allopregnanolone (LJPC-0712) / Innoviva - LARVOL DELTA

[VIRTUAL] Perceptions and Efficacy of Brexanolone for the Treatment of Postpartum Depression: A Mixed Methods Analysis (CPNP 2021) - "BRX is an aqueous form of the steroid allopregnanolone and is thought to improve depressive symptoms after childbirth by modulating neuronal excitability through positive allosteric modulation of the GABA type-A receptor. Outcomes: Through semi-structured interviews, we hope to generate rich qualitative data that informs the design of a quantitative instrument to further assess intention to utilize BRX for the treatment of PPD. The primary outcome measure for our retrospective review will be a change in the Edinburgh Postnatal Depression Scale (EDPS) before, during, and after infusion with BRX."

Clinical • CNS Disorders • Depression • Mental Retardation • Mood Disorders • Obstetrics • Postpartum Depression • Psychiatry

PCDH19-Related Epilepsy Syndrome: A Comprehensive Clinical Review. (PubMed, Pediatr Neurol) - "The recent discovery of allopregnanolone deficiency in patients with PCDH19-related epilepsy leads to opportunities in precision therapy. A phase 3 clinical study is currently active to evaluate the efficacy, safety, and tolerability of adjunctive ganaxolone (an allopregnanolone analog) therapy."

Clinical • Journal • Review • Alzheimer's Disease • Autism Spectrum Disorder • CNS Disorders • Cognitive Disorders • Epilepsy • Genetic Disorders • Psychiatry • PCDH

A Potential Mechanism Underlying the Therapeutic Effects of Progesterone and Allopregnanolone on Ketamine-Induced Cognitive Deficits. (PubMed, Front Pharmacol) - "Interestingly, ALLO (16 mg kg) significantly increased the levels of PROG. These findings suggest that PROG can exert its neuroprotective effects via activating the PGRMC1/EGFR/GLP-1R/PI3K/Akt pathway in the brain, whereas ALLO also restores cognitive deficits partially via increasing the level of PROG in the brain to activate the PGRMC1 pathway."

Journal • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia • PCR

Prenatal exposure to bisphenols and phthalates and postpartum depression: The role of neurosteroid hormone disruption. (PubMed, J Clin Endocrinol Metab) - "Endocrine disrupting chemicals may influence hormonal shifts during pregnancy as well as contribute to PPD."

Journal • CNS Disorders • Depression • Mental Retardation • Mood Disorders • Postpartum Depression • Psychiatry

[VIRTUAL] Effects of Maternal Sucrose Consumption on Inflammation and Steroids in the Placenta and Fetal Brain (ENDO 2021) - "Next, we use a liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay, which is highly precise and specific, to measure multiple steroids (e.g. corticosterone, progesterone, estradiol, allopregnanolone)...For oral presentations, the abstracts are embargoed until the session begins. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO 2021."

Immunology • Inflammation

S2k guidelines: status epilepticus in adulthood : Guidelines of the German Society for Neurology (PubMed, Nervenarzt) - "As the increasing evidence supports the relevance of inflammatory comorbidities (e.g. pneumonia) related clinical chemistry should be obtained and repeated over the course of a SE treatment, and antibiotic therapy initiated if indicated.Treatment is applied on four levels: 1. Initial SE: An adequate dose of benzodiazepine is given i.v., i.m., or i.n.; 2. Benzodiazepine-refractory SE: I.v. drugs of 1st choice are levetiracetam or valproate; 3. Refractory SE (RSE) or 4. Super-refractory SE (SRSE): I.v. propofol or midazolam alone or in combination or thiopental in anaesthetic doses are given...ketamine or inhalative isoflorane can be considered...I.v. allopregnanolone or systemic hypothermia should not be used."

Clinical • Journal • Review • Anesthesia • CNS Disorders • Epilepsy • Infectious Disease • Pneumonia • Respiratory Diseases • MRI

Ganaxolone treatment for epilepsy patients: from pharmacology to place in therapy. (PubMed, Expert Rev Neurother) - "Ganaxolone (GNX) is a synthetic analog of the endogenous neurosteroid allopregnanolone and a member of a novel class of neuroactive steroids called epalons. The availability of oral and intravenous formulations allows reaching adult and pediatric patients in acute and chronic care settings. Further evidence will complement the understanding of the potentialities of GNX and possibly lead to indications for use in clinical practice."

