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Psychopharmacology May 2024Multiple psychiatric disorders are associated with altered brain and serum levels of neuroactive steroids, including the endogenous GABAergic steroid, allopregnanolone....
RATIONALE
Multiple psychiatric disorders are associated with altered brain and serum levels of neuroactive steroids, including the endogenous GABAergic steroid, allopregnanolone. Clinically, chronic cocaine use was correlated with decreased levels of pregnenolone. Preclinically, the effect of acute cocaine on allopregnanolone levels in rodents has had mixed results, showing an increase or no change in allopregnanolone levels in some brain regions.
OBJECTIVE
We hypothesized that cocaine acutely increases allopregnanolone levels, but repeated cocaine exposure decreases allopregnanolone levels compared to controls.
METHODS
We performed two separate studies to determine how systemic administration of 15 mg/kg cocaine (1) acutely or (2) chronically alters brain (olfactory bulb, frontal cortex, dorsal striatum, and midbrain) and serum allopregnanolone levels in adult male and female Sprague-Dawley rats.
RESULTS
Cocaine acutely increased allopregnanolone levels in the midbrain, but not in olfactory bulb, frontal cortex, or dorsal striatum. Repeated cocaine did not persistently (24 h later) alter allopregnanolone levels in any region in either sex. However, allopregnanolone levels varied by sex across brain regions. In the acute study, we found that females had significantly higher allopregnanolone levels in serum and olfactory bulb relative to males. In the repeated cocaine study, females had significantly higher allopregnanolone levels in olfactory bulb, frontal cortex, and serum. Finally, acute cocaine increased allopregnanolone levels in the frontal cortex of females in proestrus, relative to non-proestrus stages.
CONCLUSION
Collectively these results suggest that allopregnanolone levels vary across brain regions and by sex, which may play a part in differential responses to cocaine by sex.
Topics: Humans; Adult; Rats; Male; Female; Animals; Rats, Sprague-Dawley; Pregnanolone; Brain; Mesencephalon; Cocaine
PubMed: 38282126
DOI: 10.1007/s00213-024-06534-8 -
Canadian Journal of Physiology and... Apr 2024Butorphanol is a synthetic opioid analgesic medication that is primarily used for the management of pain. Butorphanol may have an inhibitory effect on androgen...
Butorphanol is a synthetic opioid analgesic medication that is primarily used for the management of pain. Butorphanol may have an inhibitory effect on androgen biosynthesis and metabolism in rat immature Leydig cells. The objective of this study was to investigate the influence of butorphanol on androgen secretion by rat Leydig cells isolated from the 35-day-old male rats. Rat Leydig cells were cultured with 0.5-50 μM butorphanol for 3 h in vitro Butorphanol at 5 and 50 μM significantly inhibited androgen secretion in immature Leydig cells. At 50 μM, butorphanol also blocked the effects of luteinizing hormone (LH) and 8bromo-cAMP-stimulated androgen secretion and 22R-hydroxycholesterol- and pregnenolone-mediated androgen production. Further analysis of the results showed that butorphanol downregulated the expression of genes involved in androgen production, including (LH receptor), (cholesterol side-chain cleavage enzyme), (5α-reductase 1), and (3α-hydroxysteroid dehydrogenase). Additionally, butorphanol directly inhibited HSD3B1 (3β-hydroxysteroid dehydrogenase 1) and SRD5A1 activity. In conclusion, butorphanol may have side effects of inhibiting androgen biosynthesis and metabolism in Leydig cells.
