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Pharmacology & Therapeutics Jun 2022Positive allosteric modulators of γ-aminobutyric acid-A (GABA) receptors or GABAkines have been widely used medicines for over 70 years for anxiety, epilepsy, sleep,... (Review)
Review
Positive allosteric modulators of γ-aminobutyric acid-A (GABA) receptors or GABAkines have been widely used medicines for over 70 years for anxiety, epilepsy, sleep, and other disorders. Traditional GABAkines like diazepam have safety and tolerability concerns that include sedation, motor-impairment, respiratory depression, tolerance and dependence. Multiple GABAkines have entered clinical development but the issue of side-effects has not been fully solved. The compounds that are presently being developed and commercialized include several neuroactive steroids (an allopregnanolone formulation (brexanolone), an allopregnanolone prodrug (LYT-300), Sage-324, zuranolone, and ganaxolone), the α2/3-preferring GABAkine, KRM-II-81, and the α2/3/5-preferring GABAkine PF-06372865 (darigabat). The neuroactive steroids are in clinical development for post-partum depression, intractable epilepsy, tremor, status epilepticus, and genetic epilepsy disorders. Darigabat is in development for epilepsy and anxiety. The imidazodiazepine, KRM-II-81 is efficacious in animal models for the treatment of epilepsy and post-traumatic epilepsy, acute and chronic pain, as well as anxiety and depression. The efficacy of KRM-II-81 in models of pharmacoresistant epilepsy, preventing the development of seizure sensitization, and in brain tissue of intractable epileptic patients bodes well for improved therapeutics. Medicinal chemistry efforts are also ongoing to identify novel and improved GABAkines. The data document gaps in our understanding of the molecular pharmacology of GABAkines that drive differential pharmacological profiles, but emphasize advancements in the ability to successfully utilize GABA receptor potentiation for therapeutic gain in neurology and psychiatry.
Topics: Animals; Anticonvulsants; Epilepsy; Humans; Neurosteroids; Pregnanolone; Receptors, GABA-A; gamma-Aminobutyric Acid
PubMed: 34793859
DOI: 10.1016/j.pharmthera.2021.108035 -
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 -
CNS Drugs Aug 2023Premenstrual dysphoric disorder (PMDD) is characterized by the predictable onset of mood and physical symptoms secondary to gonadal steroid fluctuation during the luteal... (Review)
Review
Premenstrual dysphoric disorder (PMDD) is characterized by the predictable onset of mood and physical symptoms secondary to gonadal steroid fluctuation during the luteal phase of the menstrual cycle. Although menstrual-related affective dysfunction is responsible for considerable functional impairment and reduction in quality of life worldwide, currently approved treatments for PMDD are suboptimal in their effectiveness. Research over the past two decades has suggested that the interaction between allopregnanolone, a neurosteroid derivative of progesterone, and the gamma-aminobutyric acid (GABA) system represents an important relationship underlying symptom genesis in reproductive-related mood disorders, including PMDD. The objective of this narrative review is to discuss the plausible link between changes in GABAergic transmission secondary to the fluctuation of allopregnanolone during the luteal phase and mood impairment in susceptible individuals. As part of this discussion, we explore promising findings from early clinical trials of several compounds that stabilize allopregnanolone signaling during the luteal phase, including dutasteride, a 5-alpha reductase inhibitor; isoallopregnanolone, a GABA-A modulating steroid antagonist; and ulipristal acetate, a selective progesterone receptor modulator. We then reflect on the implications of these therapeutic advances, including how they may promote our knowledge of affective regulation more generally. We conclude that these and other studies of PMDD may yield critical insight into the etiopathogenesis of affective disorders, considering that (1) symptoms in PMDD have a predictable onset and offset, allowing for examination of affective state kinetics, and (2) GABAergic interventions in PMDD can be used to better understand the relationship between mood states, network regulation, and the balance between excitatory and inhibitory signaling in the brain.
Topics: Female; Humans; Premenstrual Dysphoric Disorder; Pregnanolone; Quality of Life; Menstrual Cycle; Luteal Phase; GABA Modulators; gamma-Aminobutyric Acid; Premenstrual Syndrome
PubMed: 37542704
DOI: 10.1007/s40263-023-01030-7 -
Steroids Jul 2016Steroids have been widely used in the clinical setting. They bind and activate nuclear receptors to regulate gene expression. In addition to activating genomic... (Review)
Review
Steroids have been widely used in the clinical setting. They bind and activate nuclear receptors to regulate gene expression. In addition to activating genomic transcription, steroids also exert nongenomic actions. The current article focuses on the nongenomic actions of neurosteroids, including pregnenolone (P5), 7α-hydroxypregnenolone, pregnenolone sulfate and allopregnanolone. Pregnenolone and its derivatives promote neuronal activity by enhancing learning and memory, relieving depression, enhancing locomotor activity, and promoting neuronal cell survival. They exert these effects by activating various target proteins located in the cytoplasm or cell membrane. Pregnenolone and its metabolites bind to receptors such as microtubule-associated proteins and neurotransmitter receptors to elicit a series of reactions including stabilization of microtubules, increase of ion flux into cells, and dopamine release. The wide actions of neurosteroids indicate that pregnenolone derivatives have great potential in future treatment of neurological diseases.