Clinical • Journal • CNS Disorders • Epilepsy • Pediatrics

"And neurosteroid? E.g. fascinating stuff on allopregnanolone in post natal depression, PTSD https://t.co/nLd8qFF1WE" (@dr_kevinlee)

CNS Disorders • Depression • Postpartum Depression • Post-traumatic Stress Disorder • Psychiatry

Mechanisms for establishment of GABA signaling in adrenal medullary chromaffin cells. (PubMed, J Neurochem) - "GABA receptor Cl channel activity in mouse AMC cells was enhanced by allopregnanolone, as noted with that in guinea-pig AMC cells, and the enzymes involved in allopregnanolone production were immunohistochemically detected in the zona fasciculata in both mice and guinea pigs...Stimulation of pituitary adenylate cyclase activating polypeptide (PACAP) receptors, but not nicotinic or muscarinic receptors, in PC12 cells resulted in an increase in GAD67 expression in a protein-kinase A-dependent manner. The results indicate that glucocorticoid and PACAP are mainly responsible for the expressions of GABA receptors and GAD67 involved in GABA signaling in AMC cells, respectively."

Journal • Endocrine Cancer • Neuroendocrine Tumor • Oncology • Solid Tumor • ADCYAP1

Evaluating Brexanolone for the Treatment of Postpartum Depression. (PubMed, Expert Opin Pharmacother) - "Brexanolone is a novel, soluble synthetic formulation of the natural hormone allopregnanolone and acts as a positive allosteric modulator of the gamma-aminobutryric acid A receptor (GABAA). It is appropriate for use in women with moderate to severe PPD. Experience with the medication and further research is needed to clarify whether the current recommended dosing regimen is required for efficacy."

Journal • CNS Disorders • Depression • Mood Disorders • Postpartum Depression • Psychiatry

Neurosteroid allopregnanolone (3α,5α-THP) inhibits inflammatory signals induced by activated MyD88-dependent toll-like receptors. (PubMed, Transl Psychiatry) - "Collectively, the data indicate that 3α,5α-THP inhibits MyD88- but not TRIF-dependent TLR signal activation and the production of pro-inflammatory mediators through its ability to block TLR-MyD88 binding. These results have applicability to many conditions involving pro-inflammatory TLR activation of cytokines, chemokines, and interferons and support the use of 3α,5α-THP as a therapeutic for inflammatory disease."

Journal • Addiction (Opioid and Alcohol) • Inflammation • MYD88

[VIRTUAL] A RANDOMIZED DOUBLE BLIND MULTIPLE ASCENDING DOSE PHASE 1B/2A CLINICAL TRIAL OF ALLOPREGNANOLONE AS A REGENERATIVE THERAPEUTIC FOR ALZHEIMERʼS DISEASE (ADPD 2021) - P1 | "Exploratory imaging analyses were indicative of responders and non-responders on outcomes relevant to regeneration.  Conclusions Allopregnanolone was well-tolerated and safe across all doses in this cohort. Safety, MTD and PK profiles support advancement to a phase 2 efficacy trial."

Clinical • P1/2 data • Alzheimer's Disease • Anesthesia • CNS Disorders • Fatigue • MRI

Steroid Hormone Sensitivity in Reproductive Mood Disorders: On the Role of the GABA Receptor Complex and Stress During Hormonal Transitions. (PubMed, Front Med (Lausanne)) - "We integrate both dynamics into the concept of "steroid hormone sensitivity," expanding on the concept of "reproductive hormone sensitivity." We suggest that a differential response of the stress steroid system including corticosteroids, neurosteroids, like allopregnanolone and the GABA-A Receptor complex, as well as a differential (epi)genetic risk in serotonergic and GABAergic signaling, are moderators or mediators between changes in the reproductive steroid system and the physiological, affective, and cognitive outcomes manifesting in reproductive mood disorders...This could pave the way for new research as well as medical and psychological teaching and practice- such as a new type of Practice for Gynecological Psychoneuroendocrinology- with the aim of working on and ultimately offering more integrative forms of support not yet available to women suffering from depression during hormonal transitions. In medical history women have been left alone..."

