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Neuroscience Sep 2011Emerging preclinical and clinical evidence suggests that pregnenolone may be a promising novel therapeutic candidate in schizophrenia. Pregnenolone is a neurosteroid... (Review)
Review
Emerging preclinical and clinical evidence suggests that pregnenolone may be a promising novel therapeutic candidate in schizophrenia. Pregnenolone is a neurosteroid with pleiotropic actions in rodents that include the enhancement of learning and memory, neuritic outgrowth, and myelination. Further, pregnenolone administration results in elevations in downstream neurosteroids such as allopregnanolone, a molecule with neuroprotective effects that also increases neurogenesis, decreases apoptosis and inflammation, modulates the hypothalamic-pituitary-adrenal axis, and markedly increases GABA(A) receptor responses. In addition, pregnenolone administration elevates pregnenolone sulfate, a neurosteroid that positively modulates NMDA receptors. There are thus multiple mechanistic possibilities for pregnenolone as a potential therapeutic agent in schizophrenia, including the amelioration of NMDA receptor hypofunction (via metabolism to pregnenolone sulfate) and the mitigation of GABA dysregulation (via metabolism to allopregnanolone). Additional evidence consistent with a therapeutic role for pregnenolone in schizophrenia includes neurosteroid changes following administration of certain antipsychotics in rodent models. For example, clozapine elevates pregnenolone levels in rat hippocampus, and these increases may potentially contribute to its superior antipsychotic efficacy [Marx et al. (2006a) Pharmacol Biochem Behav 84:598-608]. Further, pregnenolone levels appear to be altered in postmortem brain tissue from patients with schizophrenia compared to control subjects [Marx et al. (2006c) Neuropsychopharmacology 31:1249-1263], suggesting that neurosteroid changes may play a role in the neurobiology of this disorder and/or its treatment. Although clinical trial data utilizing pregnenolone as a therapeutic agent in schizophrenia are currently limited, initial findings are encouraging. Treatment with adjunctive pregnenolone significantly decreased negative symptoms in patients with schizophrenia or schizoaffective disorder in a pilot proof-of-concept randomized controlled trial, and elevations in pregnenolone and allopregnanolone post-treatment with this intervention were correlated with cognitive improvements [Marx et al. (2009) Neuropsychopharmacology 34:1885-1903]. Another pilot randomized controlled trial recently presented at a scientific meeting demonstrated significant improvements in negative symptoms, verbal memory, and attention following treatment with adjunctive pregnenolone, in addition to enduring effects in a small subset of patients receiving pregnenolone longer-term [Savitz (2010) Society of Biological Psychiatry Annual Meeting New Orleans, LA]. A third pilot clinical trial reported significantly decreased positive symptoms and extrapyramidal side effects following adjunctive pregnenolone, in addition to increased attention and working memory performance [Ritsner et al. (2010) J Clin Psychiatry 71:1351-1362]. Future efforts in larger cohorts will be required to investigate pregnenolone as a possible therapeutic candidate in schizophrenia, but early efforts are promising and merit further investigation. This article is part of a Special Issue entitled: Neuroactive Steroids: Focus on Human Brain.
Topics: Animals; Antipsychotic Agents; Disease Models, Animal; Dizocilpine Maleate; Drug Evaluation, Preclinical; Humans; Learning; Neurotransmitter Agents; Pregnenolone; Randomized Controlled Trials as Topic; Rats; Schizophrenia
PubMed: 21756978
DOI: 10.1016/j.neuroscience.2011.06.076 -
The Journal of Clinical Endocrinology... Apr 1950
Topics: Pregnenolone
PubMed: 15415436
DOI: 10.1210/jcem-10-4-455 -
British Journal of Pharmacology Oct 2023GABA receptors are regulated by numerous classes of allosteric modulators. However, regulation of receptor macroscopic desensitisation remains largely unexplored and may...
BACKGROUND AND PURPOSE
GABA receptors are regulated by numerous classes of allosteric modulators. However, regulation of receptor macroscopic desensitisation remains largely unexplored and may offer new therapeutic opportunities. Here, we report the emerging potential for modulating desensitisation with analogues of the endogenous inhibitory neurosteroid, pregnenolone sulfate.
EXPERIMENTAL APPROACH
New pregnenolone sulfate analogues were synthesised incorporating various heterocyclic substitutions located at the C-21 position on ring D. The pharmacological profiles of these compounds were assessed using electrophysiology and recombinant GABA receptors together with mutagenesis, molecular dynamics simulations, structural modelling and kinetic simulations.
KEY RESULTS
All seven analogues retained a negative allosteric modulatory capability whilst exhibiting diverse potencies. Interestingly, we observed differential effects on GABA current decay by compounds incorporating either a six- (compound 5) or five-membered heterocyclic ring (compound 6) on C-21, which was independent of their potencies as inhibitors. We propose that differences in molecular charges, and the targeted binding of analogues to specific states of the GABA receptor, are the most likely cause of the distinctive functional profiles.