Topics: 17-alpha-Hydroxypregnenolone; Animals; Depression; Humans; Microtubules; Neurodegenerative Diseases; Neurotransmitter Agents; Pregnanolone; Pregnenolone
PubMed: 26844377
DOI: 10.1016/j.steroids.2016.01.017 -
Epilepsy Research Mar 2023Protocadherin-19 (PCDH19)-clustering epilepsy is a distinct developmental and epileptic encephalopathy characterized by early-onset seizures that are often treatment... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
Protocadherin-19 (PCDH19)-clustering epilepsy is a distinct developmental and epileptic encephalopathy characterized by early-onset seizures that are often treatment refractory. Caused by a mutation of the PCDH19 gene on the X chromosome, this rare epilepsy syndrome primarily affects females with seizure onset commonly in the first year of life. A global, randomized, double-blind, placebo-controlled, phase 2 trial was conducted to evaluate the efficacy, safety, and tolerability of ganaxolone compared with placebo as adjunctive therapy to a standard antiseizure medication regimen in patients with PCDH19-clustering epilepsy (VIOLET; NCT03865732).
METHODS
Females aged 1-17 years with a molecularly confirmed pathogenic or likely pathogenic PCDH19 variant who were experiencing ≥12 seizures during a 12-week screening period were stratified by baseline allopregnanolone sulfate (Allo-S) levels (low: ≤2.5 ng/mL; high: >2.5 ng/mL) at screening and randomized 1:1 within each strata to receive ganaxolone (maximum daily dose of 63 mg/kg/day if ≤28 kg or 1800 mg/day if >28 kg) or matching placebo in addition to their standard antiseizure treatment for the 17-week double-blind phase. The primary efficacy endpoint was the median percentage change in 28-day seizure frequency from baseline to the 17-week double-blind phase. Treatment-emergent adverse events (TEAEs) were tabulated by overall, system organ class, and preferred term.
RESULTS
Of the 29 patients screened, 21 (median age, 7.0 years; IQR, 5.0-10.0 years) were randomized to receive either ganaxolone (n = 10) or placebo (n = 11). After the 17-week double-blind phase, the median (IQR) percentage change in 28-day seizure frequency from baseline was - 61.5% (-95.9% to -33.4%) among patients in the ganaxolone group and - 24.0% (-88.2% to -4.9%) among patients in the placebo group (Wilcoxon rank-sum test, p = 0.17). TEAEs were reported by 7 of 10 (70.0%) patients in the ganaxolone group and 11 of 11 (100%) patients in the placebo group. Somnolence was the most common TEAE (40.0% ganaxolone vs 27.3% placebo); serious TEAEs were more common in the placebo group (10.0% ganaxolone vs 45.5% placebo); and 1 (10.0%) patient in the ganaxolone group discontinued the study versus none in the placebo group.
CONCLUSIONS
Ganaxolone was generally well tolerated and led to a greater reduction in the frequency of PCDH19-clustering seizures compared to placebo; however, the trend did not reach statistical significance. Novel trial designs are likely needed to evaluate the effectiveness of antiseizure treatments for PCDH19-clustering epilepsy.
Topics: Female; Humans; Child; Anticonvulsants; Pregnanolone; Treatment Outcome; Seizures; Epilepsy, Generalized; Cluster Analysis; Protocadherins
PubMed: 36870093
DOI: 10.1016/j.eplepsyres.2023.107112 -
Frontiers in Neuroendocrinology Jan 2018Obesity is strongly associated with ill health, primarily caused by consumption of excessive calories, and promoted (inter alia) by gamma-amino-butyric-acid (GABA)... (Review)
Review
Obesity is strongly associated with ill health, primarily caused by consumption of excessive calories, and promoted (inter alia) by gamma-amino-butyric-acid (GABA) stimulating food intake by activating GABA receptors (primarily with α3 and α2 subunits) in the hypothalamic arcuate nucleus and paraventricular nucleus. Allopregnanolone is a potent positive GABA receptor modulating steroid (GAMS). As reviewed here, elevated allopregnanolone levels are associated with increases in food intake, preferences for energy-rich food, and obesity in humans and other mammals. In women with polycystic ovarian disease, high serum allopregnanolone concentrations are linked to uncontrolled eating, and perturbed sensitivity to allopregnanolone. Increases in weight during pregnancy also correlate with increases in allopregnanolone levels. Moreover, Prader-Willis syndrome is associated with massive overeating, absence of a GABA receptor (with compensatory >12-, >5- and >1.5-fold increases in α4, γ2, and α1, α3 subunits), and increases in the α4, βx, δ receptor subtype, which is highly sensitive to allopregnanolone. GABA and positive GABA-A receptor modulating steroids like allopregnanolone stimulates food intake and weight gain.
