Showing papers on "Pregnenolone published in 2010"
TL;DR: A facile synthesis of 21-triazolyl derivatives of pregnenolone and their potential antitumour activity is reported using the 'click chemistry' approach.
124 citations
TL;DR: Various compounds 4b, 4c, 4e, 4f, 4h and 4j showed significant cytotoxic activity especially against HT-29, HCT-15, 502713 cell lines.
123 citations
TL;DR: The data suggest functional relevance of TRPM3 in contractile and proliferating phenotypes of vascular smooth muscle cells, significance of constitutive channel activity, regulation by cholesterol, and potential value of pregnenolone sulfate in therapeutic vascular modulation.
Abstract: Rationale: Transient receptor potential melastatin (TRPM)3 is a calcium-permeable ion channel activated by the neurosteroid pregnenolone sulfate and positively coupled to insulin secretion in β cells. Although vascular TRPM3 mRNA has been reported, there is no knowledge of TRPM3 protein or its regulation and function in the cardiovascular system. Objective: To determine the relevance and regulation of TRPM3 in vascular biology. Methods and Results: TRPM3 expression was detected at mRNA and protein levels in contractile and proliferating vascular smooth muscle cells. Calcium entry evoked by pregnenolone sulfate or sphingosine was suppressed by TRPM3 blocking antibody or knock-down of TRPM3 by RNA interference. Low-level constitutive TRPM3 activity was also detected. In proliferating cells, channel activity was coupled negatively to interleukin-6 secretion via a calcium-dependent mechanism. In freshly isolated aorta, TRPM3 positively modulated contractile responses independently of L-type calcium channels. Concentrations of pregnenolone sulfate required to evoke responses were higher than the known plasma concentrations of the steroids, leading to a screen for other stimulators. β-Cyclodextrin was one of few stimulators of TRPM3, revealing the channels to be partially suppressed by endogenous cholesterol, the precursor of pregnenolone. Elevation of cholesterol further suppressed channel activity and loading with cholesterol to generate foam cells precluded observation of TRPM3 activity. Conclusions: The data suggest functional relevance of TRPM3 in contractile and proliferating phenotypes of vascular smooth muscle cells, significance of constitutive channel activity, regulation by cholesterol, and potential value of pregnenolone sulfate in therapeutic vascular modulation.
122 citations
TL;DR: Streptozotocin-induced diabetes resulted in a strong general decrease in neuroactive steroid levels, in both the PNS and the CNS, which may have strong implications for the development of new sex-oriented therapies for the treatment of diabetic neuropathy and diabetic encephalopathy, based on the use of neuroactive steroids.
103 citations
TL;DR: The overall evidence suggests that neurosteroids may represent a novel therapeutic strategy in epileptic disorders and a future perspective to control epileptogenicity.
Abstract: Purpose of reviewNeurosteroids are a family of compounds synthesized directly in the brain by transforming cholesterol into pregnenolone, which is then converted to compounds such as allopregnanolone and allotetrahydrodeoxycorticosterone. In view of their ability to modulate neurotransmission, neuro
82 citations
TL;DR: It is shown that rat sciatic nerve expresses both LRXα and β isoforms and that these receptors are functional, suggesting that LXR activation may represent a new pharmacological avenue to increase local neuroactive steroid levels that exert neuroprotective effects in diabetic neuropathy.
Abstract: Neuroactive steroids act in the peripheral nervous system as physiological regulators and as protective agents for acquired or inherited peripheral neuropathy. In recent years, modulation of neuroactive steroids levels has been studied as a potential therapeutic approach to protect peripheral nerves from damage induced by diabetes. Nuclear receptors of the liver X receptor (LXR) family regulate adrenal steroidogenesis via their ability to control cholesterol homeostasis. Here we show that rat sciatic nerve expresses both LRXα and β isoforms and that these receptors are functional. Activation of liver X receptors using a synthetic ligand results in increased levels of neurosteroids and protection of the sciatic nerve from neuropathy induced by diabetes. LXR ligand treatment of streptozotocin-treated rats increases expression in the sciatic nerve of steroidogenic acute regulatory protein (a molecule involved in the transfer of cholesterol into mitochondria), of the enzyme P450scc (responsible for conversion of cholesterol into pregnenolone), of 5α-reductase (an enzyme involved in the generation of neuroactive steroids) and of classical LXR targets involved in cholesterol efflux, such as ABCA1 and ABCG1. These effects were associated with increased levels of neuroactive steroids (e.g., pregnenolone, progesterone, dihydroprogesterone and 3α-diol) in the sciatic nerve, and with neuroprotective effects on thermal nociceptive activity, nerve conduction velocity, and Na+, K+-ATPase activity. These results suggest that LXR activation may represent a new pharmacological avenue to increase local neuroactive steroid levels that exert neuroprotective effects in diabetic neuropathy.
