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Christine E Marx - One of the best experts on this subject based on the ideXlab platform.
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Neurosteroid Levels in the Orbital Frontal Cortex of Subjects With PTSD and Controls: A Preliminary Report
SAGE Publishing, 2019Co-Authors: Dianne A. Cruz, Jason D Kilts, Jennifer C Naylor, Christine E Marx, Leisa A. Glantz, Kara D. Mcgaughey, Gillian Parke, Lawrence J. Shampine, Douglas E. WilliamsonAbstract:Background Neurosteroids mediate stress signaling and have been implicated in the pathogenesis of post-traumatic stress disorder (PTSD) in both preclinical and clinical studies. Compared to controls, subjects with PTSD exhibit altered neurosteroid levels in peripheral blood and cerebrospinal fluid as well as hypoactivity in the medial orbital frontal cortex (mOFC). Therefore, the aim of this study was to compare neurosteroid levels in the mOFC of subjects with PTSD ( n = 18) and controls ( n = 35). Methods Gray matter was dissected from fresh-frozen mOFC, and levels of the neurosteroids Pregnenolone, allopregnanolone, pregnanolone, epiallopregnanolone, epipregnanolone, tetrahydrodeoxycorticosterone, and androsterone were determined by gas chromatography-tandem mass spectrometry. Results Analyses of unadjusted levels revealed that males with PTSD had significantly decreased levels of allopregnanolone ( p = 0.03) compared to control males, and females with PTSD had significantly increased levels of Pregnenolone ( p = 0.03) relative to control females. After controlling for age, postmortem interval, and smoking status, results showed that males with PTSD had significantly decreased levels of androsterone ( t 46 = 2.37, p = 0.02) compared to control males and females with PTSD had significantly increased levels of pregnanolone ( t 46 = −2.25, p = 0.03) relative to control females. Conclusions To our knowledge, this is the first report of neurosteroid levels in postmortem brain tissue of subjects with PTSD. Although replication is required in other brain regions and a larger cohort of subjects, the results suggest a dysregulation of allopregnanolone and androsterone in males with PTSD and pregnanolone in females with PTSD in the mOFC
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erratum to dhea metabolism to the neurosteroid androsterone a possible mechanism of dhea s antidepressant action
Psychopharmacology, 2015Co-Authors: Rivka Ben Dor, Christine E Marx, Lawrence J. Shampine, David R Rubinow, Peter SchmidtAbstract:Alterations in neurosteroid secretion have been implicated in the efficacy of antidepressants. In a previous study, the adrenal androgen DHEA, a precursor of the neurosteroid androsterone, produced antidepressant and libido-enhancing effects in patients with midlife depression. To investigate the mechanisms underlying DHEA’s behavioral effects in this same patient group, we examined plasma levels of four additional neurosteroids implicated in the regulation of affective behavior. Blood samples were assayed for neurosteroids in men (n = 13) and women (n = 10) with midlife depression who previously participated in a crossover study in which DHEA and placebo were administered for 6 weeks each. Depression severity was measured by the Center for Epidemiologic Studies Depression Scale (CES-D). Plasma levels of androsterone (ADT), allopregnanolone, pregnanolone, and Pregnenolone were measured by GC-MS at baseline and week 6 of each treatment phase. Data were analyzed with repeated measures analysis of variance (ANOVA-R) and Bonferroni t tests. ADT levels (but not allopregnanolone, pregnanolone, and Pregnenolone) increased after DHEA but not after placebo (F 2,42 = 3.3, p < 0.05). Post-DHEA ADT levels were higher in women than men [t 63 = 2.9, p < 0.05]. However, in both men and women who met criteria for clinical response on the CES-D, baseline ADT levels significantly increased post-DHEA, and the magnitude of the ADT increase post-DHEA treatment was similar in men and women. Consequently, it was the non-responders who accounted for the sex difference in post-DHEA plasma ADT levels, a difference that was driven by values in two women (the only female non-responders). The small sample size notwithstanding, these data emphasize the potential behavioral relevance of ADT in humans, which may include contribution to the antidepressant effects of DHEA.
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proof of concept randomized controlled trial of Pregnenolone in schizophrenia
Psychopharmacology, 2014Co-Authors: Jason D Kilts, Christine E Marx, Jimmy Lee, Mythily Subramaniam, Attilio Rapisarda, Dianne Bautista, Edwin Chan, Robert W BuchananAbstract:Preclinical and clinical data suggest that Pregnenolone may be a promising therapeutic in schizophrenia. Pregnenolone is neuroprotective and enhances learning and memory, myelination, and microtubule polymerization. Treatment with Pregnenolone elevates allopregnanolone (a neurosteroid that enhances GABAA receptor responses) and Pregnenolone sulfate (a positive NMDA receptor modulator). Pregnenolone could thus potentially mitigate GABA dysregulation and/or NMDA receptor hypofunction in schizophrenia via metabolism to other neurosteroids. The objective of this study is to conduct a randomized controlled trial of adjunctive Pregnenolone in schizophrenia. Following a placebo lead-in, 120 participants were randomized to Pregnenolone or placebo for 8 weeks (Institute for Mental Health, Singapore). Primary endpoints were changes in MATRICS Consensus Cognitive Battery (MCCB) composite scores (cognitive symptoms), UCSD Performance-based Skills Assessment—Brief (UPSA-B) composite scores (functional capacity), and Scale for Assessment of Negative Symptoms (SANS) total scores (negative symptoms). A modified intent-to-treat analysis approach was utilized. No significant changes compared to placebo were demonstrated in composite MCCB scores. In contrast, participants randomized to Pregnenolone (n = 56) demonstrated greater improvements in functional capacity (UPSA-B composite changes) compared to placebo (n = 55), p = 0.03. Pregnenolone was also superior to placebo in the communication subscale of the UPSA-B (p < 0.001). Serum Pregnenolone changes post-treatment were correlated with UPSA-B composite score changes in females (r s = 0.497, p < 0.042, n = 17) but not in males. Mean total SANS scores were very low at baseline and did not improve further post-treatment. Pregnenolone was well-tolerated. Pregnenolone improved functional capacity in participants with schizophrenia, but did not improve cognitive symptoms over an 8-week treatment period. Neurosteroid changes correlated with functional improvements in female participants. Neurosteroid interventions may exhibit promise as new therapeutic leads for schizophrenia.
