (CUDs).
Treatment with progesterone protects the male and female brain against damage after middle cerebral artery occlusion (MCAO). However, in both sexes, the brain contains significant amounts of endogenous progesterone. It is not known whether endogenously produced progesterone enhances the resistance of the brain to ischemic insult.
Past research has indicated gender differences in the clinical characteristics and course of schizophrenia.
The study explored differences in the steroidogenic pathway between obese and nonobese women with polycystic ovary syndrome (PCOS) using liquid chromatography-tandem mass spectrometry (LC-MS/MS).
Steroid hormone profiling in obese and nonobese women with polycystic ovary syndrome Read More »
Little is known about the origin of the neuroactive steroids dehydroepiandrosterone sulphate (DHEAS) and pregnenolone sulphate (PregS) in the brain or of their subsequent metabolism.
The steroid hormone pregnenolone attenuates several in vivo behavioural and somatic effects of the phytocannabinoid Δ9-tetrahydrocannabinol, and it was suggested that pregnenolone can protect the brain from cannabis intoxication.
Smoking during pregnancy presents health risks for both the mother and her child. In this study we followed changes in the production of steroid hormones in pregnant smokers.
Changes to fetal steroidogenesis caused by maternal smoking Read More »
Pregnenolone, and related neurosteroids, may have antidepressant properties. Preclinical research proposes that microtubule associated protein 2 (MAP2) binding may be a mechanism for antidepressant properties of pregnenolone.
Microtubule associated protein 2 in bipolar depression: impact of pregnenolone Read More »
To test whether melatonin plays an important role in the process of early pregnancy, melatonin was given in drinking water to pregnant mice at different gestation stages.
The structural modifications of pregnenolone have been described via the introduction of heterocyclic moieties at C-17 position by limiting the acyl group.
This study aimed to examine the effect of add-on treatment with the neurosteroid pregnenolone (PREG) on neurocognitive dysfunctions of patients with recent-onset schizophrenia (SZ) and schizoaffective disorder (SA).
The gonads have long been considered endocrine glands, producing sex steroids such as estrogens, androgens, and progesterone (P4) for the sole purpose of sexual differentiation, puberty, and reproduction.
Role of sex steroids in β-cell function, growth, and survival Read More »
Considerable evidence from preclinical and clinical studies shows that steroids and in particular neurosteroids are important endogenous modulators of several brain-related functions.
Neurosteroids and potential therapeutics: focus on pregnenolone Read More »
Depression is one of the major causes of disability worldwide, but the complete etiology of depression is not fully understood. Dehydroepiandrosterone (DHEA) and its sulphated form DHEA(S) have been associated with mood and healthy aging.
The neurosteroids allopregnanolone and dehydroepiandrosterone (DHEA) are integral components of the stress response and exert positive modulatory effects on emotion in both human and animal studies.
Management of recent-onset schizophrenia (SZ) and schizoaffective disorder (SA) is challenging owing to frequent insufficient response to antipsychotic agents. This study aimed to test the efficacy and safety of the neurosteroid pregnenolone in patients with recent-onset SZ/SA.
Pregnenolone is considered the inactive precursor of all steroid hormones, and its potential functional effects have been largely uninvestigated.
Pregnenolone can protect the brain from cannabis intoxication Read More »
The neurosteroid allopregnanolone is a potent allosteric modulator of the gamma-aminobutyric acid type A receptor with anxiolytic properties. Exogenous administration of allopregnanolone reduces anxiety, and allopregnanolone blockade impairs social and affective functioning.
In the search of the sleep substance, many studies have been addressed for different hormones, responsible for sleep-wake cycle regulation. In this article we mentioned the participation of steroid hormones, besides its role regulating sexual behavior, they influence importantly in the sleep process.
Steroid hormones and sleep regulation Read More »
Mood and substance-use disorders are both associated with cognitive deficits. Patients with mood and substance-use disorders have poorer cognition than patients with only a mood disorder. Pregnenolone may have beneficial effects on mood and cognition.
Pregnenolone for cognition and mood in dual diagnosis patients Read More »
Calcium-permeable channels are known to have roles in many mammalian cell types but the expression and contribution of such ion channels in synovial cells is mostly unknown. The objective of this study was to investigate the potential relevance of Transient Receptor Potential Melastatin 3 (TRPM3) channel to fibroblast-like synoviocytes (FLSs) of patients with rheumatoid arthritis.
Although research suggests that socio-sexual behavior changes in conjunction with the menstrual cycle, several potential factors are rarely taken into consideration. We investigated the role of changing hormone concentrations on self-reported physical discomfort, sleep, exercise and socio-sexual interest in young, healthy women.
Loss of progesterone signaling in the endometrium may be a causal factor in the development of endometriosis, and progesterone resistance is commonly observed in women with this disease.
It is well established that there is mutual interaction between the neuroendocrines and immune systems and that the disturbance in any one system could affect the function of the other.
Transient receptor potential (TRP) cation channels are renowned for their ability to sense diverse chemical stimuli.
Neurosteroids are a relatively new class of neuroactive compounds brought to prominence in the past 2 decades.
Neurosteroid regulation of central nervous system development Read More »
Evidence suggests that neuroactive steroids may be candidate modulators of schizophrenia pathophysiology and therapeutics.
The neurosteroid pregnenolone (PREG) and its chemically synthesized analog 3beta-methoxypregnenolone (MePREG) bind to microtubule-associated protein 2 (MAP2) and stimulate the polymerization of microtubules.
Microtubule-associated protein 2 (MAP2) is a neurosteroid receptor Read More »
The N-methyl-D-aspartate (NMDA) receptor is believed to play a major role in learning and in excitotoxic neuronal damage associated with stroke and epilepsy.
Traditional pharmacologic approaches had identified several classes of xenobiotics that elicited characteristic biological effects in vivo but that lacked defined molecular mechanisms of action.
Our earlier biochemical studies suggested that the neurosteroid pregnenolone sulfate (PS) may reduce gamma-aminobutyric acid (GABA) action at the Cl- channel associated with GABAA receptors.