77 citations
TL;DR: The levels of neuroactive steroids present in different CNS regions of male and female rats affected by acute experimental autoimmune encephalomyelitis are assessed and indicate that the levels show sex and regional differences in control and EAE nervous system and that a clear difference is also observed between CNS and plasma levels.
54 citations
TL;DR: It is shown that astrocytes release the endozepine peptides within 10 min of exposure to the steroids cortisol, pregnanolone, pregnenolone sulfate, or progesterone, and this finding suggests an orchestratedAstrocyte-neuron cross-talk that can affect a broad spectrum of behavioral functions.
54 citations
TL;DR: Rats are unique in their pronounced elevation of GABAergic neuroactive steroids, while this effect was not observed in mice or cynomolgus monkeys at comparable ethanol doses, and no effect of ethanol (0.8 g/kg) was observed in men.
Abstract: Background: Acute ethanol administration increases plasma and brain levels of progesterone and deoxycorticosterone-derived neuroactive steroids (3a,5a)-3-hydroxypregnan-20-one (3a,5aTHP) and (3a,5a)-3,21-dihydroxypregnan-20-one (3a,5a-THDOC) in rats. However, little is known about ethanol effects on GABAergic neuroactive steroids in mice, nonhuman primates, or humans. We investigated the effects of ethanol on plasma levels of 3a,5a- and 3a,5b-reduced GABAergic neuroactive steroids derived from progesterone, deoxycorticosterone, dehydroepiandrosterone, and testosterone using gas chromatography-mass spectrometry. Methods: Serum levels of GABAergic neuroactive steroids and pregnenolone were measured in male rats, C57BL ⁄ 6J and DBA ⁄ 2J mice, cynomolgus monkeys, and humans following ethanol administration. Rats and mice were injected with ethanol (0.8 to 2.0 g ⁄ kg), cynomolgus monkeys received ethanol (1.5 g ⁄ kg) intragastrically, and healthy men consumed a beverage containing 0.8 g ⁄ kg ethanol. Steroids were measured after 60 minutes in all species and also after 120 minutes in monkeys and humans. Results: Ethanol administration to rats increased levels of 3a,5a-THP, 3a,5a-THDOC, and pregnenolone at the doses of 1.5 g ⁄ kg (+228, +134, and +860%, respectively, p < 0.001) and 2.0 g ⁄ kg (+399, +174, and +1125%, respectively, p < 0.001), but not at the dose of 0.8 g ⁄ kg. Ethanol did not alter levels of the other neuroactive steroids. In contrast, C57BL ⁄ 6J mice exhibited a 27% decrease in serum 3a,5a-THP levels (p < 0.01), while DBA ⁄ 2J mice showed no significant effect of ethanol, although both mouse strains exhibited substantial increases in precursor steroids. Ethanol did not alter any of the neuroactive steroids in cynomolgus monkeys at doses comparable to those studied in rats. Finally, no effect of ethanol (0.8 g ⁄ kg) was observed in men. Conclusions: These studies show clear species differences among rats, mice, and cynomolgus monkeys in the effects of ethanol administration on circulating neuroactive steroids. Rats are unique in their pronounced elevation of GABAergic neuroactive steroids, while this effect was not observed in mice or cynomolgus monkeys at comparable ethanol doses.
53 citations
TL;DR: In this article, the effect of chronic experimental encephalomyelitis (EAE) on neuroactive steroid levels in the brain was investigated in both male and female rats, and it was shown that chronic EAE results in sex and regional specific alterations in the levels of neuroactive steroids in brain which are in many cases different to those produced by acute EAE.
