Search Results (11)

Pregnanolone glutamate (PG) is a synthetic neurosteroid analog showing promise for treating ischemic brain injury, yet its blood–brain barrier (BBB) transport and metabolic fate remain unclear. We investigated the pharmacokinetics of PG in postnatal day 12 rats of both sexes subjected to endothelin-1 (ET-1)-induced focal hippocampal ischemia. Animals received PG (1 mg/kg intraperitoneal (i.p.)) or vehicle; serum and hippocampal steroidomes were profiled 60 min post-administration using gas chromatography-tandem mass spectrometry (GC-MS/MS) (hippocampus: n = 16 PG+, n = 27 PG−; multi-tissue subset: n = 6 PG+, n = 21 PG−). Our data revealed a “dual-fate” mechanism: PG undergoes systemic hydrolysis as a prodrug, as suggested by the tissue distribution pattern at 60 min post-administration, but also crosses the BBB intact, with significant parent conjugate accumulation in the hippocampus (42.3 pmol/g). The brain functioned as a “metabolic sink”, passively accumulating metabolites generated in peripheral organs—such as 17-hydroxypregnanolone—despite local absence of synthesizing enzymes (e.g., CYP17A1). Crucially, PG induced “metabolic segregation” within the central nervous system (CNS): the pharmacological 5β-pathway was saturated (~170-fold pregnanolone increase), while endogenous neuroprotective 5α-pathway (allopregnanolone) homeostasis remained preserved, contrasting with peripheral metabolic saturation. Preferential hippocampal accumulation of 3-oxo and 3β-isomers suggests autonomous regulatory buffering via oxidative 17β-hydroxysteroid dehydrogenase (HSD17B) enzymes, protecting against excessive GABAergic inhibition. This unique pharmacokinetic profile—combining metabolic segregation with active central buffering—defines PG as a dual-mechanism delivery system that generates central neuroactive metabolites—several with previously established GABAergic and neuroprotective activity—without disrupting endogenous neurosteroidogenesis, positioning it as a promising neurotherapeutic candidate minimizing physiological steroid homeostasis disruption. Importantly, the present study characterizes the pharmacokinetic and metabolic fate of PG; the neuroprotective efficacy of PG was demonstrated in our prior functional studies using the same model. Full article

5a-reductase (5a-R) isozymes are essential for androgen metabolism and neurosteroid biosynthesis, linking endocrinology and neuropsychiatry. This systematic review, conducted in accordance with PRISMA 2020 guidelines, aimed to synthesize current evidence on the tissue distribution of SRD5A1, SRD5A2, and SRD5A3 and their implications in mental health. A systematic search of the PubMed, Scopus, and Web of Science databases up to February 2025 identified 257 articles, of which 83 met the inclusion criteria. SRD5A1 is broadly expressed in the liver, skin, and central nervous system, contributing to allopregnanolone synthesis; SRD5A2 is mainly restricted to androgen-dependent tissues, playing a key role in prostate development and alopecia; and SRD5A3 is associated with glycosylation processes and oncogenesis. Converging evidence suggests that impaired neurosteroidogenesis due to 5α-R inhibition may underlie vulnerability to anxiety, depression, and suicidality. While earlier epidemiological findings were heterogeneous, recent pharmacovigilance data have strengthened the evidence supporting this association. Pharmacovigilance and clinical reports show that a subset of patients treated with finasteride or dutasteride may experience persistent psychiatric and sexual adverse effects, known as post-finasteride syndrome. The current findings underscore the need for careful patient counseling, systematic monitoring, and further translational studies integrating genetics, neuroendocrine markers, and standardized psychiatric outcomes to identify individuals at risk and advance personalized medicine in this field. Full article

The gut–brain axis (GBA) represents a complex bidirectional communication network that links the gut microbiota (GM) and the central nervous system (CNS). Recent research has revealed that neurosteroids (NSs) play crucial roles in modulating neuroinflammatory responses and promoting neuroprotection. Meanwhile, GM alterations have been associated with various neuroinflammatory and neurodegenerative conditions, such as multiple sclerosis, Alzheimer’s disease, and amyotrophic lateral sclerosis. This review aims to provide a comprehensive overview of the intricate interactions between NS, GM, and neuroinflammation. We discuss how NS and metabolites can influence neuroinflammatory pathways through immune, metabolic, and neuronal mechanisms. Additionally, we explore how GM modulation can impact neurosteroidogenesis, highlighting potential therapeutic strategies that include probiotics, neuroactive metabolites, and targeted interventions. Understanding these interactions may pave the way for innovative treatment approaches for neuroinflammatory and neurodegenerative diseases, promoting a more integrated view of brain health and disease management. Full article

