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Archives of Toxicology Apr 2024Recent experimental evidence suggests combined treatment with midazolam and allopregnanolone is more effective than midazolam alone in terminating seizures triggered by...
Cardiovascular responses of adult male Sprague-Dawley rats following acute organophosphate intoxication and post-exposure treatment with midazolam with or without allopregnanolone.
Recent experimental evidence suggests combined treatment with midazolam and allopregnanolone is more effective than midazolam alone in terminating seizures triggered by acute organophosphate (OP) intoxication. However, there are concerns that combined midazolam and allopregnanolone increases risk of adverse cardiovascular events. To address this, we used telemetry devices to record cardiovascular responses in adult male Sprague-Dawley rats acutely intoxicated with diisopropylfluorophosphate (DFP). Animals were administered DFP (4 mg/kg, sc), followed immediately by atropine (2 mg/kg, i.m.) and 2-PAM (25 mg/kg, i.m.). At 40 min post-exposure, a subset of animals received midazolam (0.65 mg/kg, im); at 50 min, these rats received a second dose of midazolam or allopregnanolone (12 mg/kg, im). DFP significantly increased blood pressure by ~ 80 mmHg and pulse pressure by ~ 34 mmHg that peaked within 12 min. DFP also increased core temperature by ~ 3.5 °C and heart rate by ~ 250 bpm that peaked at ~ 2 h. Heart rate variability (HRV), an index of autonomic function, was reduced by ~ 80%. All acute (within 15 min of exposure) and two-thirds of delayed (hours after exposure) mortalities were associated with non-ventricular cardiac events within 10 min of cardiovascular collapse, suggesting that non-ventricular events should be closely monitored in OP-poisoned patients. Compared to rats that survived DFP intoxication without treatment, midazolam significantly improved recovery of cardiovascular parameters and HRV, an effect enhanced by allopregnanolone. These data demonstrate that midazolam improved recovery of cardiovascular and autonomic function and that the combination of midazolam and allopregnanolone may be a better therapeutic strategy than midazolam alone.
Topics: Humans; Rats; Male; Animals; Rats, Sprague-Dawley; Midazolam; Pregnanolone; Isoflurophate; Organophosphates; Brain; Organophosphate Poisoning
PubMed: 38305864
DOI: 10.1007/s00204-023-03679-x -
Psychopharmacology May 2024Multiple psychiatric disorders are associated with altered brain and serum levels of neuroactive steroids, including the endogenous GABAergic steroid, allopregnanolone....
RATIONALE
Multiple psychiatric disorders are associated with altered brain and serum levels of neuroactive steroids, including the endogenous GABAergic steroid, allopregnanolone. Clinically, chronic cocaine use was correlated with decreased levels of pregnenolone. Preclinically, the effect of acute cocaine on allopregnanolone levels in rodents has had mixed results, showing an increase or no change in allopregnanolone levels in some brain regions.
OBJECTIVE
We hypothesized that cocaine acutely increases allopregnanolone levels, but repeated cocaine exposure decreases allopregnanolone levels compared to controls.
METHODS
We performed two separate studies to determine how systemic administration of 15 mg/kg cocaine (1) acutely or (2) chronically alters brain (olfactory bulb, frontal cortex, dorsal striatum, and midbrain) and serum allopregnanolone levels in adult male and female Sprague-Dawley rats.
RESULTS
Cocaine acutely increased allopregnanolone levels in the midbrain, but not in olfactory bulb, frontal cortex, or dorsal striatum. Repeated cocaine did not persistently (24 h later) alter allopregnanolone levels in any region in either sex. However, allopregnanolone levels varied by sex across brain regions. In the acute study, we found that females had significantly higher allopregnanolone levels in serum and olfactory bulb relative to males. In the repeated cocaine study, females had significantly higher allopregnanolone levels in olfactory bulb, frontal cortex, and serum. Finally, acute cocaine increased allopregnanolone levels in the frontal cortex of females in proestrus, relative to non-proestrus stages.
CONCLUSION
Collectively these results suggest that allopregnanolone levels vary across brain regions and by sex, which may play a part in differential responses to cocaine by sex.