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a randomized double blind placebo controlled trial of Pregnenolone for bipolar depression
Neuropsychopharmacology, 2014Co-Authors: Sherwood E Brown, Christine E Marx, John Park, Linda S Hynan, Claire Gardner, Domingo Davila, Alyson Nakamura, Prabha Sunderajan, Traci HolmesAbstract:Depression in bipolar disorder (BPD) is challenging to treat. Therefore, additional medication options are needed. In the current report, the effect of the neurosteroid Pregnenolone on depressive symptoms in BPD was examined. Adults (n=80) with BPD, depressed mood state, were randomized to Pregnenolone (titrated to 500 mg/day) or placebo, as add-on therapy, for 12 weeks. Outcome measures included the 17-item Hamilton Rating Scale for Depression (HRSD), Inventory of Depressive Symptomatology—Self-Report (IDS-SR), Hamilton Rating Scale for Anxiety (HRSA), and Young Mania Rating Scale (YMRS). Serum neurosteroid levels were assessed at baseline and week 12. Data were analyzed using a mixed model ANCOVA with a between factor of treatment assignment, a within factor (repeated) of visit, and the baseline value, as well as age and gender, as covariates. In participants with at least one postbaseline visit (n=73), a significant treatment by week interaction for the HRSD (F(5,288)=2.61, p=0.025), but not IDS-SR, was observed. Depression remission rates were greater in the Pregnenolone group (61%) compared with the placebo group (37%), as assessed by the IDS-SR (χ2(1)=3.99, p=0.046), but not the HRSD. Large baseline-to-exit changes in neurosteroid levels were observed in the Pregnenolone group but not in the placebo group. In the Pregnenolone group, baseline-to-exit change in the HRSA correlated negatively with changes in allopregnanolone (r(22)=−0.43, p=0.036) and pregNANolone (r(22)=−0.48, p=0.019) levels. Pregnenolone was well tolerated. The results suggest that Pregnenolone may improve depressive symptoms in patients with BPD and can be safely administered.
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Pregnenolone rescues schizophrenia like behavior in dopamine transporter knockout mice
PLOS ONE, 2012Co-Authors: Peiyan Wong, Christine E Marx, Cecilia Chin Roei Chang, Xiaodong Zhang, Marc G Caron, William C WetselAbstract:Pregnenolone belongs to a class of endogenous neurosteroids in the central nervous system (CNS), which has been suggested to enhance cognitive functions through GABAA receptor signaling by its metabolites. It has been shown that the level of Pregnenolone is altered in certain brain areas of schizophrenic patients, and clozapine enhances Pregnenolone in the CNS in rats, suggesting that Pregnenolone could be used to treat certain symptoms of schizophrenia. In addition, early phase proof-of-concept clinical trials have indicated that Pregnenolone is effective in reducing the negative symptoms and cognitive deficits of schizophrenia patients. Here, we evaluate the actions of Pregnenolone on a mouse model for schizophrenia, the dopamine transporter knockout mouse (DAT KO). DAT KO mice mirror certain symptoms evident in patients with schizophrenia, such as the psychomotor agitation, stereotypy, deficits of prepulse inhibition and cognitive impairments. Following acute treatment, Pregnenolone was found to reduce the hyperlocomotion, stereotypic bouts and pre-pulse inhibition (PPI) deficits in DAT KO mice in a dose-dependent manner. At 60 mg/kg of Pregnenolone, there were no significant differences in locomotor activities and stereotypy between wild-type and DAT KO mice. Similarly, acute treatment of 60 mg/kg of Pregnenolone fully rescued PPI deficits of DAT KO mice. Following chronic treatment with Pregnenolone at 60 mg/kg, the cognitive deficits of DAT KO mice were rescued in the paradigms of novel object recognition test and social transmission of food preference test. Pregnenolone thus holds promise as a therapeutic candidate in schizophrenia.
Daniel W Bradford - One of the best experts on this subject based on the ideXlab platform.