Abstract: Our previous observations have shown that neuroactive steroid levels in the brain are affected by acute experimental autoimmune encephalomyelitis (EAE) with sex and regional specificity (Giatti et al. 2010). To better understand the effect of EAE on neuroactive steroids, we have here assessed the levels of pregnenolone, progesterone and its derivatives (i.e. dihydroprogesterone, tetrahydroprogesterone and isopregnanolone), testosterone and its derivatives (dihydrotestosterone and 5alpha-androstane-3alpha, 17beta-diol) in different CNS regions of male and female rats affected by chronic EAE. Data obtained by liquid chromatography tandem mass spectrometry revealed that chronic EAE results in sex and regional specific alterations in the levels of neuroactive steroids in the brain, which are in many cases different to those produced by acute EAE. The specific changes in neuroactive steroid levels after chronic EAE may be of relevance to design new possible therapeutic strategies for the disease.
51 citations
TL;DR: Results indicate that pregnenolone dose-dependently reduces operant ethanol self-administration in P rats without locomotor impairment, suggesting that it may have potential as a novel therapeutic for reducing chronic alcohol drinking in individuals that abuse alcohol.
Abstract: Background
Neuroactive steroids modulate ethanol intake in several self-administration models with variable effects. The purpose of this work was to examine the effects of the long-acting synthetic GABAergic neurosteroid ganaxalone and the endogenous neurosteroid pregnenolone, a precursor of all GABAergic neuroactive steroids, on the maintenance of ethanol self-administration in an animal model of elevated drinking – the alcohol preferring (P) rats.
TL;DR: Testosterone synthesized in cultured human SZ95 sebocytes derives mainly from dehydroepiandrosterone, and this paper aims to demonstrate the phytochemical properties of this substance.
Abstract: Human sebaceous gland possesses all the steroidogenic enzymes required for androgen synthesis. It remains unclear whether the testosterone produced in situ mainly derives from circulating dehydroepiandrosterone (DHEA) or from de novo synthesis utilizing serum cholesterol. Using testosterone radioimmunoassay, we found that testosterone was barely detectable in the supernatant of cultured human SZ95 sebocytes when cholesterol was added alone, indicating a low basal expression of steroidogenic acute regulatory protein (StAR) in SZ95 cells. Human chorionic gonadotropin and fibroblast growth factor-9 were as potent as forskolin in activating StAR to enhance testosterone production, while interleukin-1 beta, dexamethasone, insulin and insulin-like growth factor-1 showed no stimulatory effect. A two-fold increase of testosterone production was observed in supplementation of DHEA as compared to pregnenolone, progesterone or 17 alpha-hydroxyprogesterone. Based on our findings, testosterone synthesized in cultured sebocytes derived mainly from DHEA and inhibition of 3beta-hydroxysteroid dehydrogenase and 17beta-hydroxysteroid dehydrogenase may be a new target of androgen suppression for acne treatment.
TL;DR: The ability of soy isoflavones to regulate androgen biosynthesis in Leydig cells is due in part to action on Leydigs cell 3beta-HSD activity, implying that the increasing intake of soy-based food products and their potential effect on blood androgen levels are greatly relevant to public health.
Abstract: The objective of the present study was to investigate the effects of genistein and equol on 3β-hydroxysteroid de- hydrogenase (3β-HSD) and 17β-hydroxysteroid dehydrogenase 3 (17β-HSD3) in human and rat testis microsomes. These enzymes (3β-HSD and 17β-HSD3), along with two others (cytochrome P450 side-chain cleavage enzyme and cytochrome P450 17α-hydroxylase/17-20 lyase), catalyze the reactions that convert the steroid cholesterol into the sex hormone testosterone. Genistein inhibited 3β-HSD activity (0.2 µmol L -1 pregnenolone) with half-maximal in- hibition or a half-maximal inhibitory concentration (IC50) of 87 ± 15 (human) and 636 ± 155 nmol L -1 (rat). Genistein's mode of action on 3β-HSD activity was competitive for the substrate pregnenolonrge and noncompetitive for the co- factor NAD + . There was no difference in genistein's potency of 3β-HSD inhibition between intact rat Leydig cells and testis microsomes. In contrast to its potent inhibition of 3β-HSD, genistein had lesser effects on human and rat 17β-HSD3 (0.1 µmol L -1 androstenedione), with an IC50 ≥ 100 µmol L -1 . On the other hand, equol only inhibited hu- man 3β-HSD by 42%, and had no effect on 3β-HSD and 17β-HSD3 in rat tissues. These observations imply that the ability of soy isoflavones to regulate androgen biosynthesis in Leydig cells is due in part to action on Leydig cell 3 β- HSD activity. Given the increasing intake of soy-based food products and their potential effect on blood androgen levels, these findings are greatly relevant to public health.