CONCLUSIONS AND IMPLICATIONS
Our findings reveal that heterocyclic addition to inhibitory neurosteroids not only affected their potency and macroscopic efficacy but also affected innate receptor mechanisms that underlie desensitisation. Acute modulation of macroscopic desensitisation will determine the degree and duration of GABA inhibition, which are vital for the integration of neural circuit activity. Discovery of this form of modulation could present an opportunity for next-generation GABA receptor drug design and development.
Topics: Receptors, GABA-A; Pregnenolone; gamma-Aminobutyric Acid
PubMed: 37194503
DOI: 10.1111/bph.16143 -
Steroids Jul 2016Steroids have been widely used in the clinical setting. They bind and activate nuclear receptors to regulate gene expression. In addition to activating genomic... (Review)
Review
Steroids have been widely used in the clinical setting. They bind and activate nuclear receptors to regulate gene expression. In addition to activating genomic transcription, steroids also exert nongenomic actions. The current article focuses on the nongenomic actions of neurosteroids, including pregnenolone (P5), 7α-hydroxypregnenolone, pregnenolone sulfate and allopregnanolone. Pregnenolone and its derivatives promote neuronal activity by enhancing learning and memory, relieving depression, enhancing locomotor activity, and promoting neuronal cell survival. They exert these effects by activating various target proteins located in the cytoplasm or cell membrane. Pregnenolone and its metabolites bind to receptors such as microtubule-associated proteins and neurotransmitter receptors to elicit a series of reactions including stabilization of microtubules, increase of ion flux into cells, and dopamine release. The wide actions of neurosteroids indicate that pregnenolone derivatives have great potential in future treatment of neurological diseases.
Topics: 17-alpha-Hydroxypregnenolone; Animals; Depression; Humans; Microtubules; Neurodegenerative Diseases; Neurotransmitter Agents; Pregnanolone; Pregnenolone
PubMed: 26844377
DOI: 10.1016/j.steroids.2016.01.017 -
Journal of Neuroendocrinology Feb 2022Pregnenolone methyl-ether (PME) is a synthetic derivative of the endogenous neuroactive steroid pregnenolone (PREG), which is an important modulator of several brain... (Review)
Review
Pregnenolone methyl-ether (PME) is a synthetic derivative of the endogenous neuroactive steroid pregnenolone (PREG), which is an important modulator of several brain functions. In addition to being the precursor of steroids, PREG acts directly on various targets including microtubules (MTs), the functioning of which is fundamental for the development and homeostasis of nervous system. The coordination of MT dynamics is supported by a plethora of MT-associated proteins (MAPs) and by a specific MT code that is defined by the post-translational modifications of tubulin. Defects associated with MAPs or tubulin post-translational modifications are linked to different neurological pathologies including mood and neurodevelopmental disorders. In this review, we describe the beneficial effect of PME in major depressive disorders (MDDs) and in CDKL5 deficiency disorder (CDD), two pathologies that are joint by defective MT dynamics. Growing evidence indeed suggests that PME, as well as PREG, is able to positively affect the MT-binding of MAP2 and the plus-end tracking protein CLIP170 that are both found to be deregulated in the above mentioned pathologies. Furthermore, PME influences the state of MT acetylation, the deregulation of which is often associated with neurological abnormalities including MDDs. By contrast to PREG, PME is not metabolised into other downstream molecules with specific biological properties, an aspect that makes this compound more suitable for therapeutic strategies. Thus, through the analysis of MDDs and CDD, this work focuses attention on the possible use of PME for neuronal pathologies associated with MT defects.
Topics: Depressive Disorder, Major; Epileptic Syndromes; Humans; Methyl Ethers; Microtubule-Associated Proteins; Microtubules; Pregnenolone; Protein Serine-Threonine Kinases; Spasms, Infantile; Tubulin
PubMed: 34495563
DOI: 10.1111/jne.13033 -
CNS Neuroscience & Therapeutics 2010Neurosteroids, such as pregnenolone (PREG), dehydroepiandrosterone (DHEA), and their sulfates (PREGS and DHEAS) are reported to have a modulatory effect on neuronal... (Review)
Review
Neurosteroids, such as pregnenolone (PREG), dehydroepiandrosterone (DHEA), and their sulfates (PREGS and DHEAS) are reported to have a modulatory effect on neuronal excitability and synaptic plasticity. They also have many other functions associated with neuroprotection, response to stress, mood regulation, and cognitive performance. Furthermore, these neurosteroids have been linked to, and their levels are altered in, neuropsychiatric disorders. This review highlights what is currently known about the metabolism and mode of action of PREG and DHEA, as well as about alterations of these neurosteroids in schizophrenia. This review also provides substantial information about clinical trials with DHEA and PREG augmentation with of antipsychotic agents in schizophrenia.
