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ENeuro Mar 2023Allopregnanolone (AlloP) is a neurosteroid that potentiates ionotropic GABAergic (GABA) inhibition and is approved for treating postpartum depression in women. Although...
Allopregnanolone (AlloP) is a neurosteroid that potentiates ionotropic GABAergic (GABA) inhibition and is approved for treating postpartum depression in women. Although the antidepressant mechanism of AlloP is largely unknown, it could involve selective action at GABA receptors containing the δ subunit. Despite previous evidence for selective effects of AlloP on α4/δ-containing receptors of hippocampal dentate granule cells (DGCs), other recent results failed to demonstrate selectivity at these receptors (Lu et al., 2020). In contrast to DGCs, hippocampal fast-spiking parvalbumin (PV) interneurons express an unusual variant partnership of δ subunits with α1 subunits. Here, we hypothesized that native α1/δ receptors in hippocampal fast-spiking interneurons may provide a preferred substrate for AlloP. Contrary to the hypothesis, electrophysiology from genetically tagged PV interneurons in hippocampal slices from male mice showed that 100 nm AlloP promoted phasic inhibition by increasing the sIPSC decay, but tonic inhibition was not detectably altered. Co-application of AlloP with 5 μm GABA did augment tonic current, which was not primarily through δ-containing receptors. Furthermore, AlloP decreased the membrane resistance and the number of action potentials of DGCs, but the impact on PV interneurons was weaker than on DGCs. Thus, our results indicate that hippocampal PV interneurons possess low sensitivity to AlloP and suggest they are unlikely contributors to mood-altering effects of neurosteroids through GABA effects.
Topics: Mice; Male; Female; Animals; Pregnanolone; Parvalbumins; Interneurons; Receptors, GABA-A; Hippocampus; gamma-Aminobutyric Acid
PubMed: 36725341
DOI: 10.1523/ENEURO.0392-22.2023 -
Molecules (Basel, Switzerland) Jan 2023Women have a high susceptibility to the negative effects of stress. Hormonal changes experienced throughout their reproductive life partially contribute to a higher...
Women have a high susceptibility to the negative effects of stress. Hormonal changes experienced throughout their reproductive life partially contribute to a higher incidence of anxiety and depression symptoms, particularly, during natural or surgical menopause. In preclinical research, the flavonoid chrysin (5,7-dihydroxyflavone) exerts anxiolytic- and anti-despair-like effects; however, it is unknown whether chrysin exerts a protective effect against the behavioral changes produced by acute stress on locomotor activity and behavioral despair in rats at 12-weeks post-ovariectomy. Ovariectomized female Wistar rats were assigned to eight groups: vehicle group (10% DMSO), three groups with chrysin and three groups with the same dose of allopregnanolone (0.5, 1, and 2 mg/kg), and one group with diazepam (2 mg/kg). The treatments were administered for seven consecutive days and the effects were evaluated in the locomotor activity and swimming tests. Chrysin (2 mg/kg) increased the latency to first immobility and decreased the total immobility time in the swimming test as the reference drugs allopregnanolone and diazepam (2 mg/kg); while locomotor activity prevented the behavioral changes produced by swimming. In conclusion, chrysin exerts a protective effect against the behavioral changes induced by acute stress, similarly to the neurosteroid allopregnanolone and the benzodiazepine diazepam in rats subjected to a surgical menopause model.
Topics: Rats; Female; Animals; Rats, Wistar; Pregnanolone; Flavonoids; Diazepam; Menopause
PubMed: 36677645
DOI: 10.3390/molecules28020587 -
Journal of the Endocrine Society Dec 2022Chronic stress is a risk factor for preterm birth; however, objective measures of stress in pregnancy are limited. Maternal stress biomarkers may fill this gap. Steroid...
CONTEXT
Chronic stress is a risk factor for preterm birth; however, objective measures of stress in pregnancy are limited. Maternal stress biomarkers may fill this gap. Steroid hormones and neurosteroids such as allopregnanolone (ALLO) play important roles in stress physiology and pregnancy maintenance and therefore may be promising for preterm birth prediction.