Topics: Rats; Male; Animals; Leydig Cells; Androgens; Butorphanol; Rats, Sprague-Dawley; Luteinizing Hormone; Testosterone; Cells, Cultured
PubMed: 38258745
DOI: 10.1139/cjpp-2023-0191 -
Neuroscience and Biobehavioral Reviews Mar 2024This mini-review presents emerging evidence that endogenous neurosteroids modulate both pro- and anti-inflammatory signaling by immune cells and brain cells that... (Review)
Review
This mini-review presents emerging evidence that endogenous neurosteroids modulate both pro- and anti-inflammatory signaling by immune cells and brain cells that contribute to depression, alcohol use disorders, and other inflammatory conditions. We first review the literature on pregnenolone and allopregnanolone inhibition of proinflammatory neuroimmune pathways in the periphery and the brain - effects that are independent of GABAergic mechanisms. We follow with evidence for neurosteroid enhancement of anti-inflammatory and protective pathways in brain and immune cells. These studies draw clinical relevance from a large body of evidence that pro-inflammatory immune signaling is dysregulated in many brain disorders and the fact that neurosteroids inhibit the same inflammatory pathways that are activated in depression, alcohol use disorders and other inflammatory conditions. Thus, we describe evidence that neurosteroid levels are decreased and neurosteroid supplementation has therapeutic efficacy in these neuropsychiatric conditions. We conclude with a perspective that endogenous regulation of immune balance between pro- and anti-inflammatory pathways by neurosteroid signaling is essential to prevent the onset of disease. Deficits in neurosteroids may unleash excessive pro-inflammatory activation which progresses in a feed-forward manner to disrupt brain networks that regulate stress, emotion and motivation. Neurosteroids can block various inflammatory pathways in mouse and human macrophages, rat brain and human blood and therefore provide new hope for treatment of intractable conditions that involve excessive inflammatory signaling.
Topics: Rats; Humans; Mice; Animals; Neurosteroids; Alcoholism; Brain; Pregnanolone; Anti-Inflammatory Agents
PubMed: 38244954
DOI: 10.1016/j.neubiorev.2024.105558 -
Biological Trace Element Research Jan 2024Fluorosis decreases the learning and memory ability in humans and animals, while exercise can reduce the risk of cognitive decline. However, the effect of exercise on...
Fluorosis decreases the learning and memory ability in humans and animals, while exercise can reduce the risk of cognitive decline. However, the effect of exercise on learning and memory in fluoride-exposed mice is unclear. For this purpose, in this study, mice were randomly allotted into four groups (16 mice per group, half male and half female): control group (group C), fluoride group (group F, 100 mg/L sodium fluoride (NaF)), exercise group (group E, treadmill exercise), and E plus F group (group EF, treadmill exercise, and 100 mg/L NaF). During 6 months of exposure, exercise alleviated the NaF-induced decline in memory and learning. In addition, NaF induced injuries in mitochondria and myelin sheath ultrastructure and reduced the neurons number, while exercise restored them. Metabolomics results showed that phosphatidylethanolamine, pregnenolone (PREG), and lysophosphatidic acid (LysoPA) were altered among groups C, F, and EF. Combined with previous studies, it can be suggested that PREG might be a biomarker in response to exercise-relieving fluorine neurotoxicity. The miRNA sequencing results indicated that in the differently expressed miRNAs (DEmiRNAs), miR-206-3p, miR-96-5p, and miR-144-3p were shared in groups C, F, and EF. After the QRT-PCR validation and in vitro experiments, it was proved that miR-206-3p could reduce cell death and regulate AP-1 transcription factor subunit (JunD) and histone deacetylase 4 (HDAC4) to alleviate fluoride neurotoxicity. To sum up, the current study reveals that exercise could alleviate NaF-induced neurotoxicity by targeting miR-206-3p or PREG, which will contribute to revealing the pathogenesis and therapeutic method of fluoride neurotoxicity.
PubMed: 38244175
DOI: 10.1007/s12011-024-04068-w -
Seizure progression is slowed by enhancing neurosteroid availability in the brain of epileptic rats.Epilepsia Mar 2024Trilostane is a 3β-hydroxysteroid dehydrogenase/Δ isomerase inhibitor able to produce a manyfold increase in brain levels of various neurosteroids, including...
Trilostane is a 3β-hydroxysteroid dehydrogenase/Δ isomerase inhibitor able to produce a manyfold increase in brain levels of various neurosteroids, including allopregnanolone. We previously found that treatment with trilostane can slow down epileptogenesis in the kainic acid (KA) model of temporal lobe epilepsy. It is unknown whether trilostane may have a similar effect on the progression of epilepsy severity, as observed in KA-treated rats. Consequently, we investigated the effects of trilostane (50 mg/kg/day, 1 week) in epileptic rats, given 64 days after KA administration. Seizures were monitored by video-electrocorticographic recordings before and during the treatment with trilostane or vehicle (sesame oil), and neurosteroid levels were measured in serum and cerebral tissue using liquid chromatography-electrospray tandem mass spectrometry after treatment. Pregnenolone sulfate, pregnenolone, progesterone, 5α-dihydroprogesterone, and allopregnanolone peripheral levels were massively increased by trilostane. With the only exception of hippocampal pregnenolone sulfate, the other neurosteroids augmented in both the neocortex and hippocampus. Only pregnanolone levels were not upregulated by trilostane. As expected, a significant increase in the seizure occurrence was observed in rats receiving the vehicle, but not in the trilostane group. This suggests that the increased availability of neurosteroids produced a disease-modifying effect in the brain of epileptic rats.
