Progesterone is a steroid hormone traditionally linked with female fertility and pregnancy. In current reproductive medicine, progesterone and its analogues play crucial roles. While the discovery of its effects has a long history, over recent decades, various novel actions of this interesting steroid have been documented, of which its neuro- and immunoprotective activities are the most widely discussed. Discoveries of the novel biological activities of progesterone have also driven research and development in the field of progesterone analogues used in human medicine. Progestogen treatment has traditionally and predominately been used in maintaining pregnancy, the prevention of preterm labor, various gynecological pathologies, and in lowering the negative effects of menopause. However, there are also various other medical fields where progesterone and its analogues could find application in the future. The aim of this work is to show the mechanisms of action of progesterone and its metabolites, the physiological and pharmacological actions of progesterone and its synthetic analogues in human medicine, as well as the impacts of its production and use on the environment.

• Klíčová slova
• CNS disorder, endocrine disruption, gynecology, menopause, miscarriage, neurosteroid, pregnancy, preterm birth, progestagen, progesterone, progestin, progestogen,
• MeSH
• hormony MeSH
• lidé MeSH
• novorozenec MeSH
• progesteron * farmakologie   fyziologie   MeSH
• progestiny * farmakologie   terapeutické užití   MeSH
• těhotenství MeSH
• Check Tag
• lidé MeSH
• novorozenec MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• hormony MeSH
• progesteron * MeSH
• progestiny * MeSH

Steroid sulfation and desulfation participates in the regulation of steroid bioactivity, metabolism and transport. The authors focused on sulfation and desulfation balance in three neurodegenerative diseases: Alzheimer´s disease (AD), Parkinson´s disease (PD), and multiple sclerosis (MS). Circulating steroid conjugates dominate their unconjugated counterparts, but unconjugated steroids outweigh their conjugated counterparts in the brain. Apart from the neurosteroid synthesis in the central nervous system (CNS), most brain steroids cross the blood-brain barrier (BBB) from the periphery and then may be further metabolized. Therefore, steroid levels in the periphery partly reflect the situation in the brain. The CNS steroids subsequently influence the neuronal excitability and have neuroprotective, neuroexcitatory, antidepressant and memory enhancing effects. They also exert anti-inflammatory and immunoprotective actions. Like the unconjugated steroids, the sulfated ones modulate various ligand-gated ion channels. Conjugation by sulfotransferases increases steroid water solubility and facilitates steroid transport. Steroid sulfates, having greater half-lives than their unconjugated counterparts, also serve as a steroid stock pool. Sulfotransferases are ubiquitous enzymes providing massive steroid sulfation in adrenal zona reticularis and zona fasciculata.. Steroid sulfatase hydrolyzing the steroid conjugates is exceedingly expressed in placenta but is ubiquitous in low amounts including brain capillaries of BBB which can rapidly hydrolyze the steroid sulfates coming across the BBB from the periphery. Lower dehydroepiandrosterone sulfate (DHEAS) plasma levels and reduced sulfotransferase activity are considered as risk factors in AD patients. The shifted balance towards unconjugated steroids can participate in the pathophysiology of PD and anti-inflammatory effects of DHEAS may counteract the MS.

• Klíčová slova
• Alzheimer’s disease, Parkinson's disease, brain, multiple sclerosis, neuroactive steroids, neurosteroids, steroid sulfatase, steroid sulfotransferases,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

BACKGROUND AND PURPOSE: Neurosteroids influence neuronal function and have multiple promising clinical applications. Direct modulation of postsynaptic neurotransmitter receptors by neurosteroids is well characterized, but presynaptic effects remain poorly understood. Here, we report presynaptic glutamate release potentiation by neurosteroids pregnanolone and pregnanolone sulfate and compare their mechanisms of action to phorbol 12,13-dibutyrate (PDBu), a mimic of the second messenger DAG. EXPERIMENTAL APPROACH: We use whole-cell patch-clamp electrophysiology and pharmacology in rat hippocampal microisland cultures and total internal reflection fluorescence (TIRF) microscopy in HEK293 cells expressing GFP-tagged vesicle priming protein Munc13-1, to explore the mechanisms of neurosteroid presynaptic modulation. KEY RESULTS: Pregnanolone sulfate and pregnanolone potentiate glutamate release downstream of presynaptic Ca2+ influx, resembling the action of a phorbol ester PDBu. PDBu partially occludes the effect of pregnanolone, but not of pregnanolone sulfate. Calphostin C, an inhibitor that disrupts DAG binding to its targets, reduces the effect PDBu and pregnanolone, but not of pregnanolone sulfate, suggesting that pregnanolone might interact with a well-known DAG/phorbol ester target Munc13-1. However, TIRF microscopy experiments found no evidence of pregnanolone-induced membrane translocation of GFP-tagged Munc13-1, suggesting that pregnanolone may regulate Munc13-1 indirectly or interact with other DAG targets. CONCLUSION AND IMPLICATIONS: We describe a novel presynaptic effect of neurosteroids pregnanolone and pregnanolone sulfate to potentiate glutamate release downstream of presynaptic Ca2+ influx. The mechanism of action of pregnanolone, but not of pregnanolone sulfate, partly overlaps with that of PDBu. Presynaptic effects of neurosteroids may contribute to their therapeutic potential in the treatment of disorders of the glutamate system.

