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Neurotherapeutics : the Journal of the... Apr 2009Perimenstrual catamenial epilepsy, the cyclical occurrence of seizure exacerbations near the time of menstruation, affects a high proportion of women of reproductive age... (Review)
Review
Perimenstrual catamenial epilepsy, the cyclical occurrence of seizure exacerbations near the time of menstruation, affects a high proportion of women of reproductive age with drug-refractory epilepsy. Enhanced seizure susceptibility in perimenstrual catamenial epilepsy is believed to be due to the withdrawal of the progesterone-derived GABA(A) receptor modulating neurosteroid allopregnanolone as a result of the fall in progesterone at the time of menstruation. Studies in a rat pseudopregnancy model of catamenial epilepsy indicate that after neurosteroid withdrawal there is enhanced susceptibility to chemoconvulsant seizures. There is also a transitory increase in the frequency of spontaneous seizures in epileptic rats that had experienced pilocarpine-induced status epilepticus. In the catamenial epilepsy model, there is a marked reduction in the antiseizure potency of anticonvulsant drugs, including benzodiazepines and valproate, but an increase in the anticonvulsant potency and protective index of neurosteroids such as allopregnanolone and the neurosteroid analog ganaxolone. The enhanced seizure susceptibility and benzodiazepine-resistance subsequent to neurosteroid withdrawal may be related to reduced expression and altered kinetics of synaptic GABA(A) receptors and increased expression of GABA(A) receptor subunits (such as alpha4) that confer benzodiazepine insensitivity. The enhanced potency of neurosteroids may be due to a relative increase after neurosteroid withdrawal in the expression of neurosteroid-sensitive delta-subunit-containing perisynaptic or extrasynaptic GABA(A) receptors. Positive allosteric modulatory neurosteroids and synthetic analogs such as ganaxolone may be administered to prevent catamenial seizure exacerbations, in what we call neurosteroid replacement therapy.
Topics: Animals; Anticonvulsants; Epilepsy; Female; Gonadal Steroid Hormones; Humans; Menstrual Cycle; Pregnanolone; Rats; Receptors, GABA-A
PubMed: 19332335
DOI: 10.1016/j.nurt.2009.01.006 -
Journal of Women's Health (2002) Mar 2021Brexanolone (BRX) injection was approved by the United States Food and Drug Administration in 2019 for the treatment of adults with postpartum depression (PPD) based on... (Meta-Analysis)
Meta-Analysis
Brexanolone (BRX) injection was approved by the United States Food and Drug Administration in 2019 for the treatment of adults with postpartum depression (PPD) based on two Phase 3 clinical trials. Data from the three trials were combined. PPD-specific 17-item Hamilton Rating Scale for Depression (HAMD-17) group-level minimal important difference (MID) and patient-level meaningful change (meaningful change threshold [MCT]) were estimated and applied to differences in BRX versus placebo (PBO) at hour 60 (primary endpoint) and day 30 (end of trial follow-up). Likelihood of HAMD-17 response and remission and Clinical Global Impression of Improvement (CGI-I) response for BRX versus PBO were assessed at hour 60 and as sustained through day 30 using relative risk. Associated number needed to treat (NNT) and number needed to harm (NNH) values were also estimated. Two-hundred nine patients were included. The average HAMD-17 MID estimate was -2.1; the least-squared mean difference between BRX and PBO exceeded this at hour 60 and day 30. Minimal, moderate, and large MCTs were estimated to be -9, -15, and -20 points, respectively. Significantly more BRX-treated than PBO-treated patients achieved minimal, moderate, and large change (all s < 0.05) at hour 60 and large meaningful response at day 30 ( < 0.05). BRX-treated patients were more likely to sustain HAMD-17 remission and CGI-I response through day 30 versus PBO. NNTs ranged from 4 to 8, with NNH of 97. BRX provided meaningful changes relative to PBO, rapid (hour 60), and sustained improvements (day 30) in PPD symptoms, low NNT, and large NNH. These results may help inform treatment decision-making. Clinicaltrials.gov registration numbers: NCT02614547, NCT02942004, and NCT02942017.