TL;DR: It is suggested that increased cholesterol and COPs after KA excitotoxicity could themselves lead to disturbed neuronal ion homeostasis, increased neurotransmitter release, and propagation of excitOToxicity.
Abstract: Excitotoxicity due to excess stimulation of glutamate receptors in neurons is accompanied by increased Ca(2+) influx, stimulation of Ca(2+)-dependent enzymes, ATP depletion, increase in lipid peroxidation products, and loss of glutathione. These changes resemble neurochemical alterations in acute neuronal injury (stroke, spinal cord injury, and traumatic brain injury) and chronic neurodegenerative diseases such as Alzheimer's disease. Intracerebroventricular injection of the potent glutamate analog kainate in rats results in increased cholesterol concentration in the hippocampus at short to medium time intervals, i.e., 3 days-1 week post-injection, as detected by gas chromatography-mass spectrometry in the lesioned hippocampus. This is accompanied by an early increase in levels of cholesterol biosynthetic precursors and increases in both enzymatically derived oxysterols such as 24-hydroxycholesterol and cholesterol oxidation products (COPs) generated by reactive oxygen species, including cholesterol epoxides and 7-ketocholesterol. In contrast to COPs, no change in concentration of the neurosteroid pregnenolone was found after KA injury. Cholesterol and COPs significantly increase exocytosis in cultured PC12 cells and neurons, and both oxysterols and COPs are able to induce cytotoxic and apoptotic injuries in different cell types, including neurons. Together, the findings suggest that increased cholesterol and COPs after KA excitotoxicity could themselves lead to disturbed neuronal ion homeostasis, increased neurotransmitter release, and propagation of excitotoxicity.
TL;DR: 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.
Abstract: 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.
TL;DR: Results demonstrate that EE2 can alter steroid production at specific sites within the steroidogenic pathway and can stimulate hepatic estrogen signalling, providing important information regarding the molecular mechanisms underlying the endocrine response of the mummichog to exogenous estrogen.
TL;DR: Investigation of the uptake by 11 brain regions and appearance in blood of tritium-labeled pregnenolone and progesterone after intranasal and intravenous (IV) injection shows that therapeutic levels of neurosteroids can be delivered to the brain by intran asal administration, but that the two routes have significant differences with intranAsal administration favoring some brain regions.
TL;DR: In adrenal steroidogenesis, CYP17 catalyses the 17alpha-hydroxylation of pregnenolone and progesterone and the subsequent 17,20-lyase reaction, yielding adrenal androgens, which exhibits distinctly different selectivities towards these substrates in various species.
TL;DR: In this article, the authors investigated the mechanisms that underlie the effect of ethanol on adrenal steroidogenesis and found that ethanol effects on plasma pregnenolone, progesterone, 3alpha,5alpha-THP and cortical 3α,5α-thP are highly correlated, exhibit a threshold of 1.5 g/kg, but show no dose dependence.
Abstract: The mechanisms of ethanol actions that produce its behavioral sequelae involve the synthesis of potent GABAergic neuroactive steroids, specifically the GABAergic metabolites of progesterone, (3alpha,5alpha)-3-hydroxypregnan-20-one (3alpha,5alpha-THP), and deoxycorticosterone, (3alpha,5alpha)-3,21-dihydroxypregnan-20-one. We investigated the mechanisms that underlie the effect of ethanol on adrenal steroidogenesis. We found that ethanol effects on plasma pregnenolone, progesterone, 3alpha,5alpha-THP and cortical 3alpha,5alpha-THP are highly correlated, exhibit a threshold of 1.5 g/kg, but show no dose dependence. Ethanol increases plasma adrenocorticotropic hormone (ACTH), adrenal steroidogenic acute regulatory protein (StAR), and adrenal StAR phosphorylation, but does not alter levels of other adrenal cholesterol transporters. The inhibition of ACTH release, de novo adrenal StAR synthesis or cytochrome P450 side chain cleavage activity prevents ethanol-induced increases in GABAergic steroids in plasma and brain. ACTH release and de novo StAR synthesis are independently regulated following ethanol administration and both are necessary, but not sufficient, for ethanol-induced elevation of plasma and brain neuroactive steroids. As GABAergic steroids contribute to ethanol actions and ethanol sensitivity, the mechanisms of this effect of ethanol may be important factors that contribute to the behavioral actions of ethanol and risk for alcohol abuse disorders.
