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  1. Article ; Online: Emerging evidence for endogenous neurosteroid modulation of pro-inflammatory and anti-inflammatory pathways that impact neuropsychiatric disease.

    Morrow, A Leslie / Boero, Giorgia / Balan, Irina

    Neuroscience and biobehavioral reviews

    2024  Volume 158, Page(s) 105558

    Abstract: 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 ...

    Abstract 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.
    MeSH term(s) Rats ; Humans ; Mice ; Animals ; Neurosteroids/metabolism ; Alcoholism/metabolism ; Brain/metabolism ; Pregnanolone/pharmacology ; Pregnanolone/metabolism ; Anti-Inflammatory Agents/pharmacology ; Anti-Inflammatory Agents/therapeutic use
    Chemical Substances Neurosteroids ; Pregnanolone (BXO86P3XXW) ; Anti-Inflammatory Agents
    Language English
    Publishing date 2024-01-19
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 282464-4
    ISSN 1873-7528 ; 0149-7634
    ISSN (online) 1873-7528
    ISSN 0149-7634
    DOI 10.1016/j.neubiorev.2024.105558
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  2. Article ; Online: Neuroimmune signaling in neuropsychiatric disease.

    Morrow, A Leslie / Price, Lawrence H

    Psychopharmacology

    2019  Volume 236, Issue 10, Page(s) 2855

    Language English
    Publishing date 2019-10-21
    Publishing country Germany
    Document type Editorial
    ZDB-ID 130601-7
    ISSN 1432-2072 ; 0033-3158
    ISSN (online) 1432-2072
    ISSN 0033-3158
    DOI 10.1007/s00213-019-05355-4
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  3. Article ; Online: Novel neurosteroid therapeutics for post-partum depression: perspectives on clinical trials, program development, active research, and future directions.

    Patterson, Riah / Balan, Irina / Morrow, A Leslie / Meltzer-Brody, Samantha

    Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

    2023  Volume 49, Issue 1, Page(s) 67–72

    Abstract: This article reviews novel neurosteroid therapeutics for post-partum depression, with a focus on their development, clinical trial data, current practices, and future directions in this exciting field. We discuss the clinical impact of brexanolone and ... ...

    Abstract This article reviews novel neurosteroid therapeutics for post-partum depression, with a focus on their development, clinical trial data, current practices, and future directions in this exciting field. We discuss the clinical impact of brexanolone and several other neurosteroids, particularly as they relate to the treatment of postpartum depression (PPD) and major depressive disorders outside of the perinatal period. There has been increasing interest in GABA signaling and modulation as it pertains to the development of altered circuity and depressive states. This scientific underpinning served as the rationale for the initial development of brexanolone. We review the clinical trials supporting its Food and Drug Administration (FDA) approval as the first rapidly acting antidepressant specific for PPD, and the subsequent development of a clinical brexanolone program at an academic medical center, highlighting new research and data from that site as well as the challenges with the delivery of this I.V. drug. In addition to the GABA signaling hypothesis, we discuss the new evidence demonstrating that brexanolone inhibits inflammatory signaling post-infusion, suggesting that inflammatory signaling may contribute to the etiology of PPD. Finally, we describe new and future directions in neurosteroid therapeutics, including the development of an oral agent, zuranolone, and the IV and oral formulations of ganaxolone. Ultimately, the hope is that these novel neurosteroid therapeutics will provide fast-acting treatment for these impairing disorders and improve our understanding of the underlying mechanisms of depressive disorders.
    MeSH term(s) Pregnancy ; Female ; Humans ; Depression, Postpartum/drug therapy ; Neurosteroids/therapeutic use ; Depressive Disorder, Major/drug therapy ; Program Development ; gamma-Aminobutyric Acid/therapeutic use
    Chemical Substances Neurosteroids ; gamma-Aminobutyric Acid (56-12-2)
    Language English
    Publishing date 2023-09-15
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 639471-1
    ISSN 1740-634X ; 0893-133X
    ISSN (online) 1740-634X
    ISSN 0893-133X
    DOI 10.1038/s41386-023-01721-1
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  4. Article: Neurosteroid [3α,5α]-3-hydroxy-pregnan-20-one enhances IL-10 production via endosomal TRIF-dependent TLR4 signaling pathway.

    Balan, Irina / Grusca, Adelina / O'Buckley, Todd K / Morrow, A Leslie

    Frontiers in endocrinology

    2023  Volume 14, Page(s) 1299420

    Abstract: 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. ...