Topics: Adult; Clinical Decision-Making; Depression, Postpartum; Drug Combinations; Female; Humans; Pregnanolone; Treatment Outcome; beta-Cyclodextrins
PubMed: 33181049
DOI: 10.1089/jwh.2020.8483 -
Anaesthesia Jun 1981
Topics: Anesthesia, Intravenous; Anesthetics; Humans; Pregnanolone; Safety
PubMed: 7270825
DOI: 10.1111/j.1365-2044.1981.tb10318.x -
Neurotherapeutics : the Journal of the... Oct 2017
Topics: Ataxia; Fragile X Syndrome; Humans; Male; Neurotransmitter Agents; Pregnanolone; Tremor
PubMed: 28884425
DOI: 10.1007/s13311-017-0569-0 -
International Journal of Molecular... Feb 2021Even though major depressive disorder (MDD) and post-traumatic stress disorder (PTSD) are among the most prevalent and incapacitating mental illnesses in the world,... (Review)
Review
Even though major depressive disorder (MDD) and post-traumatic stress disorder (PTSD) are among the most prevalent and incapacitating mental illnesses in the world, their diagnosis still relies solely on the characterization of subjective symptoms (many of which are shared by multiple disorders) self-reported by patients. Thus, the need for objective measures that aid in the detection of and differentiation between psychiatric disorders becomes urgent. In this paper, we explore the potential of neurosteroids and neurotrophic proteins as biomarkers for MDD and PTSD. Circulating levels of the GABAergic neuroactive steroid, allopregnanolone, are diminished in MDD and PTSD patients, which corroborates the finding of depleted neurosteroid levels observed in animal models of these disorders. The neurotrophic protein, brain-derived neurotropic factor (BDNF), is also reduced in the periphery and in the brain of MDD patients and depressed-like animals that express lower neurosteroid levels. Although the role of BDNF in PTSD psychopathology seems less clear and merits more research, we propose a causal link between allopregnanolone levels and BDNF expression that could function as a for the diagnosis of both MDD and PTSD.
Topics: Animals; Biomarkers; Brain; Brain-Derived Neurotrophic Factor; Depressive Disorder, Major; Humans; Nerve Growth Factors; Neurosteroids; Pregnanolone; Stress Disorders, Post-Traumatic
PubMed: 33578758
DOI: 10.3390/ijms22041758 -
Journal of Neuroendocrinology Feb 2022The neurosteroid allopregnanolone (3α-hydroxy-5α-pregnan-20-one; AP) elicits pleiotropic effects in the central nervous system, ranging from neuroprotective and... (Review)
Review
The neurosteroid allopregnanolone (3α-hydroxy-5α-pregnan-20-one; AP) elicits pleiotropic effects in the central nervous system, ranging from neuroprotective and anti-inflammatory functions to the regulation of mood and emotional responses. Several lines of research show that the brain rapidly produces AP in response to acute stress to reduce the allostatic load and enhance coping. These effects not only are likely mediated by GABA receptor activation but also result from the contributions of other mechanisms, such as the stimulation of membrane progesterone receptors. In keeping with this evidence, AP has been shown to exert rapid, potent antidepressant properties and has been recently approved for the therapy of moderate-to-severe postpartum depression. In addition to depression, emerging evidence points to the potential of AP as a therapy for other neuropsychiatric disorders, including anxiety, seizures, post-traumatic stress disorder and cognitive problems. Although this evidence has spurred interest in further therapeutic applications of AP, some investigations suggest that this neurosteroid may also be associated with adverse events in specific disorders. For example, our group has recently documented that AP increases tic-like manifestations in several animal models of tic disorders; furthermore, our results indicate that inhibiting AP synthesis and signalling reduces the exacerbation of tic severity associated with acute stress. Although the specific mechanisms of these effects remain partially elusive, our findings point to the possibility that the GABAergic activation by AP may also lead to disinhibitory effects, which could interfere with the ability of patients to suppress their tics. Future studies will be necessary to verify whether these mechanisms may apply to other externalising manifestations, such as impulse-control problems and manic symptoms.
