ArticleEMBO molecular medicine2017
Spironolactone is an antagonist of NRG1-ERBB4 signaling and schizophrenia-relevant endophenotypes in mice.
Article in EMBO molecular medicine, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers, 1 of them a synthesis that pooled it.
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Who cites it
23 citing papers in PubMed, 1 synthesis or guideline pooled it, 40 citations in OpenAlex.
- Repurposed antihypertensive drugs for negative symptoms in schizophrenia: A systematic review and meta-analysis.Psychiatry and clinical neurosciences · 2025Pooled it
- Efficacy of spironolactone as adjunctive therapy to sodium valproate in bipolar-I disorder: A double-blind, randomized, placebo-controlled clinical trial.Brain and behavior · 2023Trial
- Drug Repurposing for Treating NCOR-Related Intellectual Disability.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Antagonizing NRG1-ERBB4 signaling pathway with spironolactone for the treatment of schizophrenia: results of a randomized controlled drug repositioning clinical trial.Communications medicine · 2026Article
- Gonadotropin-releasing hormone alleviates chronic pain-related depression in male mice by rebalancing the anterior cingulate cortex excitatory-inhibitory processes via the protein kinase C/Erb-B2 receptor tyrosine kinase 4 pathway.Brain communications · 2026Article
- Chronic Overexpression of Neuronal NRG1-III in Mice Causes Long-Term Detrimental Changes in Lower Motor Neurons, Neuromuscular Synapses and Motor Behaviour.International journal of molecular sciences · 2025Article
- A second act for spironolactone: cognitive benefits in renal dysfunction - a critical review.Metabolic brain disease · 2025Review
- Potential for New Therapeutic Approaches by Targeting Lactate and pH Mediated Epigenetic Dysregulation in Major Mental Diseases.Biomedicines · 2024Review
- Profiling of ERBB receptors and downstream pathways reveals selectivity and hidden properties of ERBB4 antagonists.iScience · 2024Article
- Schizophrenia in the genetic era: a review from development history, clinical features and genomic research approaches to insights of susceptibility genes.Metabolic brain disease · 2024Review
- Prenatal dexamethasone exposure induces anxiety- and depressive-like behavior of male offspring rats through intrauterine programming of the activation of NRG1-ErbB4 signaling in hippocampal PV interneurons.Cell biology and toxicology · 2023Article
- Antihypertensive drugs and brain function: mechanisms underlying therapeutically beneficial and harmful neuropsychiatric effects.Cardiovascular research · 2023Review
- Spironolactone alleviates schizophrenia-related reversal learning in Tcf4 transgenic mice subjected to social defeat.Schizophrenia (Heidelberg, Germany) · 2022Article
- Spironolactone alleviates myocardial fibrosis via inhibition of Ets-1 in mice with experimental autoimmune myocarditis.Experimental and therapeutic medicine · 2022Article
- Concept of the Munich/Augsburg Consortium Precision in Mental Health for the German Center of Mental Health.Frontiers in psychiatry · 2022Review
- Efficacy of Spironolactone as an Adjunctive Therapy to Risperidone to Improve Symptoms of Schizophrenia: A Double-Blind, Randomized, Placebo-Controlled, Clinical Trial.Iranian journal of psychiatry · 2022Article
- Acute stress reveals different impacts in male and female Zdhhc7-deficient mice.Brain structure & function · 2021Article
- Drug repositioning for psychiatric and neurological disorders through a network medicine approach.Translational psychiatry · 2020Article
- Add-on spironolactone as antagonist of the NRG1-ERBB4 signaling pathway for the treatment of schizophrenia: Study design and methodology of a multicenter randomized, placebo-controlled trial.Contemporary clinical trials communications · 2020Article
- Evolutionarily conserved regulation of sleep by epidermal growth factor receptor signaling.Science advances · 2019Article
Corrections and comments
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Authors and funding
16 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Enhanced NRG1-ERBB4 signaling is a risk pathway in schizophrenia, and corresponding mouse models display several endophenotypes of the disease. Nonetheless, pathway-directed treatment strategies with clinically applicable compounds have not been identified. Here, we applied a cell-based assay using the split TEV technology to screen a library of clinically applicable compounds to identify modulators of NRG1-ERBB4 signaling for repurposing. We recovered spironolactone, known as antagonist of corticosteroids, as an inhibitor of the ERBB4 receptor and tested it in pharmacological and biochemical assays to assess secondary compound actions. Transgenic mice overexpressing Nrg1 type III display cortical Erbb4 hyperphosphorylation, a condition observed in postmortem brains from schizophrenia patients. Spironolactone treatment reverted hyperphosphorylation of activated Erbb4 in these mice. In behavioral tests, spironolactone treatment of Nrg1 type III transgenic mice ameliorated schizophrenia-relevant behavioral endophenotypes, such as reduced sensorimotor gating, hyperactivity, and impaired working memory. Moreover, spironolactone increases spontaneous inhibitory postsynaptic currents in cortical slices supporting an ERBB4-mediated mode-of-action. Our findings suggest that spironolactone, a clinically safe drug, provides an opportunity for new treatment options for schizophrenia.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.