OBJECTIVE
We evaluated maternal serum ALLO, progesterone, cortisol, cortisone, pregnanolone, and epipregnanolone twice in gestation to evaluate associations with preterm birth.
METHODS
We performed a nested case-control study using biobanked fasting serum samples from the Healthy Start prebirth cohort. We included healthy women with a singleton pregnancy and matched preterm cases with term controls (1:1; N = 27 per group). We used a new HPLC-tandem mass spectrometry assay to quantify ALLO and five related steroids. We used ANOVA, Fisher exact, χ, test, and linear and logistic regression as statistical tests.
RESULTS
Maternal serum ALLO did not associate with preterm birth nor differ between groups. Mean cortisol levels were significantly higher in the preterm group early in pregnancy (13w0d-18w0d; < 0.05) and higher early pregnancy cortisol associated with increased odds of preterm birth (at 13w0d; odds ratio, 1.007; 95% CI, 1.0002-1.014). Progesterone, cortisone, pregnanolone, and epipregnanolone did not associate with preterm birth.
CONCLUSION
The findings from our pilot study suggest potential utility of cortisol as a maternal serum biomarker for preterm birth risk assessment in early pregnancy. Further evaluation using larger cohorts and additional gestational timepoints for ALLO and the other analytes may be informative.
PubMed: 36632210
DOI: 10.1210/jendso/bvac179 -
International Journal of Molecular... Dec 2022Niemann-Pick Type C1 (NPC1, MIM 257220) is a rare, progressive, lethal, inherited autosomal-recessive endolysosomal storage disease caused by mutations in the leading...
Niemann-Pick Type C1 (NPC1, MIM 257220) is a rare, progressive, lethal, inherited autosomal-recessive endolysosomal storage disease caused by mutations in the leading to intracellular lipid storage. We analyzed mostly not jet known alterations of the weights of 14 different organs in the BALB/cNctr-/-J Jackson mice in female and male and mice under various treatment strategies. Mice were treated with (i) no therapy, (ii) vehicle injection, (iii) a combination of miglustat, allopregnanolone, and 2-hydroxypropyl-ß-cyclodextrin (HPßCD), (iv) miglustat, and (v) HPßCD alone starting at P7 and repeated weekly throughout life. The 12 respective male and female wild-type mice groups were evaluated in parallel. In total, 351 mice (176 , 175 ) were dissected at P65. In both sexes, the body weights of None and Sham mice were lower than those of respective mice. The influence of the mutation and/or sex on the weights of various organs, however, differed considerably. In males, and mice had comparable absolute weights of lungs, spleen, and adrenal glands. In mice, smaller weights of hearts, livers, kidneys, testes, vesicular, and scent glands were found. In female mice, ovaries, and uteri were significantly smaller. In mice, relative organ weights, i.e., normalized with body weights, were sex-specifically altered to different extents by the different therapies. The combination of miglustat, allopregnanolone, and the sterol chelator HPßCD partly normalized the weights of more organs than miglustat or HPßCD mono-therapies.
Topics: Animals; Female; Male; Mice; 1-Deoxynojirimycin; Body Weight; Cyclodextrins; Disease Models, Animal; Mice, Inbred BALB C; Niemann-Pick C1 Protein; Niemann-Pick Disease, Type C; Pregnanolone; Organ Size; Mice, Knockout
PubMed: 36614015
DOI: 10.3390/ijms24010573 -
International Journal of Molecular... Dec 2022Allopregnanolone (3α-THP) has been one of the most studied progesterone metabolites for decades. 3α-THP and its synthetic analogs have been evaluated as therapeutic... (Review)
Review
Allopregnanolone (3α-THP) has been one of the most studied progesterone metabolites for decades. 3α-THP and its synthetic analogs have been evaluated as therapeutic agents for pathologies such as anxiety and depression. Enzymes involved in the metabolism of 3α-THP are expressed in classical and nonclassical steroidogenic tissues. Additionally, due to its chemical structure, 3α-THP presents high affinity and agonist activity for nuclear and membrane receptors of neuroactive steroids and neurotransmitters, such as the Pregnane X Receptor (PXR), membrane progesterone receptors (mPR) and the ionotropic GABA receptor, among others. 3α-THP has immunomodulator and antiapoptotic properties. It also induces cell proliferation and migration, all of which are critical processes involved in cancer progression. Recently the study of 3α-THP has indicated that low physiological concentrations of this metabolite induce the progression of several types of cancer, such as breast, ovarian, and glioblastoma, while high concentrations inhibit it. In this review, we explore current knowledge on the metabolism and mechanisms of action of 3α-THP in normal and tumor cells.