TL;DR: The TRPM3 channel forms calcium‐permeable, non‐selective, cationic channels that are stimulated by pregnenolone sulphate and could reveal novel stimulators with physiological relevance.
Abstract: BACKGROUND AND PURPOSE The transient receptor potential melastatin-3 (TRPM3) channel forms calcium-permeable, non-selective, cationic channels that are stimulated by pregnenolone sulphate (PregS) Here, we aimed to define chemical requirements of this acute steroid action and potentially reveal novel stimulators with physiological relevance
EXPERIMENTAL APPROACH We used TRPM3 channels over-expressed in HEK 293 cells, with intracellular calcium measurement and whole-cell patch-clamp recording techniques
KEY RESULTS The stimulation of TRPM3 channels was confined to PregS and closely related steroids and not mimicked by other major classes of steroids, including progesterone Relatively potent stimulation of TRPM3-dependent calcium entry was observed A sulphate group positioned at ring A was important for strong stimulation but more striking was the requirement for a cis (β) configuration of the side group, revealing previously unrecognized stereo-selectivity and supporting existence of a specific binding site A cis-oriented side group on ring A was not the only feature necessary for high activity because loss of the double bond in ring B reduced potency and loss of the acetyl group at ring D reduced efficacy and potency Weak steroid stimulators of TRPM3 channels inhibited effects of PregS, suggesting partial agonism In silico screening of chemical libraries for non-steroid modulators of TRPM3 channels revealed the importance of the steroid backbone for stimulatory effects
CONCLUSIONS AND IMPLICATIONS Our data defined some of the chemical requirements for acute stimulation of TRPM3 channels by steroids, supporting the existence of a specific and unique steroid binding site Epipregnanolone sulphate was identified as a novel TRPM3 channel stimulator
TL;DR: The data suggest that FLSs of patients with rheumatoid arthritis express TRPM3-containing ion channels that couple negatively to hyaluronan secretion and can be stimulated by pharmacological concentrations of pregnenolone sulphate.
Abstract: 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. The study used RT-PCR and immunofluorescence to detect mRNA and protein. Intracellular calcium measurement detected channel activity in a FLS cell-line and primary cultures of FLSs from patients with rheumatoid arthritis. Enzyme-linked immunosorbent assays measured hyaluronan. Endogenous expression of TRPM3 was detected. Previously reported stimulators of TRPM3 sphingosine and pregnenolone sulphate evoked sustained elevation of intracellular calcium in FLSs. The FLS cell-line showed an initial transient response to sphingosine which may be explained by TRPV4 channels but was not observed in FLSs from patients. Blocking antibody targeted to TRPM3 inhibited sustained sphingosine and pregnenolone sulphate responses. Secretion of hyaluronan, which contributes adversely in rheumatoid arthritis, was suppressed by pregnenolone sulphate in FLSs from patients and the effect was blocked by anti-TRPM3 antibody. The data suggest that FLSs of patients with rheumatoid arthritis express TRPM3-containing ion channels that couple negatively to hyaluronan secretion and can be stimulated by pharmacological concentrations of pregnenolone sulphate.
TL;DR: Of particular significance is titanocenyl–dehydroepiandrosterone complex, which is 2 orders of magnitude more cytotoxic than titanocene dichloride and also shows much more sensitivity and selectivity for the MCF-7 cell line.