Topics: Humans; Adult; Rats; Male; Female; Animals; Rats, Sprague-Dawley; Pregnanolone; Brain; Mesencephalon; Cocaine
PubMed: 38282126
DOI: 10.1007/s00213-024-06534-8 -
Journal of Anesthesia Apr 2024Neurosteroids (NS) are a class of steroids that are synthesized within the central nervous system (CNS). Various NS can either enhance or inhibit CNS excitability and... (Review)
Review
Neurosteroids (NS) are a class of steroids that are synthesized within the central nervous system (CNS). Various NS can either enhance or inhibit CNS excitability and they play important biological roles in brain development, brain function and as mediators of mood. One class of NS, 3α-hydroxy-pregnane steroids such as allopregnanolone (AlloP) or pregnanolone (Preg), inhibits neuronal excitability; these endogenous NS and their analogues have been therapeutically applied as anti-depressants, anti-epileptics and general anesthetics. While NS have many favorable properties as anesthetics (e.g. rapid onset, rapid recovery, minimal cardiorespiratory depression, neuroprotection), they are not currently in clinical use, largely due to problems with formulation. Recent advances in understanding NS mechanisms of action and improved formulations have rekindled interest in development of NS as sedatives and anesthetics. In this review, the synthesis of NS, and their mechanism of action will be reviewed with specific emphasis on their binding sites and actions on γ-aminobutyric acid type A (GABA) receptors. The potential advantages of NS analogues as sedative and anesthetic agents will be discussed.
Topics: Anesthetics, General; Neurosteroids; Anesthetics; Pregnanolone; gamma-Aminobutyric Acid; Receptors, GABA-A
PubMed: 38252143
DOI: 10.1007/s00540-023-03291-4 -
Neuroscience and Biobehavioral Reviews Mar 2024This mini-review presents emerging evidence that endogenous neurosteroids modulate both pro- and anti-inflammatory signaling by immune cells and brain cells that... (Review)
Review
This mini-review presents emerging evidence that endogenous neurosteroids modulate both pro- and anti-inflammatory signaling by immune cells and brain cells that contribute to depression, alcohol use disorders, and other inflammatory conditions. We first review the literature on pregnenolone and allopregnanolone inhibition of proinflammatory neuroimmune pathways in the periphery and the brain - effects that are independent of GABAergic mechanisms. We follow with evidence for neurosteroid enhancement of anti-inflammatory and protective pathways in brain and immune cells. These studies draw clinical relevance from a large body of evidence that pro-inflammatory immune signaling is dysregulated in many brain disorders and the fact that neurosteroids inhibit the same inflammatory pathways that are activated in depression, alcohol use disorders and other inflammatory conditions. Thus, we describe evidence that neurosteroid levels are decreased and neurosteroid supplementation has therapeutic efficacy in these neuropsychiatric conditions. We conclude with a perspective that endogenous regulation of immune balance between pro- and anti-inflammatory pathways by neurosteroid signaling is essential to prevent the onset of disease. Deficits in neurosteroids may unleash excessive pro-inflammatory activation which progresses in a feed-forward manner to disrupt brain networks that regulate stress, emotion and motivation. Neurosteroids can block various inflammatory pathways in mouse and human macrophages, rat brain and human blood and therefore provide new hope for treatment of intractable conditions that involve excessive inflammatory signaling.
Topics: Rats; Humans; Mice; Animals; Neurosteroids; Alcoholism; Brain; Pregnanolone; Anti-Inflammatory Agents
PubMed: 38244954
DOI: 10.1016/j.neubiorev.2024.105558 -
Seizure progression is slowed by enhancing neurosteroid availability in the brain of epileptic rats.Epilepsia Mar 2024Trilostane is a 3β-hydroxysteroid dehydrogenase/Δ isomerase inhibitor able to produce a manyfold increase in brain levels of various neurosteroids, including...