Neurosteroids and benzodiazepines are modulators of the GABA_A receptors, thereby causing anxiolysis. Furthermore, benzodiazepines such as midazolam are known to cause adverse side-effects on cognition upon administration. We previously found that midazolam at nanomolar concentrations (10 nM) blocked long-term potentiation (LTP). Here, we aim to study the effect of neurosteroids and their synthesis using XBD173, which is a synthetic compound that promotes neurosteroidogenesis by binding to the translocator protein 18 kDa (TSPO), since they might provide anxiolytic activity with a favourable side-effect profile. By means of electrophysiological measurements and the use of mice with targeted genetic mutations, we revealed that XBD173, a selective ligand of the translocator protein 18 kDa (TSPO), induced neurosteroidogenesis. In addition, the exogenous application of potentially synthesised neurosteroids (THDOC and allopregnanolone) did not depress hippocampal CA1-LTP, the cellular correlate of learning and memory. This phenomenon was observed at the same concentrations that neurosteroids conferred neuroprotection in a model of ischaemia-induced hippocampal excitotoxicity. In conclusion, our results indicate that TSPO ligands are promising candidates for post-ischaemic recovery exerting neuroprotection, in contrast to midazolam, without detrimental effects on synaptic plasticity. Full article

Neurosteroids are synthesized de novo in the nervous system; they mainly moderate neuronal excitability, and reach target cells via the extracellular pathway. The synthesis of neurosteroids occurs in peripheral tissues such as gonads tissues, liver, and skin; then, because of their high lipophilia, they cross the blood–brain barrier and are stored in the brain structure. Neurosteroidogenesis occurs in brain regions such as the cortex, hippocampus, and amygdala by enzymes necessary for the in situ synthesis of progesterone from cholesterol. Neurosteroids could be considered the main players in both sexual steroid-induced hippocampal synaptic plasticity and normal transmission in the hippocampus. Moreover, they show a double function of increasing spine density and enhancing long term potentiation, and have been related to the memory-enhancing effects of sexual steroids. Estrogen and progesterone affect neuronal plasticity differently in males and females, especially regarding changes in the structure and function of neurons in different regions of the brain. Estradiol administration in postmenopausal women allowed for improving cognitive performance, and the combination with aerobic motor exercise seems to enhance this effect. The paired association between rehabilitation and neurosteroids treatment could provide a boosting effect in order to promote neuroplasticity and therefore functional recovery in neurological patients. The aim of this review is to investigate the mechanisms of action of neurosteroids as well as their sex-dependent differences in brain function and their role in neuroplasticity and rehabilitation. Full article

Silver nanoparticles (AgNPs) are one of the most widely used nanomaterials. The level of exposure to nanosilver is constantly raising, and a growing body of research highlights that it is harmful to the health, especially the nervous system, of humans. The potential pathways through which nanosilver affects neurons include the release of silver ions and the associated induction of oxidative stress. To better understand the mechanisms underlying the neurotoxicity of nanosilver, in this study we exposed male Wistar rats to 0.5 mg/kg body weight of AgNPs coated with bovine serum albumin (BSA), polyethylene glycol (PEG), or citrate, or to AgNO₃ as a source of silver ions for 28 days and assessed the expression of antioxidant defense markers in the hippocampus of the exposed animals after 1 week of spatial memory training. We also evaluated the influence of AgNPs coating on neurosteroidogenesis in the rat hippocampus. The results showed that AgNPs disrupted the antioxidant system in the hippocampus and induced oxidative stress in a coating-dependent manner, which could potentially be responsible for neurodegeneration and cognitive disorders. The analysis of the influence of AgNPs on neurosteroids also indicated coating-dependent modulation of steroid levels with a significant decrease in the concentrations of progesterone and 17α-progesterone in AgNPs(BSA), AgNPs(PEG), and Ag⁺ groups. Furthermore, exposure to AgNPs or Ag⁺ resulted in the downregulation of selected genes involved in antioxidant defense (Cat), neurosteroid synthesis (Star, Hsd3b3, Hsd17b1, and Hsd17b10), and steroid metabolism (Ar, Er1, and Er2). In conclusion, depending on the coating material used for their stabilization, AgNPs induced oxidative stress and modulated the concentrations of steroids as well as the expression of genes involved in steroid synthesis and metabolism. Full article

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. Unexpectedly, immortalized murine microglia recently exhibited this de novo biosynthesis; herein, de novo neurosteroidogenesis was characterized in immortalized human microglia. The results demonstrated that C20 and HMC3 microglial cells constitutively express members of the neurosteroidogenesis multiprotein machinery—in particular, the transduceosome members StAR and TSPO, and the enzyme CYP11A1. Moreover, both cell lines produce pregnenolone and transcriptionally express the enzymes involved in neurosteroidogenesis. The high TSPO expression levels observed in microglia prompted us to assess its role in de novo neurosteroidogenesis. TSPO siRNA and TSPO synthetic ligand treatments were used to reduce and prompt TSPO function, respectively. The TSPO expression downregulation compromised the de novo neurosteroidogenesis and led to an increase in StAR expression, probably as a compensatory mechanism. The pharmacological TSPO stimulation the de novo neurosteroidogenesis improved in turn the neurosteroid-mediated release of Brain-Derived Neurotrophic Factor. In conclusion, these results demonstrated that de novo neurosteroidogenesis occurs in human microglia, unravelling a new mechanism potentially useful for future therapeutic purposes. Full article