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Pregnenolone as a novel therapeutic candidate in schizophrenia emerging preclinical and clinical evidence
Neuroscience, 2011Co-Authors: Christine E Marx, Jennifer C Naylor, Robert M Hamer, Daniel W Bradford, Trina B Allen, Jeffrey A Lieberman, Jennifer L StraussAbstract:Abstract Emerging preclinical and clinical evidence suggests that Pregnenolone may be a promising novel therapeutic candidate in schizophrenia. Pregnenolone is a neurosteroid with pleiotropic actions in rodents that include the enhancement of learning and memory, neuritic outgrowth, and myelination. Further, Pregnenolone administration results in elevations in downstream neurosteroids such as allopregnanolone, a molecule with neuroprotective effects that also increases neurogenesis, decreases apoptosis and inflammation, modulates the hypothalamic-pituitary-adrenal axis, and markedly increases GABAA receptor responses. In addition, Pregnenolone administration elevates Pregnenolone sulfate, a neurosteroid that positively modulates NMDA receptors. There are thus multiple mechanistic possibilities for Pregnenolone as a potential therapeutic agent in schizophrenia, including the amelioration of NMDA receptor hypofunction (via metabolism to Pregnenolone sulfate) and the mitigation of GABA dysregulation (via metabolism to allopregnanolone). Additional evidence consistent with a therapeutic role for Pregnenolone in schizophrenia includes neurosteroid changes following administration of certain antipsychotics in rodent models. For example, clozapine elevates Pregnenolone levels in rat hippocampus, and these increases may potentially contribute to its superior antipsychotic efficacy [ Marx et al. (2006a) Pharmacol Biochem Behav 84:598–608]. Further, Pregnenolone levels appear to be altered in postmortem brain tissue from patients with schizophrenia compared to control subjects [ Marx et al. (2006c) Neuropsychopharmacology 31:1249–1263], suggesting that neurosteroid changes may play a role in the neurobiology of this disorder and/or its treatment. Although clinical trial data utilizing Pregnenolone as a therapeutic agent in schizophrenia are currently limited, initial findings are encouraging. Treatment with adjunctive Pregnenolone significantly decreased negative symptoms in patients with schizophrenia or schizoaffective disorder in a pilot proof-of-concept randomized controlled trial, and elevations in Pregnenolone and allopregnanolone post-treatment with this intervention were correlated with cognitive improvements [ Marx et al. (2009) Neuropsychopharmacology 34:1885–1903]. Another pilot randomized controlled trial recently presented at a scientific meeting demonstrated significant improvements in negative symptoms, verbal memory, and attention following treatment with adjunctive Pregnenolone, in addition to enduring effects in a small subset of patients receiving Pregnenolone longer-term [ Savitz (2010) Society of Biological Psychiatry Annual Meeting New Orleans, LA]. A third pilot clinical trial reported significantly decreased positive symptoms and extrapyramidal side effects following adjunctive Pregnenolone, in addition to increased attention and working memory performance [ Ritsner et al. (2010) J Clin Psychiatry 71:1351–1362]. Future efforts in larger cohorts will be required to investigate Pregnenolone as a possible therapeutic candidate in schizophrenia, but early efforts are promising and merit further investigation. This article is part of a Special Issue entitled: Neuroactive Steroids: Focus on Human Brain.
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proof of concept trial with the neurosteroid Pregnenolone targeting cognitive and negative symptoms in schizophrenia
Neuropsychopharmacology, 2009Co-Authors: Jason D Kilts, Christine E Marx, Richard S E Keefe, Robert W Buchanan, Robert M Hamer, Daniel W Bradford, Jennifer L StraussAbstract:The neurosteroid Pregnenolone and its sulfated derivative enhance learning and memory in rodents. Pregnenolone sulfate also positively modulates NMDA receptors and could thus ameliorate hypothesized NMDA receptor hypofunction in schizophrenia. Furthermore, clozapine increases Pregnenolone in rodent hippocampus, possibly contributing to its superior efficacy. We therefore investigated adjunctive Pregnenolone for cognitive and negative symptoms in patients with schizophrenia or schizoaffective disorder receiving stable doses of second-generation antipsychotics in a pilot randomized, placebo-controlled, double-blind trial. Following a 2-week single-blind placebo lead-in, patients were randomized to Pregnenolone (fixed escalating doses to 500 mg/day) or placebo, for 8 weeks. Primary end points were changes in BACS and MCCB composite and total SANS scores. Of 21 patients randomized, 18 completed at least 4 weeks of treatment (n ¼ 9/group). Pregnenolone was well tolerated. Patients receiving Pregnenolone demonstrated significantly greater improvements in SANS scores (mean change ¼ 10.38) compared with patients receiving placebo (mean change ¼ 2.33), p ¼ 0.048. Mean composite changes in BACS and MCCB scores were not significantly different in patients randomized to Pregnenolone compared with placebo. However, serum Pregnenolone increases predicted BACS composite scores at 8 