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Seizure Dec 2018The anti-seizure effects of progesterone family compounds have long been known. Over the years, however, most studies have focused on progesterone and on its secondary... (Review)
Review
The anti-seizure effects of progesterone family compounds have long been known. Over the years, however, most studies have focused on progesterone and on its secondary metabolite allopregnanolone (ALLO), with less attention being paid to its primary metabolite 5a-dihydroprogesterone (DHP). Here we review animal and clinical studies related to the anti-seizure effects of progesterone and its 5a neuroactive metabolites, including DHP and ALLO. Progesterone and its reduced metabolites all have demonstrated seizure-suppression effects in animal models - except in models of absence seizures - with the common side effects of sedation and ataxia. Progesterone and ALLO have also shown anti-seizure effects in clinical trials. A large Phase III trial has revealed that female patients with premenstrual exacerbations of seizures benefit most from progesterone therapy. A liquid suspension of ALLO has also been tested in patients with supra-refractory status epilepticus with some success in a small phase II trial. ALLO's C3 methyl analog ganaxolone is under development as an anti-seizure drug. Progesterone's anti-seizure effects are mostly independent of its genomic receptors and are, in large part, due to its active metabolites. ALLO is a potent allosteric modulator of GABA receptors. Other membrane receptors are thought to be involved in the DHP's anti-seizure actions, but their exact nature is not yet known. Potential drawbacks to the development of progesterone family compounds as anti-seizure drug are their endocrine effects. These compounds might form a basis for the future development of novel anti-seizure drugs, however, with hormonal side effects being mitigated through rational drug design.
Topics: 20-alpha-Dihydroprogesterone; Animals; Anticonvulsants; Humans; Pregnanolone; Progesterone; Seizures
PubMed: 30391663
DOI: 10.1016/j.seizure.2018.10.012 -
Psychoneuroendocrinology Aug 2016Neuroactive steroids (NAS) are allosteric modulators of the γ-aminobutyric acid (GABA) system. NAS and GABA are implicated in depression. The peripartum period involves...
Neuroactive steroids (NAS) are allosteric modulators of the γ-aminobutyric acid (GABA) system. NAS and GABA are implicated in depression. The peripartum period involves physiologic changes in NAS which may be associated with peripartum depression and anxiety. We measured peripartum plasma NAS and GABA in healthy comparison subjects (HCS) and those at-risk for postpartum depression (AR-PPD) due to current mild depressive or anxiety symptoms or a history of depression. We evaluated 56 peripartum medication-free subjects. We measured symptoms with the Hamilton Depression Rating Scale (HAM-D17), Hamilton Anxiety Rating Scale (HAM-A) and Spielberger State-Trait Anxiety Inventory-State (STAI-S). Plasma NAS and GABA were quantified by liquid chromatography-mass spectrometry. We examined the associations between longitudinal changes in NAS, GABA and depressive and anxiety symptoms using generalized estimating equation methods. Peripartum GABA concentration was 1.9±0.7ng/mL (p=0.004) lower and progesterone and pregnanolone were 15.8±7.5 (p=0.04) and 1.5±0.7ng/mL (p=0.03) higher in AR-PPD versus HCS, respectively. HAM-D17 was negatively associated with GABA (β=-0.14±0.05, p=0.01) and positively associated with pregnanolone (β=0.16±0.06, p=0.01). STAI-S was positively associated with pregnanolone (β=0.11±0.04, p=0.004), allopregnanolone (β=0.13±0.05, p=0.006) and pregnenolone (β=0.02±0.01, p=0.04). HAM-A was negatively associated with GABA (β=-0.12±0.04, p=0.004) and positively associated with pregnanolone (β=0.11±0.05, p=0.05). Altered peripartum NAS and GABA profiles in AR-PPD women suggest that their interaction may play an important role in the pathophysiology of peripartum depression and anxiety.
