Analysis of hyperforin (St. John's wort) action at TRPC6 channel leads to the development of a new class of antidepressant drugs
- Publikationstyp:
- Zeitschriftenaufsatz
- Metadaten:
-
- Autoren
- Yamina El Hamdaoui
- Fang Zheng
- Nikolas Fritz
- Lian Ye
- Anh Tran Mai
- Kevin Schwickert
- Tanja Schirmeister
- Albert Braeuning
- Dajana Lichtenstein
- Ute A Hellmich
- Dorothee Weikert
- Markus Heinrich
- Giulia Treccani
- Michael KE Schaefer
- Gabriel Nowak
- Bernd Nuernberg
- Christian Alzheimer
- Christian P Mueller
- Kristina Friedland
- Autoren-URL
- https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000866309900001&DestLinkType=FullRecord&DestApp=WOS_CPL
- DOI
- 10.1038/s41380-022-01804-3
- eISSN
- 1476-5578
- Externe Identifier
- Clarivate Analytics Document Solution ID: I3BS1
- PubMed Identifier: 36224261
- ISSN
- 1359-4184
- Ausgabe der Veröffentlichung
- 12
- Zeitschrift
- MOLECULAR PSYCHIATRY
- Paginierung
- 5070 - 5085
- Datum der Veröffentlichung
- 2022
- Status
- Published
- Titel
- Analysis of hyperforin (St. John's wort) action at TRPC6 channel leads to the development of a new class of antidepressant drugs
- Sub types
- Article
- Ausgabe der Zeitschrift
- 27
Datenquelle: Web of Science (Lite)
- Andere Metadatenquellen:
-
- Abstract
- <jats:title>Abstract</jats:title><jats:p>St. John’s wort is an herb, long used in folk medicine for the treatment of mild depression. Its antidepressant constituent, hyperforin, has properties such as chemical instability and induction of drug-drug interactions that preclude its use for individual pharmacotherapies. Here we identify the transient receptor potential canonical 6 channel (TRPC6) as a druggable target to control anxious and depressive behavior and as a requirement for hyperforin antidepressant action. We demonstrate that TRPC6 deficiency in mice not only results in anxious and depressive behavior, but also reduces excitability of hippocampal CA1 pyramidal neurons and dentate gyrus granule cells. Using electrophysiology and targeted mutagenesis, we show that hyperforin activates the channel via a specific binding motif at TRPC6. We performed an analysis of hyperforin action to develop a new antidepressant drug that uses the same TRPC6 target mechanism for its antidepressant action. We synthesized the hyperforin analog Hyp13, which shows similar binding to TRPC6 and recapitulates TRPC6-dependent anxiolytic and antidepressant effects in mice. Hyp13 does not activate pregnan-X-receptor (<jats:italic>PXR</jats:italic>) and thereby loses the potential to induce drug-drug interactions. This may provide a new approach to develop better treatments for depression, since depression remains one of the most treatment-resistant mental disorders, warranting the development of effective drugs based on naturally occurring compounds.</jats:p>
- Autoren
- Yamina El Hamdaoui
- Fang Zheng
- Nikolas Fritz
- Lian Ye
- Mai Anh Tran
- Kevin Schwickert
- Tanja Schirmeister
- Albert Braeuning
- Dajana Lichtenstein
- Ute A Hellmich
- Dorothee Weikert
- Markus Heinrich
- Giulia Treccani
- Michael KE Schäfer
- Gabriel Nowak
- Bernd Nürnberg
- Christian Alzheimer
- Christian P Müller
- Kristina Friedland
- DOI
- 10.1038/s41380-022-01804-3
- eISSN
- 1476-5578
- ISSN
- 1359-4184
- Ausgabe der Veröffentlichung
- 12
- Zeitschrift
- Molecular Psychiatry
- Sprache
- en
- Online publication date
- 2022
- Paginierung
- 5070 - 5085
- Datum der Veröffentlichung
- 2022
- Status
- Published
- Herausgeber
- Springer Science and Business Media LLC
- Herausgeber URL
- http://dx.doi.org/10.1038/s41380-022-01804-3
- Datum der Datenerfassung
- 2023
- Titel
- Analysis of hyperforin (St. John’s wort) action at TRPC6 channel leads to the development of a new class of antidepressant drugs
- Ausgabe der Zeitschrift
- 27
Datenquelle: Crossref
- Abstract
- St. John's wort is an herb, long used in folk medicine for the treatment of mild depression. Its antidepressant constituent, hyperforin, has properties such as chemical instability and induction of drug-drug interactions that preclude its use for individual pharmacotherapies. Here we identify the transient receptor potential canonical 6 channel (TRPC6) as a druggable target to control anxious and depressive behavior and as a requirement for hyperforin antidepressant action. We demonstrate that TRPC6 deficiency in mice not only results in anxious and depressive behavior, but also reduces excitability of hippocampal CA1 pyramidal neurons and dentate gyrus granule cells. Using electrophysiology and targeted mutagenesis, we show that hyperforin activates the channel via a specific binding motif at TRPC6. We performed an analysis of hyperforin action to develop a new antidepressant drug that uses the same TRPC6 target mechanism for its antidepressant action. We synthesized the hyperforin analog Hyp13, which shows similar binding to TRPC6 and recapitulates TRPC6-dependent anxiolytic and antidepressant effects in mice. Hyp13 does not activate pregnan-X-receptor (PXR) and thereby loses the potential to induce drug-drug interactions. This may provide a new approach to develop better treatments for depression, since depression remains one of the most treatment-resistant mental disorders, warranting the development of effective drugs based on naturally occurring compounds.