weeks in the Pregnenolone group (rs ¼ 0.81, p ¼ 0.022). Increases in allopregnanolone, a GABAergic Pregnenolone metabolite, also predicted BACS composite scores (rs ¼ 0.74, p ¼ 0.046). In addition, baseline Pregnenolone (rs ¼� 0.76, p ¼ 0.037), Pregnenolone sulfate (rs ¼� 0.83, p ¼ 0.015), and allopregnanolone levels (rs ¼� 0.83, p ¼ 0.015) were inversely correlated with improvements in MCCB composite scores, further supporting a possible role for neurosteroids in cognition. Mean BACS and MCCB composite scores were correlated (rs ¼ 0.74, po0.0001). Pregnenolone may be a promising therapeutic agent for negative symptoms and merits further investigation for cognitive symptoms in schizophrenia. Neuropsychopharmacology (2009) 34, 1885–1903; doi:10.1038/npp.2009.26; published online 1 April 2009
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proof of concept trial with the neurosteroid Pregnenolone targeting cognitive and negative symptoms in schizophrenia
Neuropsychopharmacology, 2009Co-Authors: Jason D Kilts, Christine E Marx, Richard S E Keefe, Robert W Buchanan, Robert M Hamer, Daniel W Bradford, Jennifer L StraussAbstract:The neurosteroid Pregnenolone and its sulfated derivative enhance learning and memory in rodents. Pregnenolone sulfate also positively modulates NMDA receptors and could thus ameliorate hypothesized NMDA receptor hypofunction in schizophrenia. Furthermore, clozapine increases Pregnenolone in rodent hippocampus, possibly contributing to its superior efficacy. We therefore investigated adjunctive Pregnenolone for cognitive and negative symptoms in patients with schizophrenia or schizoaffective disorder receiving stable doses of second-generation antipsychotics in a pilot randomized, placebo-controlled, double-blind trial. Following a 2-week single-blind placebo lead-in, patients were randomized to Pregnenolone (fixed escalating doses to 500 mg/day) or placebo, for 8 weeks. Primary end points were changes in BACS and MCCB composite and total SANS scores. Of 21 patients randomized, 18 completed at least 4 weeks of treatment (n=9/group). Pregnenolone was well tolerated. Patients receiving Pregnenolone demonstrated significantly greater improvements in SANS scores (mean change=10.38) compared with patients receiving placebo (mean change=2.33), p=0.048. Mean composite changes in BACS and MCCB scores were not significantly different in patients randomized to Pregnenolone compared with placebo. However, serum Pregnenolone increases predicted BACS composite scores at 8 weeks in the Pregnenolone group (rs=0.81, p=0.022). Increases in allopregnanolone, a GABAergic Pregnenolone metabolite, also predicted BACS composite scores (rs=0.74, p=0.046). In addition, baseline Pregnenolone (rs=−0.76, p=0.037), Pregnenolone sulfate (rs=−0.83, p=0.015), and allopregnanolone levels (rs=−0.83, p=0.015) were inversely correlated with improvements in MCCB composite scores, further supporting a possible role for neurosteroids in cognition. Mean BACS and MCCB composite scores were correlated (rs=0.74, p<0.0001). Pregnenolone may be a promising therapeutic agent for negative symptoms and merits further investigation for cognitive symptoms in schizophrenia.
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olanzapine and fluoxetine administration and coadministration increase rat hippocampal Pregnenolone allopregnanolone and peripheral deoxycorticosterone implications for therapeutic actions
Pharmacology Biochemistry and Behavior, 2006Co-Authors: Christine E Marx, Lawrence J. Shampine, Daniel W Bradford, Rahul T Khisti, William T Trost, Chistina A Grobin, Mark W Massing, Roger D Madison, Marian I Butterfield, Jeffrey A LiebermanAbstract:Olanzapine and fluoxetine elevate the GABAergic neuroactive steroid allopregnanolone to physiologically relevant concentrations in rodent cerebral cortex. It is unknown if these agents also alter Pregnenolone or deoxycorticosterone. Since olanzapine and fluoxetine in combination have clinical utility and may demonstrate synergistic effects, we investigated neuroactive steroid alterations following olanzapine, fluoxetine or coadministration. Male rats received IP vehicle, olanzapine, fluoxetine or the combination of both agents in higher-dose (0, 10, 20 or 10/20 mg/kg, respectively) and lower-dose (0, 5, 10 or 5/10 mg/kg, respectively) experiments. Pregnenolone and allopregnanolone levels in hippocampus were determined by gas chromatography/mass spectrometry. Peripheral deoxycorticosterone and other steroid levels were determined by radioimmunoassay. Olanzapine, fluoxetine or the combination increased hippocampal Pregnenolone and serum deoxycorticosterone in both higher- and lower-dose experiments, and elevated hippocampal allopregnanolone in higher-dose conditions. No synergistic effects on Pregnenolone or allopregnanolone were observed following olanzapine and fluoxetine coadministration compared to either compound alone. Pregnenolone and its sulfate enhance learning and memory in rodent models, and therefore Pregnenolone elevations may be relevant to cognitive changes in psychotic and affective disorders. Since Pregnenolone decreases have been linked to depression, it is possible that olanzapine- and fluoxetine-induced Pregnenolone elevations may contribute to the antidepressant actions of these agents.