Journal • Review • CNS Disorders • Depression • Mood Disorders • Psychiatry

Relationship between Delta Rhythm, Seizure Occurrence and Allopregnanolone Hippocampal Levels in Epileptic Rats Exposed to the Rebound Effect. (PubMed, Pharmaceuticals (Basel)) - "By stopping treatment with levetiracetam (LEV 300 mg/kg/day, n = 15; vs. saline, n = 15), we investigated the rebound effect in adult male Sprague-Dawley rats. Notably, allopregnanolone hippocampal levels were positively related to the seizure occurrence (r = 0.51, p = 0.02) and to the power of delta band (r = 0.67, p = 0.004). These findings suggest a role for the seizure postictal component in the rebound effect, which involves an imbalance of hippocampal neurosteroid levels."

Journal • CNS Disorders • Epilepsy

Allopregnanolone Decreases Evoked Dopamine Release Differently in Rats by Sex and Estrous Stage. (PubMed, Front Pharmacol) - "Since allopregnanolone is derived from progesterone, we hypothesized that high endogenous progesterone levels would result in lower sensitivity to allopregnanolone. Moreover, sex and the estrous cycle modulated this effect of allopregnanolone. These results extend our knowledge about the pharmacological effects of neurosteroids on dopamine transmission, which may contribute to their therapeutic effects."

Journal • Anesthesia • CNS Disorders • Mental Retardation • Psychiatry

Progesterone does raise disgust. (PubMed, Horm Behav) - "Manipulating progesterone directly, a recent, crucial study on female mice's disgust for infected males came up empty handed. Here, reanalyzing these data in a more statistically sensitive manner, we show that progesterone not only raises disgust but does so in a way that is both significant and substantial."

Journal • CNS Disorders • Depression • Psychiatry

Neurosteroids and Neurotrophic Factors: What Is Their Promise as Biomarkers for Major Depression and PTSD? (PubMed, Int J Mol Sci) - "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 biomarker axis for the diagnosis of both MDD and PTSD."

Biomarker • Journal • Review • CNS Disorders • Depression • Major Depressive Disorder • Mental Retardation • Mood Disorders • Post-traumatic Stress Disorder • Psychiatry • BDNF

Ethanol, Neurosteroids and Cellular Stress Responses: Impact on Central Nervous System Toxicity, Inflammation and Autophagy. (PubMed, Neurosci Biobehav Rev) - "In the brain ethanol can be detrimental to memory formation, through inducing the integrated stress response/endoplasmic reticulum stress/unfolded protein response and the molecular mechanisms linking stress to other events such as NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammation and autophagy. This literature review aims to provide an overview of our current understanding of the molecular mechanisms involved in ethanol-induced damage with endoplasmic reticulum stress, integrated stress response, NLRP3 inflammation and autophagy, while discussing the impact of neurosteroids and oxysterols, including allopregnanolone, 25-hydroxycholesterol and 24S-hydroxycholesterol, on the central nervous system."

Journal • Review • Immunology • Inflammation

Does Stress Trigger Seizures? Evidence from Experimental Models. (PubMed, Curr Top Behav Neurosci) - "Neurosteroids such as allopregnanolone and THDOC, which are allosteric modulators of GABA-A receptors, are powerful anticonvulsants and neuroprotectants...Thus, exogenous administration of neurosteroids (neurosteroid replacement therapy) may offer neuroprotection in epilepsy. Synthetic neurosteroid could offer a rational approach to control neurosteroid-sensitive, stress-related epileptic seizures."