Topics: Animals; Female; Humans; Neurosteroids; Pregnanolone; Receptors, GABA-A; Tic Disorders; Tics
PubMed: 34423500
DOI: 10.1111/jne.13022 -
Methods and Findings in Experimental... Sep 2004Catamenial epilepsy is a menstrual cycle-related seizure disorder characterized by an increase in seizures at the time of menstruation. Catamenial epilepsy affects up to... (Review)
Review
Catamenial epilepsy is a menstrual cycle-related seizure disorder characterized by an increase in seizures at the time of menstruation. Catamenial epilepsy affects up to 70% of women with epilepsy. Catamenial seizures are common among women with focal or generalized epilepsy, which affects an estimated 1 million women in the United States. Presently, there is no specific, FDA-approved drug treatment for catamenial epilepsy. Despite the increased use of wide-ranging antiepileptic and hormonal drugs, catamenial seizures are often refractory to many treatments. Recent studies have provided an improved understanding of the pathophysiology of catamenial epilepsy. Cyclical changes of ovarian hormones estrogens and progesterone are now widely believed to be essential for the genesis of catamenial seizures. Generally, progesterone has antiseizure effects, while estrogens facilitate seizure susceptibility. The progesterone metabolite allopregnanolone has been identified as a key endogenous neurosteroid with powerful antiseizure activity. Allopregnanolone is a potent, positive allosteric modulator of GABA(A) receptors. Progesterone and allopregnanolone exposure and withdrawal affects GABA(A) receptor plasticity. In animal models, withdrawal from chronic progesterone and, consequently, of allopregnanolone levels in brain, has been shown to increase seizure susceptibility. Natural progesterone therapy is proven to be effective in women with epilepsy. Consequently, synthetic neurosteroids that are devoid of hormonal side effects represent a novel class of antiepileptic drugs for women with catamenial epilepsy. Our studies suggest that ganaxolone, a GABA(A) receptor-modulating synthetic neuroactive steroid, is a particularly promising treatment for catamenial epilepsy. Future studies are clearly warranted to determine the molecular pathophysiology and an effective treatment of catamenial epilepsy.
Topics: Animals; Anticonvulsants; Area Under Curve; Epilepsy; Estrogens; Female; Half-Life; Humans; Incidence; Menstrual Cycle; Mice; Pregnanolone; Progesterone; Receptors, GABA-A
PubMed: 15538544
DOI: 10.1358/mf.2004.26.7.863737 -
Behavioural Pharmacology Dec 2010Chronic treatment with benzodiazepines, which positively modulate γ-aminobutyric acidA (GABAA) receptors, can lead to the development of tolerance. Similar effects...
Chronic treatment with benzodiazepines, which positively modulate γ-aminobutyric acidA (GABAA) receptors, can lead to the development of tolerance. Similar effects might also occur during chronic treatment with positive modulators acting at other sites on GABAA receptors (e.g. neuroactive steroids). In this study, tolerance and cross tolerance were examined in seven rats treated daily with the neuroactive steroid pregnanolone (25.6 mg/kg/day) and responding under a fixed ratio 10 schedule of food presentation. Dose-effect curves were determined for positive GABAA modulators (pregnanolone, flunitrazepam, midazolam, and pentobarbital), and other drugs (ketamine and morphine) before, during, and after chronic treatment. Initially, daily pregnanolone administration increased responding; although tolerance developed to the rate-increasing effects after 14 weeks, tolerance did not develop to the rate-decreasing effects. The potencies of pregnanolone, midazolam, and morphine to decrease responding did not change during treatment, whereas flunitrazepam was more potent and pentobarbital and ketamine were less potent during treatment as compared to before treatment. Pregnanolone and midazolam were more potent after treatment than before treatment. The development of tolerance to the rate-increasing effects of pregnanolone indicates that neuroadaptations occur during chronic treatment; the fact that tolerance develops to only some effects suggests that the behavioral consequences of these neuroadaptations are limited.