Topics: Humans; Gonadal Steroid Hormones; Pregnanolone; Progesterone; Receptors, Progesterone; Neoplasms
PubMed: 36614002
DOI: 10.3390/ijms24010560 -
Alcohol, Clinical & Experimental... Mar 2023Alcohol affects multiple circuits in the brain, mainly disrupting the delicate balance between inhibitory γ-aminobutyric acid (GABA) transmission and excitatory...
BACKGROUND
Alcohol affects multiple circuits in the brain, mainly disrupting the delicate balance between inhibitory γ-aminobutyric acid (GABA) transmission and excitatory glutamate signaling in brain areas involved in reward circuits. These include the amygdala, nucleus accumbens (Acb), and ventral tegmental area (VTA). This action impairs circuits that regulate behavioral control of craving and alcohol seeking and intake. Studies in both rodent models and postmortem human brain of patients with alcohol use disorder (AUD) have highlighted the association between the loss of GABAergic inhibition and the development of addiction. The neurosteroid (3α,5α)-3-hydroxypregnan-20-one (3α,5α-THP) is a potent positive modulator of GABA receptors. Chronic alcohol consumption reduces 3α,5α-THP levels, resulting in decreased GABA inhibition. We previously demonstrated that enhancing neurosteroid biosynthesis by overexpression of the cholesterol side-chain cleavage enzyme P450scc decreased alcohol intake in male alcohol-preferring rats (P-rats). While most of the evidence of alcohol-induced alterations comes from studies in male subjects, some data show that females are more vulnerable to alcohol's effects than males.
METHODS
In this study, we investigated the ability of 3α,5α-THP direct infusions in two brain regions that contribute to alcohol reinforcement, the VTA and Acb core (AcbC), to regulate alcohol self-administration in female P-rats.
RESULTS
Administration of 3α,5α-THP into the AcbC increased 3α,5α-THP-positive cell expression in this area and reduced alcohol self-administration. By contrast, 3α,5α-THP infusion into the VTA did not significantly affect alcohol self-administration, though trends for a reduction were found.
CONCLUSIONS
Our results show that local increases in 3α,5α-THP in the AcbC may alter mesolimbic activity that drives a reduction in alcohol self-administration.
Topics: Humans; Rats; Male; Female; Animals; Nucleus Accumbens; Neurosteroids; Ethanol; Brain; Pregnanolone; gamma-Aminobutyric Acid
PubMed: 36587947
DOI: 10.1111/acer.15008 -
BMC Anesthesiology Dec 2022Alfaxalone is a fast acting intravenous anaesthetic with high therapeutic index. It is an analogue of the naturally-occurring neurosteroid allopregnanolone responsible... (Randomized Controlled Trial)
Randomized Controlled Trial
Alfaxalone anaesthesia increases brain derived neurotrophic factor levels and preserves postoperative cognition by activating pregnane-X receptors: an in vitro study and a double blind randomised controlled trial.
BACKGROUND
Alfaxalone is a fast acting intravenous anaesthetic with high therapeutic index. It is an analogue of the naturally-occurring neurosteroid allopregnanolone responsible for maintenance of cognition and neuroprotection by activation of brain pregnane X receptors and consequent increased production of mature brain-derived neurotrophic factor (m-BDNF). Two studies are reported here: an in vitro study investigated whether alfaxalone activates human pregnane X receptors (h-PXR) as effectively as allopregnanolone; and a clinical study that measured postoperative changes in serum m-BDNF and cognition in patients after alfaxalone anaesthesia compared with propofol and sevoflurane.