Abstract: Six titanocenyls functionalized with steroidal esters have been synthesized and characterized by infrared, 1H, and 13C NMR spectroscopy and elemental analysis. Among those steroids, dehydroepiandrosterone, trans-androsterone, and androsterone are androgens and pregnenolone is a progesterone precursor. Clionasterol is a natural steroid compound. These steroid-functionalized titanocenyls were tested by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay for in vitro cytotoxicity for MCF-7 breast cancer and HT-29 colon cancer cells. All complexes exhibited more cytotoxicity than titanocene dichloride. The titanocenyls containing androgen and progesterone derivatives as pendant groups had higher antiproliferative activities than those with cholesterol steroid compounds. Of particular significance is titanocenyl–dehydroepiandrosterone complex, which is 2 orders of magnitude more cytotoxic than titanocene dichloride and also shows much more sensitivity and selectivity for the MCF-7 cell line.
TL;DR: The authors showed that [(3)H]DHEAS and PREGS are relatively high affinity substrates for the organic solute transporter, OSTα-OSTβ, and that the two proteins that constitute this transporter are selectively localized to steroidogenic cells in the cerebellum and hippocampus.
Abstract: A variety of steroids, including pregnenolone sulfate (PREGS) and dehydroepiandrosterone sulfate (DHEAS) are synthesized by specific brain cells, and are then delivered to their target sites, where they exert potent effects on neuronal excitability. The present results demonstrate that [(3)H]DHEAS and [(3)H]PREGS are relatively high affinity substrates for the organic solute transporter, OSTα-OSTβ, and that the two proteins that constitute this transporter are selectively localized to steroidogenic cells in the cerebellum and hippocampus, namely the Purkinje cells and cells in the cornu ammonis region in both mouse and human brain. Analysis of Ostα and Ostβ mRNA levels in mouse Purkinje and hippocampal cells isolated via laser capture microdissection supported these findings. In addition, Ostα-deficient mice exhibited changes in serum DHEA and DHEAS levels, and in tissue distribution of administered [(3)H]DHEAS. OSTα and OSTβ proteins were also localized to the zona reticularis of human adrenal gland, the major region for DHEAS production in the periphery. These results demonstrate that OSTα-OSTβ is localized to steroidogenic cells of the brain and adrenal gland, and that it modulates DHEA/DHEAS homeostasis, suggesting that it may contribute to neurosteroid action.
TL;DR: Findings suggest that pregnenolone use may be associated with some improvement in manic and depressive symptoms, but not cognition in depressed patients with a history of substance use.
Abstract: 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. In a proof-of-concept investigation, 70 participants with bipolar disorder or recurrent major depressive disorder and history of substance abuse/dependence (abstinent for > or =14days prior to enrollment) were randomly assigned to receive pregnenolone (titrated to 100mg/day) or placebo for 8weeks. Participants were assessed using the Mini International Neuropsychiatric Interview, Hamilton Rating Scale for Depression (HRSD), Young Mania Rating Scale (YMRS), Rey Auditory Verbal Learning Test (RAVLT), Trail Making Test (TMT-B), and Stroop Test. Mood was assessed bi-weekly, while cognition was evaluated at baseline, and weeks 4 and 8. Groups were compared using a random regression analysis that used all of the available data. The pregnenolone group showed trends toward greater improvement, relative to placebo, on the HRSD and YMRS. A post hoc analysis of completers found a statistically significant reduction in HRSD scores with pregnenolone as compared to placebo. Pregnenolone appeared to be safe and well tolerated. Findings suggest that pregnenolone use may be associated with some improvement in manic and depressive symptoms, but not cognition in depressed patients with a history of substance use. Larger trials examining the impact of pregnenolone on mood in more narrowly defined populations may be warranted.
TL;DR: It is shown that human recombinant StarD4 accelerates 7 alpha-OOH transfer to isolated liver mitochondria, and to a greater extent than Ch transfer, and that in oxidative stress states, inappropriate StAR-mediated trafficking of peroxidized Ch in steroidogenic tissues could result in damage and dysfunction selectively targeted to mitochondria.
TL;DR: Biotransformation of androst-4-ene-3,17-dione (1), 3β-hydroxypregnan-5-en-20-one (pregnenolone, 2), 3 β-hydroxyandrost-5en-17one (DHEA, 3) and estradiol (4) was investigated with fungus of Gelasinospora retispora as discussed by the authors.