Topics: Analysis of Variance; Anesthetics; Animals; Conditioning, Operant; Dose-Response Relationship, Drug; Drug Tolerance; Male; Pregnanolone; Rats; Rats, Sprague-Dawley; Reinforcement Schedule; Time Factors
PubMed: 20859199
DOI: 10.1097/FBP.0b013e32833fa79d -
Progress in Brain Research 2010This chapter provides an overview of neurosteroids, especially their impact on the brain, sex differences and their therapeutic potentials. Neurosteroids are synthesized... (Review)
Review
This chapter provides an overview of neurosteroids, especially their impact on the brain, sex differences and their therapeutic potentials. Neurosteroids are synthesized within the brain and rapidly modulate neuronal excitability. They are classified as pregnane neurosteroids, such as allopregnanolone and allotetrahydrodeoxycorticosterone, androstane neurosteroids, such as androstanediol and etiocholanolone, and sulfated neurosteroids such as pregnenolone sulfate. Neurosteroids such as allopregnanolone are positive allosteric modulators of GABA-A receptors with powerful anti-seizure activity in diverse animal models. Neurosteroids increase both synaptic and tonic inhibition. They are endogenous regulators of seizure susceptibility, anxiety, and stress. Sulfated neurosteroids such as pregnenolone sulfate, which are negative GABA-A receptor modulators, are memory-enhancing agents. Sex differences in susceptibility to brain disorders could be due to neurosteroids and sexual dimorphism in specific structures of the human brain. Synthetic neurosteroids that exhibit better bioavailability and efficacy and drugs that enhance neurosteroid synthesis have therapeutic potential in anxiety, epilepsy, and other brain disorders. Clinical trials with the synthetic neurosteroid analog ganaxolone in the treatment of epilepsy have been encouraging. Neurosteroidogenic agents that lack benzodiazepine-like side effects show promise in the treatment of anxiety and depression.
Topics: Androstane-3,17-diol; Anesthetics; Anxiety; Brain; Depression; Female; Humans; Male; Neurotransmitter Agents; Pregnanolone; Premenstrual Syndrome; Receptors, GABA-A; Seizures; Sex Characteristics; Stress, Physiological
PubMed: 21094889
DOI: 10.1016/B978-0-444-53630-3.00008-7 -
European Journal of Pharmacology Jan 2013Benzodiazepines and neuroactive steroids act at distinct binding sites on γ-aminobutyric acid(A) (GABA(A)) receptors where they positively modulate GABA, resulting in...
Acute tolerance to chlordiazepoxide qualitatively changes the interaction between flumazenil and pregnanolone and not the interaction between flumazenil and midazolam in rhesus monkeys discriminating midazolam.
Benzodiazepines and neuroactive steroids act at distinct binding sites on γ-aminobutyric acid(A) (GABA(A)) receptors where they positively modulate GABA, resulting in similar acute behavioral effects. Tolerance to benzodiazepines can develop with repeated treatment; however, cross tolerance to neuroactive steroids does not develop, perhaps due to conformational changes in benzodiazepine, and not neuroactive steroid, binding sites. Three monkeys discriminated 0.178 mg/kg midazolam while responding under a fixed-ratio 10 schedule of stimulus-shock termination. On separate occasions, dose-effect curves for midazolam and pregnanolone were determined when monkeys had not received chlordiazepoxide and when they received 10 mg/kg chlordiazepoxide 46 hours earlier; for some tests, flumazenil was given before determination of dose-effect curves. Midazolam and pregnanolone produced ≥80% midazolam-lever responding. When administered 46 h before sessions, chlordiazepoxide did not produce pregnanolone-lever responding; under those treatment conditions, midazolam dose-effect curves were shifted 2.8-fold rightward and pregnanolone dose-effect curves were not changed. Flumazenil antagonized midazolam; Schild (linear) analyses yielded slopes that were not different from unity and pA(2) values of 7.46 when monkeys had not received chlordiazepoxide and 7.44 when they received chlordiazepoxide 46 h earlier. Flumazenil did not alter the effects of pregnanolone in chlordiazepoxide-treated monkeys. Thus, interactions between flumazenil and midazolam were not qualitatively or quantitatively changed in monkeys acutely tolerant to chlordiazepoxide, suggesting that mechanisms other than alterations of benzodiazepine binding sites account for the development of acute tolerance.
Topics: Animals; Benzodiazepines; Chlordiazepoxide; Dose-Response Relationship, Drug; Drug Interactions; Drug Tolerance; Female; Flumazenil; GABA Modulators; Macaca mulatta; Midazolam; Pregnanolone
PubMed: 23305839
DOI: 10.1016/j.ejphar.2012.12.028