METHODS
In vitro Activation of h-PXR by allopregnanolone and alfaxalone solutions (206 - 50,000 nM) was measured using human embryonic kidney cells expressing h-PXR hybridised and linked to the firefly luciferase gene. Light emission by luciferase stimulated by each ligand binding with h-PXR was measured. Clinical A double blind prospective randomised study of patients undergoing hip arthroplasty anaesthetised with alfaxalone TIVA (n = 8) or propofol TIVA (n = 3) or propofol plus sevoflurane inhalational anaesthesia (n = 4). The doses of anaesthetics were titrated to the same depth of anaesthesia (BIS 40-60). Subjects' cognitive performance was assessed using the Grooved Pegboard Test, Digit Symbol Substitution Test (DSST) and Mini Mental State examination (MMSE) for 7 days postoperatively. Serum m-BDNF concentrations were measured for 7 postoperative days.
RESULTS
In vitro Allopregnanolone and alfaxalone both activated h-PXR, alfaxalone being more efficacious than allopregnanolone: 50,000 nM, p = 0.0019; 16,700 nM, p = 0.0472; 5600 nM, p = 0.0031. Clinical Alfaxalone treated subjects scored better than propofol and sevoflurane anaesthetised patients in the cognition tests: (MMSE p = 0.0251; Grooved Pegboard test dominant hand pre v post anaesthesia scores p = 0.8438 for alfaxalone and p = 0.0156 for propofol and propofol/sevoflurane combined). The higher cognition scores were accompanied by higher serum m-BDNF levels in the alfaxalone anaesthetised patients (p < 0.0001).
CONCLUSIONS
These results suggest that sedation and anaesthesia induced by the synthetic neuroactive steroid alfaxalone may be accompanied by effects normally caused by physiological actions of allopregnanolone at PXR, namely, increased secretion of m-BDNF and consequent neuroprotection and preservation of cognition.
TRIAL REGISTRATION
The clinical trial was registered on 17/01/2018 with the Australian New Zealand Clinical Trials Registry: registration number ACTRN12618000064202 [Universal Trial Number U1111-1198-0412].
Topics: Humans; Propofol; Sevoflurane; Brain-Derived Neurotrophic Factor; Prospective Studies; Pregnanolone; Australia; Anesthetics, Intravenous; Anesthetics, Inhalation; Cognition; Anesthesia, Inhalation; Double-Blind Method
PubMed: 36564723
DOI: 10.1186/s12871-022-01940-x -
Canadian Journal of Gastroenterology &... 2022A third of patients with primary biliary cholangitis (PBC) experience poorly understood cognitive symptoms, with a significant impact on quality of life (QOL), and no...
BACKGROUND AND AIMS
A third of patients with primary biliary cholangitis (PBC) experience poorly understood cognitive symptoms, with a significant impact on quality of life (QOL), and no effective medical treatment. Allopregnanolone, a neurosteroid, is a positive allosteric modulator of gamma-aminobutyricacid-A (GABA-A) receptors, associated with disordered mood, cognition, and memory. This study explored associations between allopregnanolone and a disease-specific QOL scoring system (PBC-40) in PBC patients.
METHOD
Serum allopregnanolone levels were measured in 120 phenotyped PBC patients and 40 age and gender-matched healthy controls. PBC subjects completed the PBC-40 at recruitment. Serum allopregnanolone levels were compared across PBC-40 domains for those with none/mild symptoms versus severe symptoms.
RESULTS
There were no overall differences in allopregnanolone levels between healthy controls (median = 0.03 ng/ml (IQR = 0.025)) and PBC patients (0.031 (0.42), = 0.42). Within the PBC cohort, higher allopregnanolone levels were observed in younger patients ( (120) = -0.53, < 0.001) but not healthy controls ( (39) = -0.21, = 0.21). Allopregnanolone levels were elevated in the PBC-40 domains, cognition ( = 1034, = 0.02), emotional ( = 1374, = 0.004), and itch ( = 795, = 0.03). Severe cognitive symptoms associated with a younger age: severe (50 (12)) vs. none (60 (13); = 423 = 0.001).