Abstract: Biotransformation of androst-4-ene-3,17-dione (1), 3β-hydroxypregnan-5-en-20-one (pregnenolone, 2), 3β-hydroxyandrost-5-en-17-one (DHEA, 3) and estradiol (4) was investigated with fungus of Gelasinospora retispora. Biotransformation of 1 gave 11α-hydroxyandrost-4-ene-3,17-dione (5) in good yield. In the case of compound 2, three compounds, DHEA (3), 3β,17β-dihydroxyandrost-5-ene (6) and 3β,15β-dihydroxyandrost-5-en-17-one (7) were obtained. Moreover, DHEA (3) was converted to 3β,7α-dihydroxyandrost-5-en-17-one (8) and 3β,11α-dihydroxyandrost-5-ene-7,17-dione (9). And it was found that biotransformation of 4 affords 6β-hydroxyestradiol (10).
TL;DR: In this paper, the authors investigated the mechanisms of tolerance to ethanol-induced increases in neuroactive steroids, specifically (3α,5α)-3-hydroxypregnan-20-one and 3α, 5α-THP, in male Sprague-Dawley rats.
Abstract: Acute ethanol administration increases potent GABAergic neuroactive steroids, specifically (3α,5α)-3-hydroxypregnan-20-one (3α,5α-THP) and (3α,5α)-3,21-dihydroxypregnan-20-one. In addition, neuroactive steroids contribute to ethanol actions. Chronic ethanol exposure results in tolerance to many effects of ethanol, including ethanol-induced increases in neuroactive steroid levels. To determine the mechanisms of tolerance to ethanol-induced increases in neuroactive steroids, we investigated critical signaling molecules that are required for acute ethanol effects. Male Sprague-Dawley rats were administered ethanol via liquid diet for 2 weeks and steroid levels, adrenocorticotrophic hormone (ACTH) and adrenal steroidogenic acute regulatory (StAR) protein expression were measured. Chronic ethanol exposure elicits tolerance to ethanol-induced elevation of serum ACTH and the steroids pregnenolone and progesterone. Surprisingly, chronic ethanol exposure does not result in tolerance to ethanol-induced increases in adrenal StAR protein. However, ethanol-induced StAR phosphorylation is decreased when compared to acute ethanol administration. A separate group of rats exposed to chronic ethanol diet were subsequently challenged with ethanol (2 g/kg) and exhibited a blunted elevation of serum ACTH and progesterone as well as cerebral cortical and hippocampal 3α,5α-THP. Administration of ACTH with the ethanol challenge restored the elevation of serum ACTH and progesterone as well as cerebral cortical 3α,5α-THP levels to those observed in ethanol-naive rats. Thus, chronic ethanol exposure disrupts ACTH release, which results in tolerance to ethanol-induced increases in neuroactive steroid levels. Loss of the ethanol-induced increases in neuroactive steroids may contribute to behavioral tolerance to ethanol and influence the progression towards alcoholism.
TL;DR: Evidence is given of steroidogenic activity in the brain of cephalopods of Sepia and Octopus that supports the hypothesis that progesterone may be a metabolite product along the steroidogenic chain leading to androgens.
Abstract: The presence of vertebrate-like steroids, steroidogenic enzymes and steroid receptors has been reported exclusively in cephalopods gonads. The role played by these steroids has been also recently investigated. We here give evidence of steroidogenic activity in the brain of cephalopods. The activity of two key steroidogenic enzymes: 3beta-hydroxysteroid dehydrogenase (HSD) and 17beta-HSD is present in the lobes of the nervous system of both Sepia and Octopus. Such enzymes convert pregnenolone to progesterone and androstenedione to testosterone respectively. Binding experiments seem to assign a functional role to the androgens in the brain of cephalopods. According to the present results, the absence of any progesterone binding moiety supports the hypothesis that progesterone may be a metabolite product along the steroidogenic chain leading to androgens. The presence of steroidogenic enzymes in specific lobes of the central nervous system is discussed in terms of the possible role that steroids can play in the sexual differentiation of the brain and in influencing some coded behaviours of cephalopods, such as learning processes.
TL;DR: The findings provide excellent models for multiple identification and quantification of sex steroid and their precursors in biological samples exposed to endocrine-disrupting chemicals and for direct extrapolation of such effects across taxonomic groups and phyla.
TL;DR: A sex-specific influence of progesterone during the early neonatal period on the development of the serotonergic system, depending on brain region in addition to of the dopaminergic system is indicated.