Trilostane is a 3β-hydroxysteroid dehydrogenase/Δ isomerase inhibitor able to produce a manyfold increase in brain levels of various neurosteroids, including allopregnanolone. We previously found that treatment with trilostane can slow down epileptogenesis in the kainic acid (KA) model of temporal lobe epilepsy. It is unknown whether trilostane may have a similar effect on the progression of epilepsy severity, as observed in KA-treated rats. Consequently, we investigated the effects of trilostane (50 mg/kg/day, 1 week) in epileptic rats, given 64 days after KA administration. Seizures were monitored by video-electrocorticographic recordings before and during the treatment with trilostane or vehicle (sesame oil), and neurosteroid levels were measured in serum and cerebral tissue using liquid chromatography-electrospray tandem mass spectrometry after treatment. Pregnenolone sulfate, pregnenolone, progesterone, 5α-dihydroprogesterone, and allopregnanolone peripheral levels were massively increased by trilostane. With the only exception of hippocampal pregnenolone sulfate, the other neurosteroids augmented in both the neocortex and hippocampus. Only pregnanolone levels were not upregulated by trilostane. As expected, a significant increase in the seizure occurrence was observed in rats receiving the vehicle, but not in the trilostane group. This suggests that the increased availability of neurosteroids produced a disease-modifying effect in the brain of epileptic rats.
Topics: Rats; Animals; Neurosteroids; Pregnanolone; Epilepsy; Brain; Seizures
PubMed: 38243753
DOI: 10.1111/epi.17887 -
Clinical Pharmacology in Drug... Mar 2024Ganaxolone, a neuroactive steroid anticonvulsant that modulates both synaptic and extrasynaptic γ-aminobutyric acid type A (GABA ) receptors, is in development for...
Ganaxolone, a neuroactive steroid anticonvulsant that modulates both synaptic and extrasynaptic γ-aminobutyric acid type A (GABA ) receptors, is in development for treatment of status epilepticus (SE) and rare epileptic disorders, and has been approved in the United States for treatment of seizures associated with cyclin-dependent kinase-like 5 deficiency disorder in patients ≥2 years old. This phase 1 study in 36 healthy volunteers evaluated the pharmacokinetics, pharmacodynamics, and safety of intravenous ganaxolone administered as a (i) single bolus, (ii) infusion, and (iii) bolus followed by continuous infusion. After a single bolus over 2 minutes (20 mg) or 5 minutes (10 or 30 mg), ganaxolone was detected in plasma with a median T of 5 minutes, whereas a 60-minute infusion (10 or 30 mg) or a bolus (6 mg over 5 minutes) followed by infusion (20 mg/h) for 4 hours achieved a median T of approximately 1 and 3 hours, respectively. C was dose and administration-time dependent, ranging from 73.8 ng/mL (10 mg over 5 minutes) to 1240 ng/mL (30 mg over 5 minutes). Bolus doses above 10 mg of ganaxolone markedly influenced the bispectral index score with a rapid decline; smaller changes occurred on the Modified Observer's Assessment of Alertness/Sedation scale and in quantitative electroencephalogram. Most adverse events were of mild severity, with 2 events of moderate severity; none were reported as serious. No effects on systemic hemodynamics or respiratory functions were reported. Overall, ganaxolone was generally well tolerated at the doses studied and demonstrated pharmacokinetic and pharmacodynamic properties suitable to treat SE.
Topics: Adult; Humans; Child, Preschool; Seizures; Administration, Intravenous; Anticonvulsants; Epileptic Syndromes; Receptors, GABA-A; Pregnanolone
PubMed: 38231434
DOI: 10.1002/cpdd.1365 -
Frontiers in Endocrinology 2023Allopregnanolone (Allo) is a neurosteroid with pleiotropic action in the brain that includes neurogenesis, oligogenesis, human and rodent neural stem cell regeneration,...
OBJECTIVE
Allopregnanolone (Allo) is a neurosteroid with pleiotropic action in the brain that includes neurogenesis, oligogenesis, human and rodent neural stem cell regeneration, increased glucose metabolism, mitochondrial respiration and biogenesis, improved cognitive function, and reduction of both inflammation and Alzheimer's disease (AD) pathology. Because the breadth of Allo-induced responses requires activation of multiple systems of biology in the absence of an Allo-specific nuclear receptor, analyses were conducted in both neurons and astrocytes to identify unifying systems and signaling pathways.