    Abstract 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.
    MeSH term(s) Animals ; Female ; Male ; Rats ; Adaptor Proteins, Vesicular Transport ; Endosomes/metabolism ; Interleukin-10 ; Neurosteroids ; Pregnanolone ; Signal Transduction ; Toll-Like Receptor 4/metabolism ; RAW 264.7 Cells ; Mice
    Chemical Substances Adaptor Proteins, Vesicular Transport ; Interleukin-10 (130068-27-8) ; Neurosteroids ; Pregnanolone (BXO86P3XXW) ; Toll-Like Receptor 4
    Language English
    Publishing date 2023-12-21
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2592084-4
    ISSN 1664-2392
    ISSN 1664-2392
    DOI 10.3389/fendo.2023.1299420
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  5. Article ; Online: Mechanisms Underlying Recovery From Postpartum Depression Following Brexanolone Therapy.

    Morrow, A Leslie / Balan, Irina / Boero, Giorgia

    Biological psychiatry

    2021  Volume 91, Issue 3, Page(s) 252–253

    MeSH term(s) Depression, Postpartum/drug therapy ; Drug Combinations ; Female ; Humans ; Pregnanolone ; beta-Cyclodextrins
    Chemical Substances Drug Combinations ; beta-Cyclodextrins ; brexanolone ; Pregnanolone (BXO86P3XXW)
    Language English
    Publishing date 2021-12-26
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Comment
    ZDB-ID 209434-4
    ISSN 1873-2402 ; 0006-3223
    ISSN (online) 1873-2402
    ISSN 0006-3223
    DOI 10.1016/j.biopsych.2021.11.006
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    Zs.A 720: Show issues Location:
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  6. Article ; Online: Divergent Population-Specific Effects of Chronic Ethanol Exposure on Excitability and Inhibitory Transmission in Male and Female Rat Central Amygdala.

    Crofton, Elizabeth J / O'Buckley, Todd K / Bohnsack, John P / Morrow, A Leslie / Herman, Melissa A

    The Journal of neuroscience : the official journal of the Society for Neuroscience

    2023  Volume 43, Issue 42, Page(s) 7056–7068

    Abstract: The central nucleus of the amygdala (CeA) is implicated in alcohol use disorder (AUD) and AUD-associated plasticity. The CeA is a primarily GABAergic nucleus that is subdivided into lateral and medial compartments with genetically diverse subpopulations. ...

    Abstract The central nucleus of the amygdala (CeA) is implicated in alcohol use disorder (AUD) and AUD-associated plasticity. The CeA is a primarily GABAergic nucleus that is subdivided into lateral and medial compartments with genetically diverse subpopulations. GABA
    MeSH term(s) Rats ; Female ; Male ; Animals ; Ethanol/pharmacology ; Central Amygdaloid Nucleus/metabolism ; Alcoholism/metabolism ; Receptors, GABA-A/metabolism ; Synaptic Transmission/physiology ; Somatostatin/metabolism
    Chemical Substances Ethanol (3K9958V90M) ; Receptors, GABA-A ; Somatostatin (51110-01-1)
    Language English
    Publishing date 2023-09-01
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 604637-x
    ISSN 1529-2401 ; 0270-6474
    ISSN (online) 1529-2401
    ISSN 0270-6474
    DOI 10.1523/JNEUROSCI.0717-23.2023
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  7. Article ; Online: GABAergic neuroactive steroid response to sertraline in premenstrual dysphoric disorder.

    Miller, Kristen N / Standeven, Lindsay / Morrow, A Leslie / Payne, Jennifer L / Epperson, C Neill / Hantsoo, Liisa

    Psychoneuroendocrinology

    2023  Volume 160, Page(s) 106684

    Abstract: Rationale: Premenstrual dysphoric disorder (PMDD) affects approximately 5% of menstruating individuals, with significant negative mood symptoms in the luteal phase of the menstrual cycle. PMDD's pathophysiology and treatment mechanisms are poorly ... ...