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clozapine markedly elevates Pregnenolone in rat hippocampus cerebral cortex and serum candidate mechanism for superior efficacy
Pharmacology Biochemistry and Behavior, 2006Co-Authors: Christine E Marx, Lawrence J. Shampine, Chistina A Grobin, Mark W Massing, Roger D Madison, Gary E Duncan, Margaret J Vandoren, Daniel W BradfordAbstract:Clozapine demonstrates superior efficacy in patients with schizophrenia, but the precise mechanisms contributing to this clinical advantage are not clear. Clozapine and olanzapine increase the GABAergic neuroactive steroid (NS) allopregnanolone, and it has been hypothesized that NS induction may contribute to the therapeutic actions of these agents. Pregnenolone administration improves learning and memory in rodent models, and decreases in this NS have been associated with depressive symptoms in humans. These Pregnenolone characteristics may be relevant to the actions of antipsychotics. We therefore investigated potential Pregnenolone alterations in rat hippocampus and cerebral cortex following clozapine, olanzapine, and other second generation agents as a candidate NS mechanism contributing to antipsychotic efficacy. In the first set of experiments, intact, adrenalectomized, and sham-operated male rats received vehicle or clozapine (20 mg/kg) IP. In the second set, male rats received vehicle, olanzapine (5 mg/kg), quetiapine (20 mg/kg), ziprasidone (10 mg/kg) or aripiprazole (5 mg/kg) IP. Pregnenolone levels were determined by gas chromatography/mass spectrometry. Clozapine markedly elevates Pregnenolone in rat hippocampus, cerebral cortex, and serum; hippocampal levels were strongly correlated with serum levels (r = 0.987). Olanzapine also elevates Pregnenolone levels, but to a lesser degree than clozapine. Pregnenolone induction may contribute to the clinical actions of clozapine and olanzapine.
Willy Mayo - One of the best experts on this subject based on the ideXlab platform.
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The neurosteroid Pregnenolone sulfate infused into the medial septum nucleus increases hippocampal acetylcholine and spatial memory in rats.
Brain Research, 2002Co-Authors: Muriel Darnaudéry, Marc Pallarès, Michel Le Moal, Pier Vincenzo Piazza, Willy MayoAbstract:The effects of an infusion of the neurosteroid Pregnenolone sulfate into the medial septum on acetylcholine release in the hippocampus and on spatial memory were evaluated in two experiments. Results show that Pregnenolone sulfate enhanced acetylcholine release by more than 50% of baseline and improved recognition memory of a familiar environment. Therefore, our results suggest that the septo-hippocampal pathway could be involved in the promnesic properties of this neurosteroid.
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The neurosteroid Pregnenolone sulfate infused into the nucleus basalis increases both acetylcholine release in the frontal cortex or amygdala and spatial memory
Neuroscience, 1998Co-Authors: Marc Pallarès, Muriel Darnaudéry, Michel Le Moal, Willy MayoAbstract:Abstract The effects of an infusion (5 ng) of the neurosteroid Pregnenolone sulfate into the nucleus basalis magnocellularis on acetylcholine release in the frontoparietal cortex and basolateral amygdala were evaluated during the 130 min post-injection in male Sprague–Dawley rats using in vivo microdialysis coupled “on line” with high performance liquid chromatography detection. One week later, the same animals were tested for spatial memory after another infusion of Pregnenolone sulfate (5 ng) into the nucleus basalis. Results show that Pregnenolone sulfate enhanced acetylcholine release by more than 50% of baseline concentrations in the two structures relative to a control injection. The duration of this effect was longer in cortex (130 min) than in amygdala (30 min). Furthermore, Pregnenolone sulfate improved memory performance in a task based upon spatial recognition of a familiar environment. A significant positive correlation ( r =0.49) was found between the recognition score in the spatial memory test and the levels of acetylcholine release in the frontoparietal cortex but not in the basolateral amygdala. Therefore, our results suggest that the nucleus basalis magnocellularis-cortical pathway could be in part responsible for the promnesic effect of Pregnenolone sulfate. This neurosteroid acts as a negative modulator of the GABA A receptor complex and positively modulates the N -methyl- d -aspartate receptor, possibly resulting in a global stimulatory effect on central cholinergic neurotransmission.
Marc Pallarès - One of the best experts on this subject based on the ideXlab platform.
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neurosteroids infusion into the ca1 hippocampal region on exploration anxiety like behaviour and aversive learning
Behavioural Brain Research, 2011Co-Authors: Laura Modol, Sonia Darbra, Marc PallarèsAbstract:Neurosteroids (NS) are substances synthesised de novo in the brain that have rapid modulatory effects on ionotropic receptors. Specifically, NS can act as positive allosteric modulators of GABAA receptors as pregnanolone or allopregnanolone (Allop), or GABAA negative modulators and NMDA positive modulators as Pregnenolone (PREG) or dehydroepiandrosterone (DHEA) and their sulphate esters (PREGS and DHEAS). Given this, their role in anxiety and emotional disturbances has been suggested. In addition, NS such as PREGS or DHEAS have demonstrated a promnesic role in several learning tests. The aim of the present work is to highlight the role that the dorsal (CA1) hippocampus plays in the behavioural profile of NS such as Allop and PREGS in tests assessing exploration, anxiety and aversive learning in rats. For this purpose, animals were administered intrahippocampally with Allop (0.2μg/0.5μl), PREGS (5ng/0.5μl) or vehicle in each hippocampus, and tested in the Boissier and elevated plus maze (EPM) tests. For learning test we have chosen the passive avoidance paradigm. Results indicate that intrahippocampal administration of Allop enhances exploration, reflected in an increase in the total and the inner number of head-dips. Allop-injected animals also showed an increase in the percentage of entries into the open arms of the EPM, suggesting an anxiolytic-like profile. In addition, post-acquisition PREGS administration enhanced passive avoidance retention, while post-acquisition Allop administration had no effects on aversive learning retention. These results point out the important role of the dorsal (CA1) hippocampus in several NS behavioural effects, such as exploration, anxiety, learning and memory.