METHODS
Mechanisms of Allo action were investigated in embryonic hippocampal neurons and astrocytes cultured in an Aging Model (AM) media. Cellular morphology, mitochondrial function, and transcriptomics were investigated followed by mechanistic pathway analyses.
RESULTS
In hippocampal neurons, Allo significantly increased neurite outgrowth and synaptic protein expression, which were paralleled by upregulated synaptogenesis and long-term potentiation gene expression profiles. Mechanistically, Allo induced Ca/CREB signaling cascades. In parallel, Allo significantly increased maximal mitochondrial respiration, mitochondrial membrane potential, and Complex IV activity while reducing oxidative stress, which required both the GABA and L-type Ca channels. In astrocytes, Allo increased ATP generation, mitochondrial function and dynamics while reducing oxidative stress, inflammasome indicators, and apoptotic signaling. Mechanistically, Allo regulation of astrocytic mitochondrial function required both the GABA and L-type Ca channels. Furthermore, Allo activated NRF1-TFAM signaling and increased the DRP1/OPA1 protein ratio, which led to increased mitochondrial biogenesis and dynamics.
CONCLUSION
Collectively, the cellular, mitochondrial, transcriptional, and pharmacological profiles provide evidence in support of calcium signaling as a unifying mechanism for Allo pleiotropic actions in the brain.
Topics: Humans; Calcium Signaling; Astrocytes; Pregnanolone; Neurons; gamma-Aminobutyric Acid
PubMed: 38189047
DOI: 10.3389/fendo.2023.1286931 -
Frontiers in Neuroendocrinology Apr 2024Rates of alcohol use disorder (AUD) are increasing in men and women and there are high rates of concurrent posttraumatic stress disorder (PTSD) and AUD. AUD and PTSD... (Review)
Review
Rates of alcohol use disorder (AUD) are increasing in men and women and there are high rates of concurrent posttraumatic stress disorder (PTSD) and AUD. AUD and PTSD synergistically increase symptomatology and negatively affect treatment outcomes; however, there are very limited pharmacological treatments for PTSD/AUD. Neurosteroids have been implicated in the underlying neurobiological mechanisms of both PTSD and AUD and may be a target for treatment development. This review details the past ten years of research on pregnenolone, progesterone, allopregnanolone, pregnanolone, estradiol, testosterone and dehydroepiandrosterone/dehydroepiandrosterone-sulfate (DHEA/DHEA-S) in the context of PTSD and AUD, including examination of trauma/alcohol-related variables, such as stress-reactivity. Emerging evidence that exogenous pregnenolone, progesterone, and allopregnanolone may be promising, novel interventions is also discussed. Specific emphasis is placed on examining the application of sex as a biological variable in this body of literature, given that women are more susceptible to both PTSD diagnoses and stress-related alcohol consumption.
Topics: Humans; Stress Disorders, Post-Traumatic; Neurosteroids; Alcoholism; Animals; Female; Male
PubMed: 38184208
DOI: 10.1016/j.yfrne.2023.101119 -
Frontiers in Endocrinology 2023Previous studies demonstrated the inhibitory effect of allopregnanolone (3α,5α-THP) on the activation of inflammatory toll-like receptor 4 (TLR4) signals in RAW264.7...
BACKGROUND
Previous studies demonstrated the inhibitory effect of allopregnanolone (3α,5α-THP) on the activation of inflammatory toll-like receptor 4 (TLR4) signals in RAW264.7 macrophages and the brains of selectively bred alcohol-preferring (P) rats. In the current study, we investigated the impact of 3α,5α-THP on the levels of IL-10 and activation of the TRIF-dependent endosomal TLR4 pathway.
METHODS
The amygdala and nucleus accumbens (NAc) of P rats, which exhibit innately activated TLR4 pathways as well as RAW264.7 cells, were used. Enzyme-linked immunosorbent assays (ELISA) and immunoblotting assays were used to ascertain the effects of 3α,5α-THP on the TRIF-dependent endosomal TLR4 pathway and endosomes were isolated to examine translocation of TLR4 and TRIF. Additionally, we investigated the effects of 3α,5α-THP and 3α,5α-THDOC (0.1, 0.3, and 1.0 µM) on the levels of IL-10 in RAW264.7 macrophages. Finally, we examined whether inhibiting TRIF (using TRIF siRNA) in RAW264.7 cells altered the levels of IL-10.