Topics: 20-alpha-Dihydroprogesterone; Adult; Case-Control Studies; Depression, Postpartum; Desoxycorticosterone; Female; Humans; Longitudinal Studies; Peripartum Period; Pregnancy; Pregnanolone; Progesterone; Receptors, GABA-A; Risk Factors; Steroids; gamma-Aminobutyric Acid
PubMed: 27209438
DOI: 10.1016/j.psyneuen.2016.05.010 -
International Journal of Molecular... May 2021Under stressful conditions, the hypothalamic-pituitary-adrenal (HPA) axis acts to promote transitory physiological adaptations that are often resolved after the... (Review)
Review
Under stressful conditions, the hypothalamic-pituitary-adrenal (HPA) axis acts to promote transitory physiological adaptations that are often resolved after the stressful stimulus is no longer present. In addition to corticosteroids (e.g., cortisol), the neurosteroid allopregnanolone (3α,5α-tetrahydroprogesterone, 3α-hydroxy-5α-pregnan-20-one) participates in negative feedback mechanisms that restore homeostasis. Chronic, repeated exposure to stress impairs the responsivity of the HPA axis and dampens allopregnanolone levels, participating in the etiopathology of psychiatric disorders, such as major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). MDD and PTSD patients present abnormalities in the HPA axis regulation, such as altered cortisol levels or failure to suppress cortisol release in the dexamethasone suppression test. Herein, we review the neurophysiological role of allopregnanolone both as a potent and positive GABAergic neuromodulator but also in its capacity of inhibiting the HPA axis. The allopregnanolone function in the mechanisms that recapitulate stress-induced pathophysiology, including MDD and PTSD, and its potential as both a treatment target and as a biomarker for these disorders is discussed.
Topics: Adaptation, Physiological; Animals; Antidepressive Agents; Chronic Disease; Corticosterone; Depressive Disorder, Major; Feedback, Physiological; Female; GABA-A Receptor Agonists; Humans; Hypothalamo-Hypophyseal System; Male; Models, Biological; Pituitary-Adrenal System; Pregnanolone; Receptors, GABA-A; Sex Characteristics; Stress Disorders, Post-Traumatic; Stress, Physiological; Stress, Psychological; gamma-Aminobutyric Acid
PubMed: 34071053
DOI: 10.3390/ijms22115495 -
Neuropsychopharmacology : Official... May 20183α-5α-Tetrahydroprogesterone, a progesterone metabolite also known as allopregnanolone, and 5α-androstane-3α,17β-diol, a testosterone metabolite also known as...
3α-5α-Tetrahydroprogesterone, a progesterone metabolite also known as allopregnanolone, and 5α-androstane-3α,17β-diol, a testosterone metabolite also known as 3α-androstanediol, are neuroactive steroids and positive GABA receptor allosteric modulators. Both anorexia nervosa (AN) and obesity are complicated by affective comorbidities and hypothalamic-pituitary-gonadal dysregulation. However, it is not known whether neuroactive steroid levels are abnormal at the extremes of the weight spectrum. We hypothesized that serum allopregnanolone and 3α-androstanediol levels would be decreased in AN compared with healthy controls (HC) and negatively associated with affective symptoms throughout the weight spectrum, independent of body mass index (BMI). Thirty-six women were 1 : 1 age-matched across three groups: AN, HC, and overweight/obese (OW/OB). AN were amenorrheic; HC and OW/OB were studied in the follicular phase. Fasting serum neuroactive steroids were measured by gas chromatography/mass spectrometry. Mean Hamilton depression and anxiety scores were highest in AN (p<0.0001). Mean serum allopregnanolone was lower in AN and OW/OB than HC (AN 95.3±56.4 vs OW/OB 73.8±31.3 vs HC 199.5±167.8 pg/ml, p=0.01), despite comparable mean serum progesterone. Allopregnanolone levels, but not progesterone levels, were negatively associated with depression and anxiety symptom severity, independent of BMI. Serum 3α-androstanediol levels did not differ among groups and were not associated with depression or anxiety scores, despite a significant negative association between free testosterone levels and both anxiety and depression severity. In conclusion, women at both extremes of the weight spectrum have low mean serum allopregnanolone, which is associated with increased depression and anxiety severity, independent of BMI. Neuroactive steroids such as allopregnanolone may be potential therapeutic targets for depression and anxiety in traditionally treatment-resistant groups, including AN.
Topics: Adult; Affective Symptoms; Androstane-3,17-diol; Anorexia Nervosa; Anxiety; Body Mass Index; Cross-Sectional Studies; Depression; Female; Humans; Overweight; Pregnanolone; Progesterone; Psychiatric Status Rating Scales; Severity of Illness Index; Testosterone; Thinness
PubMed: 29090684
DOI: 10.1038/npp.2017.269 -
Genes Jun 2023Brexanolone, a formulation of the neurosteroid allopregnanolone (ALLO), is approved for treating postpartum depression (PPD) and is being investigated for therapeutic...