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The neurosteroid Pregnenolone sulfate infused into the medial septum nucleus increases hippocampal acetylcholine and spatial memory in rats.
Brain Research, 2002Co-Authors: Muriel Darnaudéry, Marc Pallarès, Michel Le Moal, Pier Vincenzo Piazza, Willy MayoAbstract:The effects of an infusion of the neurosteroid Pregnenolone sulfate into the medial septum on acetylcholine release in the hippocampus and on spatial memory were evaluated in two experiments. Results show that Pregnenolone sulfate enhanced acetylcholine release by more than 50% of baseline and improved recognition memory of a familiar environment. Therefore, our results suggest that the septo-hippocampal pathway could be involved in the promnesic properties of this neurosteroid.
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The neurosteroid Pregnenolone sulfate infused into the nucleus basalis increases both acetylcholine release in the frontal cortex or amygdala and spatial memory
Neuroscience, 1998Co-Authors: Marc Pallarès, Muriel Darnaudéry, Michel Le Moal, Willy MayoAbstract:Abstract The effects of an infusion (5 ng) of the neurosteroid Pregnenolone sulfate into the nucleus basalis magnocellularis on acetylcholine release in the frontoparietal cortex and basolateral amygdala were evaluated during the 130 min post-injection in male Sprague–Dawley rats using in vivo microdialysis coupled “on line” with high performance liquid chromatography detection. One week later, the same animals were tested for spatial memory after another infusion of Pregnenolone sulfate (5 ng) into the nucleus basalis. Results show that Pregnenolone sulfate enhanced acetylcholine release by more than 50% of baseline concentrations in the two structures relative to a control injection. The duration of this effect was longer in cortex (130 min) than in amygdala (30 min). Furthermore, Pregnenolone sulfate improved memory performance in a task based upon spatial recognition of a familiar environment. A significant positive correlation ( r =0.49) was found between the recognition score in the spatial memory test and the levels of acetylcholine release in the frontoparietal cortex but not in the basolateral amygdala. Therefore, our results suggest that the nucleus basalis magnocellularis-cortical pathway could be in part responsible for the promnesic effect of Pregnenolone sulfate. This neurosteroid acts as a negative modulator of the GABA A receptor complex and positively modulates the N -methyl- d -aspartate receptor, possibly resulting in a global stimulatory effect on central cholinergic neurotransmission.
Jason D Kilts - One of the best experts on this subject based on the ideXlab platform.
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effect of Pregnenolone vs placebo on self reported chronic low back pain among us military veterans a randomized clinical trial
JAMA Network Open, 2020Co-Authors: Jason D Kilts, Jennifer C Naylor, Gillian Parke, Lawrence J. Shampine, Ryan H WagnerAbstract:Importance In response to the national opioid public health crisis, there is an urgent need to develop nonopioid solutions for effective pain management. Neurosteroids are endogenous molecules with pleotropic actions that show promise for safe and effective treatment of chronic low back pain. Objective To determine whether adjunctive Pregnenolone has therapeutic utility for the treatment of chronic low back pain in Iraq- and Afghanistan-era US military veterans. Design, Setting, and Participants Randomized, double-blind, placebo-controlled clinical trial that enrolled for 42 months, from September 2013 to April 2017. Participants were Iraq- and Afghanistan-era veterans aged 18 to 65 years with chronic low back pain who received treatment in the Durham VA Health Care System in Durham, North Carolina, over 6 weeks. Data analysis began in 2018 and was finalized in March, 2019. Interventions Following a 1-week placebo lead-in, participants were randomized to Pregnenolone or placebo for 4 weeks. Pregnenolone and placebo were administered at fixed, escalating doses of 100 mg for 1 week, 300 mg for 1 week, and 500 mg for 2 weeks. Main Outcomes and Measures The primary outcome measure was the change in mean pain intensity ratings from a daily pain diary (numerical rating scale, 0-10) between visit 3 (baseline) and visit 6. Secondary outcomes included pain interference scores (Brief Pain Inventory, Short Form). Preintervention and postintervention neurosteroid levels were quantified by gas chromatography with tandem mass spectrometry. Hypotheses tested were formulated prior to data collection. Results A total of 94 participants (84 [89.4%] male; mean [SD] age, 37.5 [9.8] years; 53 [56.4%] of self-reported Caucasian race and 31 [33.0%] of self-reported African American race) were included. Forty-eight participants were randomized to Pregnenolone and 52 to placebo, of whom 45 and 49, respectively, were included in baseline demographic characteristics secondary to noncompliance with medications as per protocol. Veterans randomized to Pregnenolone reported significant reductions in low back pain relative to those randomized to placebo. Baseline unadjusted mean (SE) pain diary ratings were 4.83 (0.23) and 5.24 (0.22) for the placebo- and Pregnenolone-treated groups, respectively (baseline unadjusted mean [SE] ratings for pain recall were 4.78 [0.24] and 5.15 [0.23], respectively). Unadjusted mean (SE) ratings following treatment (visit 6) were 4.74 (0.26) in the placebo group and 4.19 (0.30) in the Pregnenolone-treated group. Unadjusted mean (SE) ratings for pain recall following treatment were 4.86 (0.27) for placebo and 4.18 (0.29) for Pregnenolone. Least-square mean (LSM) analysis showed that pain scores significantly improved in the Pregnenolone-treated group compared with placebo (LSM [SE] change in pain diary rating, −0.56 [0.25];P = .02; LSM [SE] change in pain recall, −0.70 [0.27];P = .01). Pain interference scores for work (LSM [SE] change, 0.71 [0.12];P = .04) and activity (LSM [SE] change, 0.71 [0.11];P = .03) were also improved in veterans randomized to Pregnenolone compared with placebo. Pregnenolone was well tolerated. Conclusions and Relevance Participants receiving Pregnenolone reported a clinically meaningful reduction in low back pain and 2 pain interference domains compared with those receiving placebo. Pregnenolone may represent a novel, safe, and potentially efficacious treatment for the alleviation of chronic low back pain in Iraq- and Afghanistan-era veterans. Trial Registration ClinicalTrials.gov Identifier:NCT01898013