    Abstract Rationale: Premenstrual dysphoric disorder (PMDD) affects approximately 5% of menstruating individuals, with significant negative mood symptoms in the luteal phase of the menstrual cycle. PMDD's pathophysiology and treatment mechanisms are poorly characterized, but may involve altered neuroactive steroid function in the brain. Selective serotonin reuptake inhibitors (SSRIs), a first-line PMDD treatment, reportedly alter gamma-aminobutyric acid (GABA)ergic neuroactive steroid levels in PMDD.
    Aims: The aims of this study were to determine whether the SSRI sertraline increased serum levels of neuroactive steroids that modulate the effect of GABA at GABA-A receptors (GABAAR) and if so, whether an increase was associated with improvement in PMDD symptoms.
    Methods: Participants included controls and individuals with PMDD. Serum levels of 9 neuroactive steroids were measured (3α,5α-THP; 3α5β-THP; pregnenolone; 3α,5α-androsterone; 3α,5β-androsterone; 3α,5α-A-diol; 3α5β-A-diol; 3α,5α-THDOC; 3α5β-THDOC) in the follicular and luteal phases. In the subsequent luteal phase, neuroactive steroids were measured during sertraline treatment (50 mg sertraline from approximate ovulation to menses onset) in the PMDD group. Mixed models assessed associations among diagnostic group, menstrual cycle phase, and sertraline treatment.
    Results: Participants included 38 controls and 32 women with PMDD. There were no significant differences in neuroactive steroid levels between controls and participants with PMDD in the luteal phase (p > 0.05). Within the PMDD group, sertraline treatment significantly increased serum pregnanolone levels and the pregnanolone:progesterone ratio, and decreased 3α,5α-androsterone.
    Conclusions: This was the first study to assess the impact of SSRI treatment on peripheral levels of GABAergic neuroactive steroids in PMDD. Within the PMDD group, sertraline treatment was associated with a significant increase in luteal phase serum pregnanolone levels and a significantly increased pregnanolone:progesterone ratio, a novel finding. Future research should examine alterations in the metabolic pathways among GABAergic neuroactive steroids in individuals with PMDD, in a placebo-controlled design.
    MeSH term(s) Humans ; Female ; Premenstrual Dysphoric Disorder/drug therapy ; Neurosteroids ; Sertraline/pharmacology ; Sertraline/therapeutic use ; Progesterone ; Pregnanolone ; Androsterone ; gamma-Aminobutyric Acid ; Premenstrual Syndrome/drug therapy
    Chemical Substances Neurosteroids ; Sertraline (QUC7NX6WMB) ; Progesterone (4G7DS2Q64Y) ; Pregnanolone (BXO86P3XXW) ; Androsterone (C24W7J5D5R) ; gamma-Aminobutyric Acid (56-12-2)
    Language English
    Publishing date 2023-11-30
    Publishing country England
    Document type Journal Article
    ZDB-ID 197636-9
    ISSN 1873-3360 ; 0306-4530
    ISSN (online) 1873-3360
    ISSN 0306-4530
    DOI 10.1016/j.psyneuen.2023.106684
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    Zs.A 1235: Show issues Location:
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  8. Article ; Online: Special issue in memory of Robert H. Purdy.

    Morrow, A Leslie

    Psychopharmacology

    2014  Volume 231, Issue 17, Page(s) 3241–3242

    MeSH term(s) Animals ; History, 20th Century ; History, 21st Century ; Humans ; Neurotransmitter Agents/chemistry ; Neurotransmitter Agents/immunology ; Psychopharmacology/history
    Chemical Substances Neurotransmitter Agents
    Language English
    Publishing date 2014-04-22
    Publishing country Germany
    Document type Biography ; Editorial ; Historical Article ; Portrait
    ZDB-ID 130601-7
    ISSN 1432-2072 ; 0033-3158
    ISSN (online) 1432-2072
    ISSN 0033-3158
    DOI 10.1007/s00213-014-3585-3
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  9. Article ; Online: Pharmacological administration of 3α,5α-THP into the nucleus accumbens core increases 3α,5α-THP expression and reduces alcohol self-administration.

    Ornelas, Laura C / Boero, Giorgia / Van Voorhies, Kalynn / O'Buckley, Todd K / Besheer, Joyce / Morrow, A Leslie

    Alcohol, clinical & experimental research

    2023  Volume 47, Issue 3, Page(s) 459–469

    Abstract: Background: Alcohol affects multiple circuits in the brain, mainly disrupting the delicate balance between inhibitory γ-aminobutyric acid (GABA) transmission and excitatory glutamate signaling in brain areas involved in reward circuits. These include ... ...