• Klíčová slova
• Munc13-1, glutamate, neurosteroid, phorbol ester, pregnanolone, presynaptic,
• MeSH
• HEK293 buňky MeSH
• krysa rodu Rattus MeSH
• kyselina glutamová MeSH
• lidé MeSH
• neurosteroidy * MeSH
• pregnanolon * farmakologie   MeSH
• sírany MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• kyselina glutamová MeSH
• neurosteroidy * MeSH
• pregnanolon * MeSH
• sírany MeSH

UNLABELLED: Background: Only few studies have monitored the potential of physical activity training and physical therapy to modulate the reaction of the endocrine system. In this study, the effect of neuroproprioceptive facilitation and inhibition physical therapy on clinical outcomes and neuroactive steroids production in people with multiple sclerosis was evaluated. Moreover, we were interested in the factors that influence the treatment effect. METHODS: In total, 44 patients with multiple sclerosis were randomly divided into two groups. Each group underwent a different kind of two months ambulatory therapy (Motor program activating therapy and Vojta's reflex locomotion). During the following two months, participants were asked to continue the autotherapy. Primary (serum level of cortisol, cortisone, 7α-OH-DHEA, 7β-OH-DHEA, 7-oxo-DHEA, DHEA) and secondary (balance, cognition and patient-reported outcomes) outcomes were examined three times (pre, post, and washout assessments). RESULTS: In both groups, there is a decreasing trend of 7-oxo-DHEA concentration in post-assessment and 7β-OH-DHEA in washout versus pre-assessment. A higher impact on neuroactive steroids is visible after Vojta's reflex locomotion. As for clinical outcomes, the Paced Auditory Serial Addition Test and Multiple Sclerosis Impact Scale significantly improved between post-assessment and washout assessment. The improvement was similar for both treatments. CONCLUSIONS: Neuroproprioceptive facilitation and inhibition improved the clinical outcomes and led to non-significant changes in neuroactive steroids. Trial registration (NCT04379193).

• Klíčová slova
• cortisol, dehydroepiandrosterone, multiple sclerosis, neuroactive steroids, neuroproprioceptive facilitation and inhibition, physical therapy,
• Publikační typ
• časopisecké články MeSH

BACKGROUND AND PURPOSE: NMDA receptors are glutamatergic ionotropic receptors involved in excitatory neurotransmission, synaptic plasticity and excitotoxic cell death. Many allosteric modulators can influence the activity of these receptors positively or negatively, with behavioural consequences. 20-Oxo-5β-pregnan-3α-yl sulphate (pregnanolone sulphate; PA-6) is an endogenous neurosteroid that inhibits NMDA receptors and is neuroprotective. We tested the hypothesis that the interaction of PA-6 with the plasma membrane is critical for its inhibitory effect at NMDA receptors. EXPERIMENTAL APPROACH: Electrophysiological recordings and live microscopy were performed on heterologous HEK293 cells expressing GluN1/GluN2B receptors and cultured rat hippocampal neurons. KEY RESULTS: Our experiments showed that the kinetics of the steroid inhibition were slow and not typical of drug-receptor interaction in an aqueous solution. In addition, the recovery from steroid inhibition was accelerated by β- and γ-cyclodextrin. Values of IC(50) assessed for novel synthetic C3 analogues of PA-6 differed by more than 30-fold and were positively correlated with the lipophilicity of the PA-6 analogues. Finally, the onset of inhibition induced by C3 analogues of PA-6 ranged from use-dependent to use-independent. The onset and offset of cell staining by fluorescent analogues of PA-6 were slower than those of steroid-induced inhibition of current responses mediated by NMDA receptors. CONCLUSION AND IMPLICATIONS: We conclude that steroid accumulation in the plasma membrane is the route by which it accesses a binding site on the NMDA receptor. Thus, our results provide a possible structural framework for pharmacologically targeting the transmembrane domains of the receptor.

• MeSH
• akční potenciály účinky léků   MeSH
• antagonisté excitačních aminokyselin chemie   farmakologie   MeSH
• buněčná membrána účinky léků   metabolismus   MeSH
• fluorescenční mikroskopie MeSH
• HEK293 buňky MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• neurony účinky léků   metabolismus   MeSH
• neuroprotektivní látky chemie   farmakologie   MeSH
• neurotransmiterové látky chemie   farmakologie   MeSH
• pregnany chemie   farmakologie   MeSH
• receptory N-methyl-D-aspartátu antagonisté a inhibitory   genetika   MeSH
• transfekce MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 20-oxo-5beta-pregnan-3alpha-yl sulfate MeSH Prohlížeč
• antagonisté excitačních aminokyselin MeSH
• neuroprotektivní látky MeSH
• neurotransmiterové látky MeSH
• pregnany MeSH
• receptory N-methyl-D-aspartátu MeSH