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Neurosteroid Levels in the Orbital Frontal Cortex of Subjects With PTSD and Controls: A Preliminary Report
SAGE Publishing, 2019Co-Authors: Dianne A. Cruz, Jason D Kilts, Jennifer C Naylor, Christine E Marx, Leisa A. Glantz, Kara D. Mcgaughey, Gillian Parke, Lawrence J. Shampine, Douglas E. WilliamsonAbstract:Background Neurosteroids mediate stress signaling and have been implicated in the pathogenesis of post-traumatic stress disorder (PTSD) in both preclinical and clinical studies. Compared to controls, subjects with PTSD exhibit altered neurosteroid levels in peripheral blood and cerebrospinal fluid as well as hypoactivity in the medial orbital frontal cortex (mOFC). Therefore, the aim of this study was to compare neurosteroid levels in the mOFC of subjects with PTSD ( n = 18) and controls ( n = 35). Methods Gray matter was dissected from fresh-frozen mOFC, and levels of the neurosteroids Pregnenolone, allopregnanolone, pregnanolone, epiallopregnanolone, epipregnanolone, tetrahydrodeoxycorticosterone, and androsterone were determined by gas chromatography-tandem mass spectrometry. Results Analyses of unadjusted levels revealed that males with PTSD had significantly decreased levels of allopregnanolone ( p = 0.03) compared to control males, and females with PTSD had significantly increased levels of Pregnenolone ( p = 0.03) relative to control females. After controlling for age, postmortem interval, and smoking status, results showed that males with PTSD had significantly decreased levels of androsterone ( t 46 = 2.37, p = 0.02) compared to control males and females with PTSD had significantly increased levels of pregnanolone ( t 46 = −2.25, p = 0.03) relative to control females. Conclusions To our knowledge, this is the first report of neurosteroid levels in postmortem brain tissue of subjects with PTSD. Although replication is required in other brain regions and a larger cohort of subjects, the results suggest a dysregulation of allopregnanolone and androsterone in males with PTSD and pregnanolone in females with PTSD in the mOFC
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19 randomized controlled trial of a neurosteroid intervention in schizophrenia
Schizophrenia Bulletin, 2017Co-Authors: Chris Marx, Jason D Kilts, Jennifer C Naylor, Richard S E Keefe, Trina Allan, Karen H Smith, Steven T Szabo, Ryan Wagner, Robert Buchanan, Lawrence J. ShampineAbstract:Abstract Background: Neurosteroids are endogenous molecules synthesized de novo in brain, adrenals, and other tissues. They demonstrate pleiotropic actions that are highly relevant to the neurobiology of schizophrenia. Clozapine markedly elevates neurosteroids in rodent hippocampus, potentially contributing to its superior therapeutic efficacy. Clinical evidence from a randomized controlled trial (RCT) conducted in Singapore suggests that Pregnenolone significantly enhances functional capacity (as demonstrated by improvements in the UPSA Total Score and UPSA Communication Subscale Score) and that neurosteroid changes posttreatment predict therapeutic response (Marx et al 2014; Psychopharmacology). We thus conducted an RCT investigating adjunctive Pregnenolone in schizophrenia. Methods: After a 2-week placebo lead-in, 88 participants with schizophrenia were randomized to Pregnenolone (n = 42) or placebo (n = 46) for 8 weeks. Neurosteroids were quantified at baseline and posttreatment by mass spectrometry. Functional end points included the UPSA Total Score and UPSA Communication Subscale. Cognitive end points included the MCCB Composite Score and MCCB Subscales. Modified intent-to-treat analyses were conducted. Results: Participants randomized to the Pregnenolone group did not outperform placebo on the UPSA Total Score or MCCB Composite Score. However, the Pregnenolone group demonstrated significantly greater improvement in the UPSA Communication Subscale compared to participants randomized to placebo (P = .034), replicating prior RCT findings from Singapore. Elevations in Pregnenolone post-treatment also predicted improvements in UPSA Total Score (r = .373; P = .039), again replicating prior efforts. In addition, the Pregnenolone group demonstrated significantly greater improvement in the MCCB Verbal Learning Subscale compared to placebo (P = .023). Pregnenolone did not outperform placebo in the BACS Composite Score, SANS Total Score, or PANSS Total Score. Pregnenolone was well tolerated. Conclusion: Treatment with Pregnenolone appears to improve functional capacity in a US population with schizophrenia, as assessed by the UPSA Communication Subscale and also supported by a significant positive correlation between Pregnenolone changes and UPSA Total Score improvements—thus replicating findings from a prior RCT conducted in Singapore. Pregnenolone may also improve verbal memory. Given the positive correlation between Pregnenolone increases posttreatment and UPSA Total Score improvements, it is possible that higher doses of Pregnenolone may be clinically efficacious, and that neurosteroid quantification has biomarker potential for the predication of therapeutic response. Additional dose-finding investigations will be required to test these hypotheses. A Pregnenolone decanoate formulation is currently in preclinical development.