    Abstract Background: Alcohol affects multiple circuits in the brain, mainly disrupting the delicate balance between inhibitory γ-aminobutyric acid (GABA) transmission and excitatory glutamate signaling in brain areas involved in reward circuits. These include the amygdala, nucleus accumbens (Acb), and ventral tegmental area (VTA). This action impairs circuits that regulate behavioral control of craving and alcohol seeking and intake. Studies in both rodent models and postmortem human brain of patients with alcohol use disorder (AUD) have highlighted the association between the loss of GABAergic inhibition and the development of addiction. The neurosteroid (3α,5α)-3-hydroxypregnan-20-one (3α,5α-THP) is a potent positive modulator of GABA
    Methods: In this study, we investigated the ability of 3α,5α-THP direct infusions in two brain regions that contribute to alcohol reinforcement, the VTA and Acb core (AcbC), to regulate alcohol self-administration in female P-rats.
    Results: Administration of 3α,5α-THP into the AcbC increased 3α,5α-THP-positive cell expression in this area and reduced alcohol self-administration. By contrast, 3α,5α-THP infusion into the VTA did not significantly affect alcohol self-administration, though trends for a reduction were found.
    Conclusions: Our results show that local increases in 3α,5α-THP in the AcbC may alter mesolimbic activity that drives a reduction in alcohol self-administration.
    MeSH term(s) Humans ; Rats ; Male ; Female ; Animals ; Nucleus Accumbens/metabolism ; Neurosteroids/metabolism ; Neurosteroids/pharmacology ; Ethanol ; Brain ; Pregnanolone/metabolism ; gamma-Aminobutyric Acid/metabolism
    Chemical Substances Neurosteroids ; Ethanol (3K9958V90M) ; Pregnanolone (BXO86P3XXW) ; gamma-Aminobutyric Acid (56-12-2)
    Language English
    Publishing date 2023-02-21
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ISSN 2993-7175
    ISSN (online) 2993-7175
    DOI 10.1111/acer.15008
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  10. Article ; Online: Inhibition of human macrophage activation

    Balan, Irina / Aurelian, Laure / Williams, Kimberly S / Campbell, Brian / Meeker, Rick B / Morrow, A Leslie

    Frontiers in immunology

    2022  Volume 13, Page(s) 940095

    Abstract: We recently discovered that (3α,5α)3-hydroxypregnan-20-one (allopregnanolone) inhibits pro-inflammatory toll-like receptor (TLR) activation and cytokine/chemokine production in mouse macrophage RAW264.7 cells. The present studies evaluate neurosteroid ... ...

    Abstract We recently discovered that (3α,5α)3-hydroxypregnan-20-one (allopregnanolone) inhibits pro-inflammatory toll-like receptor (TLR) activation and cytokine/chemokine production in mouse macrophage RAW264.7 cells. The present studies evaluate neurosteroid actions upon TLR activation in human macrophages from male and female healthy donors. Buffy coat leukocytes were obtained from donors at the New York Blood Center (http://nybloodcenter.org/), and peripheral blood mononuclear cells were isolated and cultured to achieve macrophage differentiation. TLR4 and TLR7 were activated by lipopolysaccharide (LPS) or imiquimod in the presence/absence of allopregnanolone or related neurosteroids and pro-inflammatory markers were detected by ELISA or western blotting. Cultured human monocyte-derived-macrophages exhibited typical morphology, a mixed immune profile of both inflammatory and anti-inflammatory markers, with no sex difference at baseline. Allopregnanolone inhibited TLR4 activation in male and female donors, preventing LPS-induced elevations of TNF-α, MCP-1, pCREB and pSTAT1. In contrast, 3α,5α-THDOC and SGE-516 inhibited the TLR4 pathway activation in female, but not male donors. Allopregnanolone completely inhibited TLR7 activation by imiquimod, blocking IL-1-β, IL-6, pSTAT1 and pIRF7 elevations in females only. 3α,5α-THDOC and SGE-516 partially inhibited TLR7 activation, only in female donors. The results indicate that allopregnanolone inhibits TLR4 and TLR7 activation in cultured human macrophages resulting in diminished cytokine/chemokine production. Allopregnanolone inhibition of TLR4 activation was found in males and females, but inhibition of TLR7 signals exhibited specificity for female donors. 3α,5α-THDOC and SGE-516 inhibited TLR4 and TLR7 pathways only in females. These studies demonstrate anti-inflammatory effects of allopregnanolone in human macrophages for the first time and suggest that inhibition of pro-inflammatory cytokines/chemokines may contribute to its therapeutic actions.
    MeSH term(s) Animals ; Chemokines/pharmacology ; Cytokines/metabolism ; Female ; Humans ; Imiquimod/pharmacology ; Leukocytes, Mononuclear/metabolism ; Lipopolysaccharides/pharmacology ; Macrophage Activation ; Male ; Mice ; Neurosteroids ; Pregnanolone/pharmacology ; Signal Transduction ; Toll-Like Receptor 4/metabolism ; Toll-Like Receptor 7 ; Toll-Like Receptors
    Chemical Substances Chemokines ; Cytokines ; Lipopolysaccharides ; Neurosteroids ; Toll-Like Receptor 4 ; Toll-Like Receptor 7 ; Toll-Like Receptors ; Pregnanolone (BXO86P3XXW) ; Imiquimod (P1QW714R7M)
    Language English
    Publishing date 2022-07-29
    Publishing country Switzerland
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2022.940095
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