Brexanolone, a formulation of the neurosteroid allopregnanolone (ALLO), is approved for treating postpartum depression (PPD) and is being investigated for therapeutic efficacy across numerous neuropsychiatric disorders. Given ALLO's beneficial effects on mood in women with PPD compared to healthy control women, we sought to characterize and compare the cellular response to ALLO in women with ( = 9) or without ( = 10, i.e., Controls) past PPD, utilizing our previously established patient-derived lymphoblastoid cell lines (LCLs). To mimic in vivo PPD ALLO-treatment, LCLs were exposed to ALLO or DMSO vehicle for 60 h and RNA-sequenced to detect differentially expressed genes (DEGs, p < 0.05). Between ALLO-treated Control and PPD LCLs, 269 DEGs were identified, including Glutamate Decarboxylase 1 (), which was decreased 2-fold in PPD. Network analysis of PPD:ALLO DEGs revealed enriched terms related to synaptic activity and cholesterol biosynthesis. Within-diagnosis analyses (i.e., DMSO vs. ALLO) detected 265 ALLO-induced DEGs in Control LCLs compared to only 98 within PPD LCLs, with just 11 DEGs overlapping. Likewise, the gene ontologies underlying ALLO-induced DEGs in PPD and Control LCLs were divergent. These data suggest that ALLO may activate unique and opposing molecular pathways in women with PPD, which may be tied to its antidepressant mechanism.
Topics: Humans; Female; Pregnanolone; Depression, Postpartum; Transcriptome; Dimethyl Sulfoxide; Antidepressive Agents
PubMed: 37372414
DOI: 10.3390/genes14061234 -
Antioxidants (Basel, Switzerland) Apr 2023We obtained evidence that mouse BV2 microglia synthesize neurosteroids dynamically to modify neurosteroid levels in response to oxidative damage caused by rotenone....
We obtained evidence that mouse BV2 microglia synthesize neurosteroids dynamically to modify neurosteroid levels in response to oxidative damage caused by rotenone. Here, we evaluated whether neurosteroids could be produced and altered in response to rotenone by the human microglial clone 3 (HMC3) cell line. To this aim, HMC3 cultures were exposed to rotenone (100 nM) and neurosteroids were measured in the culture medium by liquid chromatography with tandem mass spectrometry. Microglia reactivity was evaluated by measuring interleukin 6 (IL-6) levels, whereas cell viability was monitored by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. After 24 h (h), rotenone increased IL-6 and reactive oxygen species levels by approximately +37% over the baseline, without affecting cell viability; however, microglia viability was significantly reduced at 48 h ( < 0.01). These changes were accompanied by the downregulation of several neurosteroids, including pregnenolone, pregnenolone sulfate, 5α-dihydroprogesterone, and pregnanolone, except for allopregnanolone, which instead was remarkably increased ( < 0.05). Interestingly, treatment with exogenous allopregnanolone (1 nM) efficiently prevented the reduction in HMC3 cell viability. In conclusion, this is the first evidence that human microglia can produce allopregnanolone and that this neurosteroid is increasingly released in response to oxidative stress, to tentatively support the microglia's survival.
PubMed: 37107338
DOI: 10.3390/antiox12040963 -
Cell Jan 2019During the postpartum period, the brain's inhibitory GABAA receptors may not recover in time following their reduced numbers during pregnancy. This is likely the cause...
During the postpartum period, the brain's inhibitory GABAA receptors may not recover in time following their reduced numbers during pregnancy. This is likely the cause of postpartum depression prevalent in ∼12% of childbearing women. A new therapy for this condition consists of administering a synthetic neurosteroid during the postpartum period to alleviate the mood disorder. To view this Bench to Bedside, open or download the PDF.
Topics: Adult; Depression, Postpartum; Depressive Disorder, Major; Drug Combinations; Female; Humans; Mood Disorders; Neurotransmitter Agents; Postpartum Period; Pregnancy; Pregnanolone; Prevalence; Receptors, GABA-A; beta-Cyclodextrins
PubMed: 30633900
DOI: 10.1016/j.cell.2018.12.016 -
Psychoneuroendocrinology Jan 2021Autism spectrum disorder (ASD) has been associated with imbalance between excitatory and inhibitory (E/I) neurotransmission systems, as well as with neuroinflammation....
Autism spectrum disorder (ASD) has been associated with imbalance between excitatory and inhibitory (E/I) neurotransmission systems, as well as with neuroinflammation. Sitting at the crossroads between E/I imbalance and neuroinflammation is a class of endogenous hormones known as neurosteroids. Current literature points to dysregulated steroid metabolism and atypical neurosteroid levels in ASD as early as in utero. However, due to the complexity of neurosteroid metabolomics, including possible sex differences, the impact of neurosteroids on ASD symptomatology remains unclear. In this study, we assessed neurosteroid levels and ASD symptom severity of 21 males with ASD and 20 full-scale-IQ-matched typically developing (TD) males, all aged 18-39. Using liquid chromatography-tandem mass spectrometry, concentrations of allopregnanolone, cortisol, dehydroepiandrosterone, progesterone, and testosterone were measured in saliva and serum. With the exception of cortisol's, all neurosteroids' concentrations were found to have ASD vs. TD group differences in distribution, where one group was normally distributed and the other non-normally distributed. Serum allopregnanolone levels in males with ASD were found to negatively correlate with clinician-rated measures of restricted and repetitive behavior measures (ADOS-2 RRB and ADI-R RRSB domain scores). Additionally, lower serum allopregnanolone levels were found to predict more negative camouflaging scores, which represent greater differences in self- and clinician-rated symptom severity, of both ASD symptomatology overall and repetitive behaviors in particular. Taken together, our findings demonstrate that in adult males with ASD, decreased serum allopregnanolone levels are associated with more severe restricted and repetitive behaviors and with less insight into the severity of these behaviors.