The translocator protein (TSPO, 18 kDa) plays an important role in the synthesis of neurosteroids by promoting the transport of cholesterol from the outer to the inner mitochondrial membrane, which is the rate-limiting step in neurosteroidogenesis. Stimulation of TSPO by appropriate ligands increases the level of neurosteroids. The present study describes the design, synthesis and investigation of anxiolytic-like effects of a series of N-acyl-tryptophanyl-containing dipeptides. These novel dipeptide TSPO ligands were designed with the original drug-based peptide design strategy using alpidem as non-peptide prototype. The anxiolytic activities were investigated in Balb/C mice using the illuminated open-field and elevated plus-maze tests in outbred laboratory mice ICR (CD-1). Dipeptide GD-102 (N-phenylpropionyl-l-tryptophanyl-l-leucine amide) in the dose range of 0.01–0.5 mg/kg intraperitoneally (i.p.) has a pronounced anxiolytic activity. The anxiolytic effect of GD-102 was abolished by PK11195, a specific TSPO antagonist. The structure–activity relationship study made it possible to identify a pharmacophore fragment for the dipeptide TSPO ligand. It was shown that l,d-diastereomer of GD-102 has no activity, and the d,l-isomer has less pronounced activity. The anxiolytic activity also disappears by replacing the C-amide group with the methyl ester, a free carboxyl group or methylamide. Consecutive replacement of each amino acid residue with glycine showed the importance of each of the amino acid residues in the structure of the ligand. The most active and technologically available compound GD-102, was selected for evaluation as a potential anxiolytic drug. Full article

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. Here, we show for the first time that mitochondrial neurosteroidogenesis follows a circadian rhythm and correlates with the rhythmic changes in mitochondrial morphology. We used synchronized human A172 glioma cells, which are steroidogenic cells with a functional core molecular clock, to show that pregnenolone levels and translocator protein (TSPO) are controlled by the clock, probably via circadian regulation of mitochondrial fusion/fission. Key findings were recapitulated in mouse brains. We also showed that genetic or pharmacological abrogation of fusion/fission activity, as well as disturbing the core molecular clock, abolished circadian rhythms of pregnenolone and TSPO. Our findings provide new insights into the crosstalk between mitochondrial function (here, neurosteroidogenesis) and circadian cycles. Full article

Abnormal tau protein aggregation in the brain is a hallmark of tauopathies, such as frontotemporal lobar degeneration and Alzheimer’s disease. Substantial evidence has been linking tau to neurodegeneration, but the underlying mechanisms have yet to be clearly identified. Mitochondria are paramount organelles in neurons, as they provide the main source of energy (adenosine triphosphate) to these highly energetic cells. Mitochondrial dysfunction was identified as an early event of neurodegenerative diseases occurring even before the cognitive deficits. Tau protein was shown to interact with mitochondrial proteins and to impair mitochondrial bioenergetics and dynamics, leading to neurotoxicity. In this review, we discuss in detail the different impacts of disease-associated tau protein on mitochondrial functions, including mitochondrial transport, network dynamics, mitophagy and bioenergetics. We also give new insights about the effects of abnormal tau protein on mitochondrial neurosteroidogenesis, as well as on the endoplasmic reticulum-mitochondria coupling. A better understanding of the pathomechanisms of abnormal tau-induced mitochondrial failure may help to identify new targets for therapeutic interventions. Full article

The steroidogenic 18 kDa translocator protein (TSPO) is an emerging, attractive therapeutic tool for several pathological conditions of the nervous system. Here, 13 high affinity TSPO ligands belonging to our previously described N,N-dialkyl-2-phenylindol-3-ylglyoxylamide (PIGA) class were evaluated for their potential ability to affect the cellular Oxidative Metabolism Activity/Proliferation index, which is used as a measure of astrocyte well-being. The most active PIGA ligands were also assessed for steroidogenic activity in terms of pregnenolone production, and the values were related to the metabolic index in rat and human models. The results showed a positive correlation between the increase in the Oxidative Metabolism Activity/Proliferation index and the pharmacologically induced stimulation of steroidogenesis. The specific involvement of steroid molecules in mediating the metabolic effects of the PIGA ligands was demonstrated using aminoglutethimide, a specific inhibitor of the first step of steroid biosynthesis. The most promising steroidogenic PIGA ligands were the 2-naphthyl derivatives that showed a long residence time to the target, in agreement with our previous data. In conclusion, TSPO ligand-induced neurosteroidogenesis was involved in astrocyte well-being. Full article