Topics: Adjuvants, Immunologic; Animals; Antipsychotic Agents; Central Nervous System; Clinical Trials as Topic; Dehydroepiandrosterone; Humans; Neuroprotective Agents; Pregnenolone; Receptors, Neurotransmitter; Schizophrenia
PubMed: 20070787
DOI: 10.1111/j.1755-5949.2009.00118.x -
Neurochemistry International 2008Pregnenolone sulfate (PREGS) has been shown, either at high nanomolar or at micromolar concentrations, to increase neuronal activity by inhibiting GABAergic and by... (Review)
Review
Pregnenolone sulfate (PREGS) has been shown, either at high nanomolar or at micromolar concentrations, to increase neuronal activity by inhibiting GABAergic and by stimulating glutamatergic neurotransmission. PREGS is also a potent modulator of sigma type 1 (sigma1) receptors. It has been proposed that these actions of PREGS underlie its neuropharmacological effects, and in particular its influence on memory processes. On the other hand, the PREGS-mediated increase in neuronal excitability may become dangerous under particular conditions, for example in the case of excitotoxic stress or convulsions. However, the physiopathological significance of these observations has recently been put into question by the failure to detect significant levels of PREGS within the brain and plasma of rats and mice, either by direct analytical methods based on liquid chromatography/mass spectrometry (LC/MS) or enzyme linked immunosorbent assay (ELISA) with specific antibodies against PREGS, or by indirect gas chromatography/mass spectrometry (GC/MS) analysis with improved sample workup. These recent results have not come to the attention of a large number of neurobiologists interested in steroid sulfates. However, although available direct analytical methods have failed to detect levels of PREGS above 0.1-0.3 ng/g in brain tissue, it may be premature to completely exclude the local formation of biologically active PREGS within specific and limited compartments of the nervous system. In contrast to the situation in rodents, significant levels of sulfated 3beta-hydroxysteroids have been measured in human plasma and brain. Previous indirect measures of steroid sulfates by radioimmunoassays (RIA) or GC/MS had detected elevated levels of PREGS in rodent brain. The discrepancies between the results of different assay procedures have revealed the danger of indirect analysis of steroid sulfates. Indeed, PREGS must be solvolyzed/hydrolyzed prior to RIA or GC/MS analysis, and it is the released, unconjugated PREG which is then quantified. Extreme caution needs to be exercised during the preparation of samples for RIA or GC/MS analysis, because the fraction presumed to contain only steroid sulfates can be contaminated by nonpolar components from which PREG is generated by the solvolysis/hydrolysis/derivatization reactions.
Topics: Animals; Blood-Brain Barrier; Brain; Brain Chemistry; Humans; Mice; Pregnenolone; Rats; Receptors, Neurotransmitter; Sulfatases; Sulfotransferases
PubMed: 18068870
DOI: 10.1016/j.neuint.2007.08.022 -
The Journal of Steroid Biochemistry and... Jun 2016Considerable evidence from preclinical and clinical studies shows that steroids and in particular neurosteroids are important endogenous modulators of several... (Review)
Review
Considerable evidence from preclinical and clinical studies shows that steroids and in particular neurosteroids are important endogenous modulators of several brain-related functions. In this context, it remains to be elucidated whether neurosteroids may serve as biomarkers in the diagnosis of disorders and might have therapeutic potential for the treatment of these disorders. Pregnenolone (PREG) is the main steroid synthesized from cholesterol in mammals and invertebrates. PREG has three main sources of synthesis, the gonads, adrenal glands and brain and is submitted to various metabolizing pathways which are modulated depending on various factors including species, steroidogenic tissues and steroidogenic enzymes. Looking at the whole picture of steroids, PREG is often known as the precursor to other steroids and not as an active steroid per se. Actually, physiological and brain functions have been studied mainly for steroids that are very active either binding to specific intracellular receptors, or modulating with high affinity the abundant membrane receptors, GABAA or NMDA receptors. However, when high sensitive and specific methodological approaches were available to analyze low concentrations of steroids and then match endogenous levels of different steroid metabolomes, several studies have reported more significant alterations in PREG than in other steroids in extraphysiological or pathological conditions, suggesting that PREG could play a functional role as well. Additionally, several molecular targets of PREG were revealed in the mammalian brain and beneficial effects of PREG have been demonstrated in preclinical and clinical studies. On this basis, this review will be divided into three parts. The first provides a brief overview of the molecular targets of PREG and the pharmacological effects observed in animal and human studies. The second will focus on the possible functional role of PREG with an outline of the modulation of PREG levels in animal and in human research. Finally, the review will highlight the possible therapeutic uses of PREG that point towards the development of pregnenolone-like molecules.
Topics: Animals; Cognition; Depression; Drug Discovery; Humans; Pregnenolone; Schizophrenia
PubMed: 26433186
DOI: 10.1016/j.jsbmb.2015.09.030 -
Nihon Rinsho. Japanese Journal of... Aug 2005
Review
Topics: Adrenal Hyperplasia, Congenital; Biomarkers; Chromatography, High Pressure Liquid; Disorders of Sex Development; Female; Gas Chromatography-Mass Spectrometry; Humans; Male; Pregnancy; Pregnenolone; Radioimmunoassay
PubMed: 16149523
DOI: No ID Found -
Nihon Rinsho. Japanese Journal of... Dec 1999
Review
Topics: Adolescent; Adult; Child; Child, Preschool; Female; Humans; Infant; Infant, Newborn; Male; Pregnenolone
PubMed: 10778089
DOI: No ID Found