Topics: Adult; Autism Spectrum Disorder; Humans; Male; Pregnanolone
PubMed: 33161257
DOI: 10.1016/j.psyneuen.2020.105039 -
Epilepsia Open Sep 2019Our objective was to evaluate the protective efficacy of the neurosteroid pregnanolone (3α-hydroxy-5β pregnan-20-one), a GABA receptor-positive allosteric modulator,...
OBJECTIVE
Our objective was to evaluate the protective efficacy of the neurosteroid pregnanolone (3α-hydroxy-5β pregnan-20-one), a GABA receptor-positive allosteric modulator, as an adjunct to benzodiazepine therapy against the chemical warfare nerve agent (CWNA) sarin (GB), using whole-body exposure, an operationally relevant route of exposure to volatile GB.
METHODS
Rats implanted with telemetry transmitters for the continuous measurement of cortical electroencephalographic (EEG) activity were exposed for 60 minutes to 3.0 LCt of GB via whole-body exposure. At the onset of toxic signs, rats were administered an intramuscular injection of atropine sulfate (2 mg/kg) and the oxime HI-6 (93.6 mg/kg) to increase survival rate and, 30 minutes after seizure onset, treated subcutaneously with diazepam (10 mg/kg) and intravenously with pregnanolone (4 mg/kg) or vehicle. Animals were evaluated for GB-induced status epilepticus (SE), spontaneous recurrent seizures (SRS), impairment in spatial memory acquisition, and brain pathology, and treatment groups were compared.
RESULTS
Delayed dual therapy with pregnanolone and diazepam reduced time in SE in GB-exposed rats compared to those treated with delayed diazepam monotherapy. The combination therapy of pregnanolone with diazepam also prevented impairment in the Morris water maze and reduced the neuronal loss and neuronal degeneration, evaluated at one and three months after exposure.
SIGNIFICANCE
Neurosteroid administration as an adjunct to benzodiazepine therapy offers an effective means to treat benzodiazepine-refractory SE, such as occurs following delayed treatment of GB exposure. This study is the first to present data on the efficacy of delayed pregnanolone and diazepam dual therapy in reducing seizure activity, performance deficits and brain pathology following an operationally relevant route of exposure to GB and supports the use of a neurosteroid as an adjunct to standard anticonvulsant therapy for the treatment of CWNA-induced SE.
PubMed: 31440720
DOI: 10.1002/epi4.12344 -
Neuroendocrinology 2021Neurosteroids modulate epileptic activity by interacting with the γ-aminobutyric acid type A receptor, but their brain levels are still undetermined.
BACKGROUND
Neurosteroids modulate epileptic activity by interacting with the γ-aminobutyric acid type A receptor, but their brain levels are still undetermined.
OBJECTIVES
We aimed to establish neurosteroid levels in the neocortex and hippocampus by liquid chromatography/mass spectrometry in epileptic rats.
METHODS
Kainic acid-treated rats were continuously monitored up to 9 weeks to determine seizure frequency by video electrocorticography (n = 23) and compared to age-matched controls monitored in the same manner (n = 11).
RESULTS
Decreased allopregnanolone (-50%; p < 0.05, Mann-Whitney test) and pregnanolone levels (-64%; p < 0.01) were found in the hippocampus, whereas pregnenolone sulfate, pregnenolone, progesterone, and 5α-dihydroprogesterone were nonsignificantly reduced. No changes were found in the neocortex. Moreover, allopregnanolone (but not pregnanolone) levels were positively correlated with seizure frequency (r2 = 0.4606, p < 0.01).
CONCLUSION
These findings indicate a selective reduction in hippocampal levels of 3α-reduced neurosteroids. This reduction was partially mitigated by seizures in the case of allopregnanolone.
Topics: Animals; Disease Models, Animal; Electrocorticography; Epilepsy; Hippocampus; Male; Neocortex; Pregnanolone; Rats; Rats, Sprague-Dawley; Status Epilepticus
PubMed: 32492675
DOI: 10.1159/000509093