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proof of concept randomized controlled trial of Pregnenolone in schizophrenia
Psychopharmacology, 2014Co-Authors: Jason D Kilts, Christine E Marx, Jimmy Lee, Mythily Subramaniam, Attilio Rapisarda, Dianne Bautista, Edwin Chan, Robert W BuchananAbstract:Preclinical and clinical data suggest that Pregnenolone may be a promising therapeutic in schizophrenia. Pregnenolone is neuroprotective and enhances learning and memory, myelination, and microtubule polymerization. Treatment with Pregnenolone elevates allopregnanolone (a neurosteroid that enhances GABAA receptor responses) and Pregnenolone sulfate (a positive NMDA receptor modulator). Pregnenolone could thus potentially mitigate GABA dysregulation and/or NMDA receptor hypofunction in schizophrenia via metabolism to other neurosteroids. The objective of this study is to conduct a randomized controlled trial of adjunctive Pregnenolone in schizophrenia. Following a placebo lead-in, 120 participants were randomized to Pregnenolone or placebo for 8 weeks (Institute for Mental Health, Singapore). Primary endpoints were changes in MATRICS Consensus Cognitive Battery (MCCB) composite scores (cognitive symptoms), UCSD Performance-based Skills Assessment—Brief (UPSA-B) composite scores (functional capacity), and Scale for Assessment of Negative Symptoms (SANS) total scores (negative symptoms). A modified intent-to-treat analysis approach was utilized. No significant changes compared to placebo were demonstrated in composite MCCB scores. In contrast, participants randomized to Pregnenolone (n = 56) demonstrated greater improvements in functional capacity (UPSA-B composite changes) compared to placebo (n = 55), p = 0.03. Pregnenolone was also superior to placebo in the communication subscale of the UPSA-B (p < 0.001). Serum Pregnenolone changes post-treatment were correlated with UPSA-B composite score changes in females (r s = 0.497, p < 0.042, n = 17) but not in males. Mean total SANS scores were very low at baseline and did not improve further post-treatment. Pregnenolone was well-tolerated. Pregnenolone improved functional capacity in participants with schizophrenia, but did not improve cognitive symptoms over an 8-week treatment period. Neurosteroid changes correlated with functional improvements in female participants. Neurosteroid interventions may exhibit promise as new therapeutic leads for schizophrenia.
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proof of concept trial with the neurosteroid Pregnenolone targeting cognitive and negative symptoms in schizophrenia
Neuropsychopharmacology, 2009Co-Authors: Jason D Kilts, Christine E Marx, Richard S E Keefe, Robert W Buchanan, Robert M Hamer, Daniel W Bradford, Jennifer L StraussAbstract:The neurosteroid Pregnenolone and its sulfated derivative enhance learning and memory in rodents. Pregnenolone sulfate also positively modulates NMDA receptors and could thus ameliorate hypothesized NMDA receptor hypofunction in schizophrenia. Furthermore, clozapine increases Pregnenolone in rodent hippocampus, possibly contributing to its superior efficacy. We therefore investigated adjunctive Pregnenolone for cognitive and negative symptoms in patients with schizophrenia or schizoaffective disorder receiving stable doses of second-generation antipsychotics in a pilot randomized, placebo-controlled, double-blind trial. Following a 2-week single-blind placebo lead-in, patients were randomized to Pregnenolone (fixed escalating doses to 500 mg/day) or placebo, for 8 weeks. Primary end points were changes in BACS and MCCB composite and total SANS scores. Of 21 patients randomized, 18 completed at least 4 weeks of treatment (n ¼ 9/group). Pregnenolone was well tolerated. Patients receiving Pregnenolone demonstrated significantly greater improvements in SANS scores (mean change ¼ 10.38) compared with patients receiving placebo (mean change ¼ 2.33), p ¼ 0.048. Mean composite changes in BACS and MCCB scores were not significantly different in patients randomized to Pregnenolone compared with placebo. However, serum Pregnenolone increases predicted BACS composite scores at 8 weeks in the Pregnenolone group (rs ¼ 0.81, p ¼ 0.022). Increases in allopregnanolone, a GABAergic Pregnenolone metabolite, also predicted BACS composite scores (rs ¼ 0.74, p ¼ 0.046). In addition, baseline Pregnenolone (rs ¼� 0.76, p ¼ 0.037), Pregnenolone sulfate (rs ¼� 0.83, p ¼ 0.015), and allopregnanolone levels (rs ¼� 0.83, p ¼ 0.015) were inversely correlated with improvements in MCCB composite scores, further supporting a possible role for neurosteroids in cognition. Mean BACS and MCCB composite scores were correlated (rs ¼ 0.74, po0.0001). Pregnenolone may be a promising therapeutic agent for negative symptoms and merits further investigation for cognitive symptoms in schizophrenia. Neuropsychopharmacology (2009) 34, 1885–1903; doi:10.1038/npp.2009.26; published online 1 April 2009