Medical Studies on Pregnenolone

The Neuroactive Steroid Pregnanolone Glutamate: Anticonvulsant Effect, Metabolites and Its Effect on Neurosteroid Levels in Developing Rat Brains

2021-12 Kudova E, Mares P, Hill M, Vondrakova K, Tsenov G, Chodounska H, Kubova H, Vales K

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).

Circadian rhythms of 11-oxygenated C19 steroids and ∆5-steroid sulfates in healthy men

2021-08 Turcu AF, Zhao L, Chen X, Yang R, Rege J, Rainey WE, Veldhuis JD, Auchus RJ

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.

Comparison of pregnenolone sulfate, pregnanolone and estradiol levels between patients with menstrually-related migraine and controls: an exploratory study

2021-03 Rustichelli C, Bellei E, Bergamini S, Monari E, Lo Castro F, Baraldi C, Tomasi A, Ferrari A

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.

De novo neurosteroidogenesis in human microglia: involvement of the 18 kDa translocator protein

2021-03 Germelli L, Da Pozzo E, Giacomelli C, Tremolanti C, Marchetti L, Wetzel CH, Barresi E, Taliani S, Da Settimo F, Martini C, Costa B

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.

Epigenetic regulation of GABAergic neurotransmission and neurosteroid biosynthesis in alcohol use disorder

2021-02 Gatta E, Guidotti A, Saudagar V, Grayson DR, Aspesi D, Pandey SC, Pinna G

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.

Plasma dehydroepiandrosterone sulfate and cardiovascular disease risk in older men and women

2020-12 Jia X, Sun C, Tang O, Gorlov I, Nambi V, Virani SS, Villareal DT, Taffet GE, Yu B, Bressler J, Boerwinkle E, Windham BG, de Lemos JA, Matsushita K, Selvin E, Michos ED, Hoogeveen RC, Ballantyne CM

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.

Longitudinal proneuroactive and neuroactive steroid profiles in medication-free women with, without and at-risk for perinatal depression: a liquid chromatography-tandem mass spectrometry analysis

2020-11 Deligiannidis KM, Kroll-Desrosiers AR, Tan Y, Dubuke ML, Shaffer SA

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.

Augmentation of endogenous neurosteroid synthesis alters experimental status epilepticus dynamics

2020-09 Lucchi C, Costa AM, Senn L, Messina S, Rustichelli C, Biagini G

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.

BV-2 microglial cells respond to rotenone toxic insult by modifying pregnenolone, 5α-dihydroprogesterone and pregnanolone levels

2020-09 Avallone R, Lucchi C, Puja G, Codeluppi A, Filaferro M, Vitale G, Rustichelli C, Biagini G

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.

Site of action of brain neurosteroid pregnenolone sulfate at the N-Methyl-D-Aspartate Receptor

2020-07 Hrcka Krausova B, Kysilov B, Cerny J, Vyklicky V, Smejkalova T, Ladislav M, Balik A, Korinek M, Chodounska H, Kudova E, Vyklicky L

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).

Role of endocannabinoids in energy-balance regulation in participants in the postobese state – a PREVIEW Study

2020-07 Drummen M, Tischmann L, Gatta-Cherifi B, Cota D, Matias I, Raben A, Adam T, Westerterp-Plantenga M

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.

Steroids and TRP channels: a close relationship

2020-05 Méndez-Reséndiz KA, Enciso-Pablo Ó, González-Ramírez R, Juárez-Contreras R, Rosenbaum T, Morales-Lázaro SL

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.

Sex dimorphism in an animal model of multiple sclerosis: focus on pregnenolone synthesis

2020-05 Giatti S, Rigolio R, Diviccaro S, Falvo E, Caruso D, Garcia-Segura LM, Cavaletti G, Melcangi RC

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.

Assessment of adrenal function at birth using adrenal glucocorticoid precursor to product ratios to predict short-term neonatal outcomes

2020-03 Karsli T, Jain VG, Mhanna M, Wu Q, Pepkowitz SH, Chandler DW, Shekhawat PS

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.

Pregnenolone and pregnenolone-methyl-ether rescue neuronal defects caused by dysfunctional CLIP170 in a neuronal model of CDKL5 Deficiency Disorder

2020-03 Barbiero I, Peroni D, Siniscalchi P, Rusconi L, Tramarin M, De Rosa R, Motta P, Bianchi M, Kilstrup-Nielsen C

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.

Sexual dimorphism following in vitro ischemia in the response to neurosteroids and mechanisms of injury

2020-01 Altaee R, Gibson C

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.

Stress and drug abuse-related disorders: the promising therapeutic value of neurosteroids focus on pregnenolone-progesterone-allopregnanolone pathway

2019-10 Tomaselli G , Vallée M

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.

Effect of SULT2B1 genetic polymorphisms on the sulfation of dehydroepiandrosterone and pregnenolone by SULT2B1b allozymes

2019-10 Alherz FA, El Daibani AA, Abunnaja MS, Bairam AF, Rasool MI, Sakakibara Y, Suiko M, Kurogi K, Liu MC

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 neurosteroid pregnenolone promotes degradation of key proteins in the innate immune signaling to suppress inflammation

2019-03 Murugan S, Jakka P, Namani S, Mujumdar V, Radhakrishnan G

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.

Pregnenolone as a potential candidate for hormone therapy for female reproductive disorders targeting ERβ

2019-01 Shin YY, Kang EJ, Jeong JS, Kim MJ, Jung EM, Jeung EB, An BS

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.

Neurosteroid levels in patients with bipolar disorder and a history of cannabis use disorders

2017-12 Van Enkevort E, Filbey F, Marx CE, Park J, Nakamura A, Sunderajan P, Brown ES

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).

A role of endogenous progesterone in stroke cerebroprotection revealed by the neural-specific deletion of its intracellular receptors

2017-11 Zhu X, Fréchou M, Liere P, Zhang S, Pianos A, Fernandez N, Denier C, Mattern C, Schumacher M, Guennoun R

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.

Pregnenolone can protect the brain from cannabis intoxication

2014-01 Vallée M, Vitiello S, Bellocchio L, Hébert-Chatelain E, Monlezun S, Martin-Garcia E, Kasanetz F, Baillie GL, Panin F, Cathala A, Roullot-Lacarrière V, Fabre S, Hurst DP, Lynch DL, Shore DM, Deroche-Gamonet V, Spampinato U, Revest JM, Maldonado R, Reggio PH, Ross RA, Marsicano G, Piazza PV

Pregnenolone is considered the inactive precursor of all steroid hormones, and its potential functional effects have been largely uninvestigated.

TRPM3 channel stimulated by pregnenolone sulphate in synovial fibroblasts and negatively coupled to hyaluronan

2010-06 Ciurtin C, Majeed Y, Naylor J, Sukumar P, English AA, Emery P, Beech DJ

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.

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