Topics: Rats; Animals; Neurosteroids; Pregnanolone; Epilepsy; Brain; Seizures
PubMed: 38243753
DOI: 10.1111/epi.17887 -
Acta Pharmaceutica Sinica. B Jan 2024Neurons are believed to be non-proliferating cells. However, neuronal stem cells are still present in certain areas of the adult brain, although their proliferation... (Review)
Review
Neurons are believed to be non-proliferating cells. However, neuronal stem cells are still present in certain areas of the adult brain, although their proliferation diminishes with age. Just as with other cells, their proliferation and differentiation are modulated by various mechanisms. These mechanisms are foundational to the strategies developed to induce neuronal proliferation and differentiation, with potential therapeutic applications for neurodegenerative diseases. The most common among these diseases are Parkinson's disease and Alzheimer's disease, associated with the formation of -amyloid (A) aggregates which cause a reduction in the number of neurons. Compounds such as LiCl, 4-aminothiazoles, Pregnenolone, ACEA, harmine, D2AAK1, methyl 3,4-dihydroxybenzoate, and shikonin may induce neuronal proliferation/differentiation through the activation of pathways: MAPK ERK, PI3K/AKT, NFB, Wnt, BDNF, and NPAS3. Moreover, combinations of these compounds can potentially transform somatic cells into neurons. This transformation process involves the activation of neuron-specific transcription factors such as NEUROD1, NGN2, ASCL1, and SOX2, which subsequently leads to the transcription of downstream genes, culminating in the transformation of somatic cells into neurons. Neurodegenerative diseases are not the only conditions where inducing neuronal proliferation could be beneficial. Consequently, the impact of pro-proliferative compounds on neurons has also been researched in mouse models of Alzheimer's disease.
PubMed: 38239239
DOI: 10.1016/j.apsb.2023.10.007 -
Journal of Pharmaceutical Analysis Dec 2023The central nervous system is susceptible to the modulation of various neurophysiological processes by the cytochrome P450 enzyme (CYP), which plays a crucial role in...
The central nervous system is susceptible to the modulation of various neurophysiological processes by the cytochrome P450 enzyme (CYP), which plays a crucial role in the metabolism of neurosteroids. The antiepileptic drug phenytoin (PHT) has been observed to induce neuronal side effects in patients, which could be attributed to its induction of CYP expression and testosterone (TES) metabolism in the hippocampus. While pregnane X receptor (PXR) is widely known for its regulatory function of CYPs in the liver, we have discovered that the treatment of mice with pregnenolone 16α-carbonitrile (PCN), a PXR agonist, has differential effects on CYP expression in the liver and hippocampus. Specifically, the PCN treatment resulted in the induction of cytochrome P450, family 3, subfamily a, polypeptide 11 (CYP3A11), and CYP2B10 expression in the liver, while suppressing their expression in the hippocampus. Functionally, the PCN treatment protected mice from PHT-induced hippocampal nerve injury, which was accompanied by the inhibition of TES metabolism in the hippocampus. Mechanistically, we found that the inhibition of hippocampal CYP expression and attenuation of PHT-induced neurotoxicity by PCN were glucocorticoid receptor dependent, rather than PXR independent, as demonstrated by genetic and pharmacological models. In conclusion, our study provides evidence that PCN can negatively regulate hippocampal CYP expression and attenuate PHT-induced hippocampal neurotoxicity independently of PXR. Our findings suggest that glucocorticoids may be a potential therapeutic strategy for managing the neuronal side effects of PHT.
PubMed: 38223454
DOI: 10.1016/j.jpha.2023.07.013 -
Cellular and Molecular Life Sciences :... Jan 2024N-methyl-D-aspartate receptors (NMDARs) play a critical role in normal brain function, and variants in genes encoding NMDAR subunits have been described in individuals...
Disease-associated nonsense and frame-shift variants resulting in the truncation of the GluN2A or GluN2B C-terminal domain decrease NMDAR surface expression and reduce potentiating effects of neurosteroids.