Journal • CNS Disorders • Vascular Neurology

Neurochemical Effects of 4-(2Chloro-4-Fluorobenzyl)-3-(2-Thienyl)-1,2,4-Oxadiazol-5(4H)-One in the Pentylenetetrazole (PTZ)-Induced Epileptic Seizure Zebrafish Model. (PubMed, Int J Mol Sci) - "GM-90432 effectively improved PTZ-induced epileptic behaviors via upregulation of 5-hydroxytryptamine, 17-β-estradiol, dihydrotestosterone, progesterone, 5α -dihydroprogesterone, and allopregnanolone levels, and downregulation of normetanephrine, gamma-aminobutyric acid, and cortisol levels in brain tissue. GM-90432 also had a protective effect against PTZ-induced oxidative stress and zebrafish death, suggesting that it exhibits biphasic neuroprotective effects via scavenging of reactive oxygen species and anti-epileptic activities in a zebrafish model. In conclusion, our results suggest that neurochemical profiling study could be used to better understand of anti-epileptic mechanism of GM-90432, potentially leading to new drug discovery and development of anti-seizure agents."

Journal • CNS Disorders • Epilepsy

Structure-Activity Relationship of Neuroactive Steroids, Midazolam, and Perampanel towards Mitigating Tetramine-Triggered Activity in Murine Hippocampal Neuronal Networks. (PubMed, Toxicol Sci) - "The neuroactive steroid (NAS) allopregnanolone (ALLO; 0.1-3.0 µM) normalized TETS-triggered patterns by selectively suppressing HASE and increasing LASE, a pharmacological pattern distinct from its epimeric form eltanolone, ganaxolone, alphaxolone and XJ-42, which significantly potentiated TETS-triggered HASE in a biphasic manner. Cortisol failed to mitigate TETS-triggered patterns and at > 1 µM augmented them. Combinations of ALLO and MDZ were significantly more effective at normalizing TETS-triggered SCO patterns, ESA patterns, and more potently enhanced GABA-activated Cl- current, than either drug alone."

Journal • Preclinical • CNS Disorders • Epilepsy

Progesterone's Effects on Cognitive Performance of Male Mice Are Independent of Progestin Receptors but Relate to Increases in GABA Activity in the Hippocampus and Cortex. (PubMed, Front Endocrinol (Lausanne)) - "Progestogens' (e.g., progesterone and its neuroactive metabolite, allopregnanolone), cognitive effects and mechanisms among males are not well-understood. Wild-type as well as PRKO mice administered progesterone experienced significant increases in maximal GABA agonist, muscimol, binding in hippocampus and cortex, compared to their vehicle-administered counterparts. Thus, adult male mice can be responsive to progesterone for cognitive performance, and such effects may be independent of PRs trophic actions of BDNF levels in the hippocampus and/or increases in GABA activity in the hippocampus and cortex."

Journal • BDNF

Efficient expression of concatenated α1β2δ and α1β3δ GABA receptors, their pharmacology and stoichiometry. (PubMed, Br J Pharmacol) - "Our data answers important outstanding questions regarding the pharmacology and stoichiometry of α1δ-containing GABA receptors and pave the way for future analysis and drug-discovery efforts."

Journal

A Study of Brexanolone for Acute Respiratory Distress Syndrome Due to COVID-19 (clinicaltrials.gov) - P3; N=100; Recruiting; Sponsor: Sage Therapeutics; Not yet recruiting ➔ Recruiting

Enrollment open • Acute Respiratory Distress Syndrome • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • PCR

Intranasal Allopregnanolone Confers Rapid Seizure Protection: Evidence for Direct Nose-to-Brain Delivery. (PubMed, Neurotherapeutics) - "At an allopregnanolone dose (16 mg/kg) that conferred comparable effects on seizure threshold as the benzodiazepines midazolam and diazepam (both at doses of 1 mg/kg), allopregnanolone caused minimal sedation or motor toxicity in the horizontal screen test whereas both benzodiazepines produced marked behavioral impairment. This is the first study demonstrating rapid functional central nervous system activity of a nose-to-brain-delivered steroid. Intranasal delivery circumvents the poor oral bioavailability of allopregnanolone providing a route of administration permitting its evaluation as a treatment for diverse neuropsychiatric indications."

Journal • Anesthesia • CNS Disorders • Epilepsy • Psychiatry