CONCLUSION
Elevated serum allopregnanolone is associated with severe cognitive, emotional, and itch symptoms in PBC, in keeping with its known action on GABA-A receptors. Existing novel compounds targeting allopregnanolone could offer new therapies in severely symptomatic PBC, satisfying a significant unmet need.
Topics: Humans; Liver Cirrhosis, Biliary; Neurosteroids; Pregnanolone; Quality of Life; Receptors, GABA-A
PubMed: 36523650
DOI: 10.1155/2022/3618090 -
Nature Communications Dec 2022Early-life adversity (ELA) increases the likelihood of neuropsychiatric diagnoses, which are more prevalent in women than men. Since changes in reproductive hormone...
Early-life adversity (ELA) increases the likelihood of neuropsychiatric diagnoses, which are more prevalent in women than men. Since changes in reproductive hormone levels can also increase the probability of anxiety disorders in women, we examined the effects of ELA on adult female mice across the estrous cycle. We found that during diestrus, when progesterone levels are relatively high, ELA mice exhibit increased avoidance behavior and increased theta oscillation power in the ventral hippocampus (vHIP). We also found that diestrus ELA mice had higher levels of progesterone and lower levels of allopregnanolone, a neurosteroid metabolite of progesterone, in the vHIP compared with control-reared mice. Progesterone receptor antagonism normalized avoidance behavior in ELA mice, while treatment with a negative allosteric modulator of allopregnanolone promoted avoidance behavior in control mice. These results suggest that altered vHIP progesterone and allopregnanolone signaling during diestrus increases avoidance behavior in ELA mice.
Topics: Animals; Female; Mice; Avoidance Learning; Estrous Cycle; Progesterone; Pregnanolone
PubMed: 36476469
DOI: 10.1038/s41467-022-35068-w -
Pharmacological Reports : PR Feb 2023Neurosteroids are investigated as effective antidotes for the poisoning induced by tetramethylenedisulfotetramine (TMDT) as well as treatments for epileptic spasms...
Novel neurosteroid pregnanolone pyroglutamate suppresses neurotoxicity syndrome induced by tetramethylenedisulfotetramine but is ineffective in a rodent model of infantile spasms.
BACKGROUND
Neurosteroids are investigated as effective antidotes for the poisoning induced by tetramethylenedisulfotetramine (TMDT) as well as treatments for epileptic spasms during infancy. Both these conditions are quite resistant to pharmacotherapy; thus, a search for new treatments is warranted.
METHODS
In this study, we determined the efficacy of two novel neurosteroids, pregnanolone glutamate (PAG) and pregnanolone pyroglutamate (PPG), and tested these drugs in doses of 1-10 mg/kg (ip) against the TMDT syndrome and in our rodent model of infantile spasms.
RESULTS
Only PPG in doses 5 and 10 mg/kg suppressed the severity of the TMDT syndrome and TMDT-induced lethality, while the 1 mg/kg dose was without an effect. Interestingly, the 1 mg/kg dose of PPG in combination with 1 mg/kg of diazepam was also effective against TMDT poisoning. Neither PAG nor PPG were effective against experimental spasms in the N-methyl-D-aspartate (NMDA)-triggered model of infantile spasms.
CONCLUSIONS
While evidence suggests that PAG can act through multiple actions which include allosteric inhibition of NMDA-induced and glycine receptor-evoked currents as well as augmentation of ɣ-aminobutyric acid subtype A (GABAA) receptor-induced currents, the agent appears to neither have the appropriate mechanistic signature for activity in the infantile spasm model, nor the adequate potency, relative to PPG, for ameliorating the TMDT syndrome. The full mechanisms of action of PPG, which may become a potent TMDT antidote either alone or in combination with diazepam are yet unknown and thus require further investigation.
Topics: Animals; Spasms, Infantile; Pregnanolone; Pyrrolidonecarboxylic Acid; Neurosteroids; N-Methylaspartate; Rodentia; Diazepam; Neurotoxicity Syndromes; Glutamic Acid; Spasm
PubMed: 36422805
DOI: 10.1007/s43440-022-00437-1