N-methyl-D-aspartate receptors (NMDARs) play a critical role in normal brain function, and variants in genes encoding NMDAR subunits have been described in individuals with various neuropsychiatric disorders. We have used whole-cell patch-clamp electrophysiology, fluorescence microscopy and in-silico modeling to explore the functional consequences of disease-associated nonsense and frame-shift variants resulting in the truncation of GluN2A or GluN2B C-terminal domain (CTD). This study characterizes variant NMDARs and shows their reduced surface expression and synaptic localization, altered agonist affinity, increased desensitization, and reduced probability of channel opening. We also show that naturally occurring and synthetic steroids pregnenolone sulfate and epipregnanolone butanoic acid, respectively, enhance NMDAR function in a way that is dependent on the length of the truncated CTD and, further, is steroid-specific, GluN2A/B subunit-specific, and GluN1 splice variant-specific. Adding to the previously described effects of disease-associated NMDAR variants on the receptor biogenesis and function, our results improve the understanding of the molecular consequences of NMDAR CTD truncations and provide an opportunity for the development of new therapeutic neurosteroid-based ligands.
Topics: Humans; Electrophysiological Phenomena; Neurosteroids; Receptors, N-Methyl-D-Aspartate
PubMed: 38214768
DOI: 10.1007/s00018-023-05062-6 -
Zoological Research Jan 2024Omega-3 polyunsaturated fatty acids (n-3 PUFAs), particularly docosahexaenoic acid (22:6n-3, DHA), play crucial roles in the reproductive health of vertebrates,...
Omega-3 polyunsaturated fatty acids (n-3 PUFAs), particularly docosahexaenoic acid (22:6n-3, DHA), play crucial roles in the reproductive health of vertebrates, including humans. Nevertheless, the underlying mechanism related to this phenomenon remains largely unknown. In this study, we employed two zebrafish genetic models, i.e., mutant as an endogenous DHA-deficient model and (omega-3 desaturase encoding gene) transgenic zebrafish as an endogenous DHA-rich model, to investigate the effects of DHA on oocyte maturation and quality. Results show that the mutants had much lower fecundity and poorer oocyte quality than the wild-type controls, while the zebrafish had higher fecundity and better oocyte quality than wild-type controls. DHA deficiency in embryos led to defects in egg activation, poor microtubule stability, and reduced pregnenolone levels. Further study revealed that DHA promoted pregnenolone synthesis by enhancing transcription of , which encodes the cholesterol side-chain cleavage enzyme, thereby stabilizing microtubule assembly during oogenesis. In turn, the hypothalamic-pituitary-gonadal axis was enhanced by DHA. In conclusion, using two unique genetic models, our findings demonstrate that endogenously synthesized DHA promotes oocyte maturation and quality by promoting pregnenolone production via transcriptional regulation of .
Topics: Animals; Humans; Docosahexaenoic Acids; Zebrafish; Cholesterol Side-Chain Cleavage Enzyme; Oogenesis; Oocytes
PubMed: 38199972
DOI: 10.24272/j.issn.2095-8137.2023.032 -
Frontiers in Neuroendocrinology Apr 2024Rates of alcohol use disorder (AUD) are increasing in men and women and there are high rates of concurrent posttraumatic stress disorder (PTSD) and AUD. AUD and PTSD... (Review)
Review
Rates of alcohol use disorder (AUD) are increasing in men and women and there are high rates of concurrent posttraumatic stress disorder (PTSD) and AUD. AUD and PTSD synergistically increase symptomatology and negatively affect treatment outcomes; however, there are very limited pharmacological treatments for PTSD/AUD. Neurosteroids have been implicated in the underlying neurobiological mechanisms of both PTSD and AUD and may be a target for treatment development. This review details the past ten years of research on pregnenolone, progesterone, allopregnanolone, pregnanolone, estradiol, testosterone and dehydroepiandrosterone/dehydroepiandrosterone-sulfate (DHEA/DHEA-S) in the context of PTSD and AUD, including examination of trauma/alcohol-related variables, such as stress-reactivity. Emerging evidence that exogenous pregnenolone, progesterone, and allopregnanolone may be promising, novel interventions is also discussed. Specific emphasis is placed on examining the application of sex as a biological variable in this body of literature, given that women are more susceptible to both PTSD diagnoses and stress-related alcohol consumption.
Topics: Humans; Stress Disorders, Post-Traumatic; Neurosteroids; Alcoholism; Animals; Female; Male
PubMed: 38184208
DOI: 10.1016/j.yfrne.2023.101119