Spironolactone is an antagonist of
            <scp>NRG</scp>
            1‐
            <scp>ERBB</scp>
            4 signaling and schizophrenia‐relevant endophenotypes in mice

Wehr, Michael C.; Hinrichs, Wilko; Brzózka, Magdalena M.; Unterbarnscheidt, Tilmann; Herholt, Alexander; Wintgens, Jan P.; Papiol, Sergi; Soto-Bernardini, Maria Clara; Kravchenko, Mykola; Zhang, Mingyue; Nave, Klaus‐Armin; Wichert, Sven P.; Falkai, Peter; Zhang, Weiqi; Schwab, Markus H.; Rossner, Moritz J.

doi:10.15252/emmm.201707691

Cited by 34 publications

(41 citation statements)

References 54 publications

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“…The sensitivity and robustness of a genetic screen is likely as dependent on the performance and dynamic range of the reporter as in cell-based compound screens 26 . Therefore, a panel of 70 cis-regulatory pathway reporters was generated to identify a sensor with excellent performance in a given cellular paradigm.…”

Section: Resultsmentioning

confidence: 99%

“…At the end of the assay, cells were lysed using Passive lysis buffer (Promega). The luciferase activity was measured by a Mithras LB 940 Microplate Reader (Berthold Technologies) 26 . Two-sided Student’s T-Test was applied for statistical analysis.…”

Section: Methodsmentioning

confidence: 99%

“…Subsequently, all cultures were lysed in passive lysis buffer (Promega). Lysate was transferred into white 96-well assay plates and measurement of luciferase bioluminescence was performed in a Mithras LB 940 Microplate Reader (Berthold Technologies) as described previously 26 .…”

Section: Methodsmentioning

confidence: 99%

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Pathway sensor-based functional genomics screening identifies modulators of neuronal activity

Herholt

Brankatschk²,

Kannaiyan³

et al. 2018

Sci Rep

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Neuronal signal transduction shapes brain function and malfunction may cause mental disorders. Despite the existence of functional genomics screens for proliferation and toxicity, neuronal signalling has been difficult to address so far. To overcome this limitation, we developed a pooled screening assay which combines barcoded activity reporters with pooled genetic perturbation in a dual-expression adeno-associated virus (AAV) library. With this approach, termed pathScreener, we comprehensively dissect signalling pathways in postmitotic neurons. This overcomes several limitations of lentiviral-based screens. By applying first a barcoded and multiplexed reporter assay, termed cisProfiler, we identified the synaptic-activity responsive element (SARE) as top performance sensor of neuronal activity. Next, we targeted more than 4,400 genes and screened for modulatory effects on SARE activity in primary cortical neurons. We identified with high replicability many known genes involved in glutamatergic synapse-to-nucleus signalling of which a subset was validated in orthogonal assays. Several others have not yet been associated with the regulation of neuronal activity such as the hedgehog signalling members Ptch2 and Ift57. This assay thus enhances the toolbox for analysing regulatory processes during neuronal signalling and may help identifying novel targets for brain disorders.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Pathway sensor-based functional genomics screening identifies modulators of neuronal activity

Herholt

Brankatschk²,

Kannaiyan³

et al. 2018

Sci Rep

Self Cite

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“…Previous computer-based or experimental drug repositioning frameworks have relied on gene expression, drug-trarget binding or phenotypical screenings to find candidates 76,77 . WDD does not distinguish associations between genes and disorders that occur due to SNPs, epigenetic modifications, or differences in expression.…”

Section: Discussionmentioning

confidence: 99%

“…Six drugs that could treat schizophrenia were found to target ERBB2. Recently, the NRG1-ERBB4 signaling antagonist Spironolactone was identified in a cell-based drug repositioning screening as a candidate for clinical trials for schizophrenia 77 . These drugs have the potential to reduce dysconnectivity and hallucination by regulating the NRG1-ErbB signaling.…”

Section: Discussionmentioning

confidence: 99%

Drug repositioning for psychiatric and neurological disorders through a network medicine approach

et al. 2020

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Psychiatric and neurological disorders (PNDs) affect millions worldwide and only a few drugs achieve complete therapeutic success in the treatment of these disorders. Due to the high cost of developing novel drugs, drug repositioning represents a promising alternative method of treatment. In this manuscript, we used a network medicine approach to investigate the molecular characteristics of PNDs and identify novel drug candidates for repositioning. Using IBM Watson for Drug Discovery, a powerful machine learning text-mining application, we built knowledge networks containing connections between PNDs and genes or drugs mentioned in the scientific literature published in the past 50 years. This approach revealed several drugs that target key PND-related genes, which have never been used to treat these disorders to date. We validate our framework by detecting drugs that have been undergoing clinical trial for treating some of the PNDs, but have no published results in their support. Our data provides comprehensive insights into the molecular pathology of PNDs and offers promising drug repositioning candidates for follow-up trials.

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Efficacy of spironolactone as adjunctive therapy to sodium valproate in bipolar‐I disorder: A double‐blind, randomized, placebo‐controlled clinical trial

Zandifar,

Badrfam,

Gholamian

et al. 2023

Brain and Behavior

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IntroductionTreatment of mood and cognitive symptoms of patients with bipolar disorder is associated with many complications and is generally not associated with therapeutic satisfaction. In this clinical trial, we evaluated the effectiveness of spironolactone in controlling mood and cognitive symptoms, sleep quality, appetite, and body mass index in patients with bipolar disorder in manic episodes.MethodsSixty inpatients with bipolar disorder in manic episodes were treated with spironolactone/placebo in an 8‐week randomized, double‐blind, placebo‐controlled clinical trial. They were evaluated using the Young Mania Rating Scale (YMRS), mini‐mental state examination (MMSE), Pittsburgh sleep quality index, Simplified Nutritional Appetite Questionnaire, and body mass index in weeks 1, 4, and 8.ResultsFor cognitive impairment (MMSE), there were significant interaction effects of group and time at week 8 (B = −1.60, SE = 0.69, t = −2.33, p = .021) such that individuals in the spironolactone group experienced more improvement in their cognitive performance. For manic symptoms (YMRS), there were no significant interaction effects of group and time at week 8 (B = −2.53, SE = 1.46, t = −1.73, p = .085).ConclusionsConsidering the promising findings in this clinical trial, further study of spironolactone as adjunctive therapy in bipolar disorder in manic episodes with larger sample sizes, multicenter settings, and longer follow‐ups are recommended.

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Spironolactone is an antagonist of NRG 1‐ ERBB 4 signaling and schizophrenia‐relevant endophenotypes in mice

Cited by 34 publications

References 54 publications

Pathway sensor-based functional genomics screening identifies modulators of neuronal activity

Pathway sensor-based functional genomics screening identifies modulators of neuronal activity

Drug repositioning for psychiatric and neurological disorders through a network medicine approach

Efficacy of spironolactone as adjunctive therapy to sodium valproate in bipolar‐I disorder: A double‐blind, randomized, placebo‐controlled clinical trial

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