Topics: Animals; Female; Humans; Hyperphagia; Obesity; Polycystic Ovary Syndrome; Pregnancy; Pregnanolone; Receptors, GABA-A; gamma-Aminobutyric Acid
PubMed: 28694181
DOI: 10.1016/j.yfrne.2017.07.002 -
Nature Neuroscience Oct 2021Compromised placental function or premature loss has been linked to diverse neurodevelopmental disorders. Here we show that placenta allopregnanolone (ALLO), a...
Compromised placental function or premature loss has been linked to diverse neurodevelopmental disorders. Here we show that placenta allopregnanolone (ALLO), a progesterone-derived GABA-A receptor (GABAR) modulator, reduction alters neurodevelopment in a sex-linked manner. A new conditional mouse model, in which the gene encoding ALLO's synthetic enzyme (akr1c14) is specifically deleted in trophoblasts, directly demonstrated that placental ALLO insufficiency led to cerebellar white matter abnormalities that correlated with autistic-like behavior only in male offspring. A single injection of ALLO or muscimol, a GABAR agonist, during late gestation abolished these alterations. Comparison of male and female human preterm infant cerebellum also showed sex-linked myelination marker alteration, suggesting similarities between mouse placental ALLO insufficiency and human preterm brain development. This study reveals a new role for a placental hormone in shaping brain regions and behaviors in a sex-linked manner. Placental hormone replacement might offer novel therapeutic opportunities to prevent later neurobehavioral disorders.
Topics: Aldehyde Reductase; Animals; Autism Spectrum Disorder; Cerebellum; Endocrine Glands; Female; GABA Agonists; GABA Modulators; Gene Deletion; Humans; Infant; Infant, Newborn; Male; Mice; Muscimol; Placenta; Pregnancy; Pregnanolone; Receptors, GABA-A; Sex Characteristics; Social Behavior; Trophoblasts; White Matter
PubMed: 34400844
DOI: 10.1038/s41593-021-00896-4 -
Journal of Neuroendocrinology Feb 2022Allopregnanolone, a 3α,5α-progesterone metabolite, acts as a potent allosteric modulator of the γ-aminobutyric acid type A receptor. In the present review, the... (Review)
Review
Allopregnanolone, a 3α,5α-progesterone metabolite, acts as a potent allosteric modulator of the γ-aminobutyric acid type A receptor. In the present review, the synthesis of this neuroactive steroid occurring in the nervous system is discussed with respect to physiological and pathological conditions. In addition, its physiological and neuroprotective effects are also reported. Interestingly, the levels of this neuroactive steroid, as well as its effects, are sex-dimorphic, suggesting a possible gender medicine based on this neuroactive steroid for neurological disorders. However, allopregnanolone presents low bioavailability and extensive hepatic metabolism, limiting its use as a drug. Therefore, synthetic analogues or a different therapeutic strategy able to increase allopregnanolone levels have been proposed to overcome any pharmacokinetic issues.
Topics: Neurosteroids; Pregnanolone; Progesterone
PubMed: 34189791
DOI: 10.1111/jne.12996 -
Pharmacological Research Jul 2021The neuroactive steroid allopregnanolone (ALLO) is an endogenous positive allosteric modulator of GABA type A receptor (GABAR), and the down-regulation of its... (Review)
Review
The neuroactive steroid allopregnanolone (ALLO) is an endogenous positive allosteric modulator of GABA type A receptor (GABAR), and the down-regulation of its biosynthesis have been attributed to the development of mood disorders, such as depression, anxiety and post-traumatic stress disorder (PTSD). ALLO mediated depression/anxiety involves GABAergic mechanisms and appears to be related to brain-derived neurotrophic factor (BDNF), dopamine receptor, glutamate neurotransmission, and Ca channel. In the clinical, brexanolone, as a newly developed intravenous ALLO preparation, has been approved for the treatment of postpartum depression (PPD). In addition, traditional antidepressants such as selective serotonin reuptake inhibitor (SSRI) could reverse ALLO decline. Recently, the translocation protein (TSPO, 18 kDa), which involves in the speed-limiting step of ALLO synthesis, and ALLO derivatization have been identified as new directions for antidepressant therapy. This review provides an overview of ALLO researches in animal model and patients, discusses its role in the development and treatment of depression/anxiety, and directs its therapeutic potential in future.
Topics: Animals; Anti-Anxiety Agents; Antidepressive Agents; Anxiety; Depression; Humans; Mood Disorders; Pregnanolone; Receptors, GABA-A
PubMed: 34019980
DOI: 10.1016/j.phrs.2021.105682 -
Frontiers in Endocrinology 2022
Topics: Neurosteroids; Pregnanolone; Receptors, GABA-A
PubMed: 35966056
DOI: 10.3389/fendo.2022.951990