RESULTS
3α,5α-THP administration facilitated activation of the endosomal TRIF-dependent TLR4 pathway in males, but not female P rats. 3α,5α-THP increased IL-10 levels (+13.2 ± 6.5%) and BDNF levels (+21.1 ± 11.5%) in the male amygdala. These effects were associated with increases in pTRAM (+86.4 ± 28.4%), SP1 (+122.2 ± 74.9%), and PI(3)K-p110δ (+61.6 ± 21.6%), and a reduction of TIRAP (-13.7 ± 6.0%), indicating the activation of the endosomal TRIF-dependent TLR4 signaling pathway. Comparable effects were observed in NAc of these animals. Furthermore, 3α,5α-THP enhanced the accumulation of TLR4 (+43.9 ± 11.3%) and TRIF (+64.8 ± 32.8%) in endosomes, with no significant effect on TLR3 accumulation. Additionally, 3α,5α-THP facilitated the transition from early endosomes to late endosomes (increasing Rab7 levels: +35.8 ± 18.4%). In RAW264.7 cells, imiquimod (30 µg/mL) reduced IL-10 while 3α,5α-THP and 3α,5α-THDOC (0.1, 0.3, and 1.0 µM) restored IL-10 levels. To determine the role of the TRIF-dependent TLR4 signaling pathway in IL-10 production, the downregulation of TRIF (-62.9 ± 28.2%) in RAW264.7 cells led to a reduction in IL-10 levels (-42.3 ± 8.4%). TRIF (-62.9 ± 28.2%) in RAW264.7 cells led to a reduction in IL-10 levels (-42.3 ± 8.4%) and 3α,5α-THP (1.0 µM) no longer restored the reduced IL-10 levels.
CONCLUSION
The results demonstrate 3α,5α-THP enhancement of the endosomal TLR4-TRIF anti-inflammatory signals and elevations of IL-10 in male P rat brain that were not detected in female P rat brain. These effects hold significant implications for controlling inflammatory responses in both the brain and peripheral immune cells.
Topics: Animals; Female; Male; Rats; Adaptor Proteins, Vesicular Transport; Endosomes; Interleukin-10; Neurosteroids; Pregnanolone; Signal Transduction; Toll-Like Receptor 4; RAW 264.7 Cells; Mice
PubMed: 38179300
DOI: 10.3389/fendo.2023.1299420 -
Expert Opinion on Pharmacotherapy 2024Major depressive disorder (MDD) is a common and debilitating mental illness. Postpartum depression (PPD) impacts women globally and is one of the most common... (Review)
Review
INTRODUCTION
Major depressive disorder (MDD) is a common and debilitating mental illness. Postpartum depression (PPD) impacts women globally and is one of the most common complications of childbirth that is underdiagnosed and undertreated, adversely impacting the mental health of women, children, and partners.Available antidepressant medications require weeks to months before showing effect. In this setting, zuranolone, an oral neuroactive steroid and a positive allosteric modulator of GABA receptors, is an attractive alternative as a rapid-acting antidepressant treatment.
AREAS COVERED
This article reviews zuranolone (SAGE217), focusing on available clinical studies in individuals with PPD and MDD. This paper adds to the extant literature by presenting the efficacy data as Number Needed to Treat (NNT) to facilitate indirect comparisons with other antidepressants.
EXPERT OPINION
Zuranolone is a novel rapid-acting (i.e. two week course) oral antidepressant for the treatment of adults with PPD with ongoing clinical trials evaluating its efficacy in adults with MDD. Zuranolone is well tolerated with no significant safety concerns in any clinical trials completed to date. Zuranolone will be scheduled by the Drug Enforcement Agency (DEA).
Topics: Adult; Child; Female; Humans; Depressive Disorder, Major; Depression, Postpartum; Antidepressive Agents; Pregnanolone; Pyrazoles
PubMed: 38164653
DOI: 10.1080/14656566.2023.2298340