- Addresses
- Pharmacology & Toxicology, Institute for Pharmaceutical and Biomedical Sciences, Johannes-Gutenberg Universität Mainz (JGU), Mainz, Germany.
- Autoren
- Yamina El Hamdaoui
- Fang Zheng
- Nikolas Fritz
- Lian Ye
- Mai Anh Tran
- Kevin Schwickert
- Tanja Schirmeister
- Albert Braeuning
- Dajana Lichtenstein
- Ute A Hellmich
- Dorothee Weikert
- Markus Heinrich
- Giulia Treccani
- Michael KE Schäfer
- Gabriel Nowak
- Bernd Nürnberg
- Christian Alzheimer
- Christian P Müller
- Kristina Friedland
- DOI
- 10.1038/s41380-022-01804-3
- eISSN
- 1476-5578
- Externe Identifier
- PubMed Identifier: 36224261
- PubMed Central ID: PMC9763113
- Funding acknowledgements
- Deutsche Forschungsgemeinschaft: 270949263/ GRK 2162
- Deutsche Forschungsgemeinschaft: AL 294/10-2
- Deutsche Forschungsgemeinschaft: NU 53/12-2
- Loewe Dynamem:
- Carl-Zeiss-Stiftung:
- EU Eranet HypziTRP:
- EU Eranet HypZiTRP:
- Deutsche Forschungsgemeinschaft: EXC 2051 - Project ID 390713860
- Open access
- true
- ISSN
- 1359-4184
- Ausgabe der Veröffentlichung
- 12
- Zeitschrift
- Molecular psychiatry
- Schlüsselwörter
- Animals
- Mice
- Hypericum
- Terpenes
- Phloroglucinol
- Antidepressive Agents
- TRPC6 Cation Channel
- Sprache
- eng
- Medium
- Print-Electronic
- Online publication date
- 2022
- Open access status
- Open Access
- Paginierung
- 5070 - 5085
- Datum der Veröffentlichung
- 2022
- Status
- Published
- Publisher licence
- CC BY
- Datum der Datenerfassung
- 2022
- Titel
- Analysis of hyperforin (St. John's wort) action at TRPC6 channel leads to the development of a new class of antidepressant drugs.
- Sub types
- Research Support, Non-U.S. Gov't
- research-article
- Journal Article
- Ausgabe der Zeitschrift
- 27
Files
https://www.nature.com/articles/s41380-022-01804-3.pdf https://europepmc.org/articles/PMC9763113?pdf=render
Datenquelle: Europe PubMed Central
- Abstract
- St. John's wort is an herb, long used in folk medicine for the treatment of mild depression. Its antidepressant constituent, hyperforin, has properties such as chemical instability and induction of drug-drug interactions that preclude its use for individual pharmacotherapies. Here we identify the transient receptor potential canonical 6 channel (TRPC6) as a druggable target to control anxious and depressive behavior and as a requirement for hyperforin antidepressant action. We demonstrate that TRPC6 deficiency in mice not only results in anxious and depressive behavior, but also reduces excitability of hippocampal CA1 pyramidal neurons and dentate gyrus granule cells. Using electrophysiology and targeted mutagenesis, we show that hyperforin activates the channel via a specific binding motif at TRPC6. We performed an analysis of hyperforin action to develop a new antidepressant drug that uses the same TRPC6 target mechanism for its antidepressant action. We synthesized the hyperforin analog Hyp13, which shows similar binding to TRPC6 and recapitulates TRPC6-dependent anxiolytic and antidepressant effects in mice. Hyp13 does not activate pregnan-X-receptor (PXR) and thereby loses the potential to induce drug-drug interactions. This may provide a new approach to develop better treatments for depression, since depression remains one of the most treatment-resistant mental disorders, warranting the development of effective drugs based on naturally occurring compounds.
- Date of acceptance
- 2022
- Autoren
- Yamina El Hamdaoui
- Fang Zheng
- Nikolas Fritz
- Lian Ye
- Mai Anh Tran
- Kevin Schwickert
- Tanja Schirmeister
- Albert Braeuning
- Dajana Lichtenstein
- Ute A Hellmich
- Dorothee Weikert
- Markus Heinrich
- Giulia Treccani
- Michael KE Schäfer
- Gabriel Nowak
- Bernd Nürnberg
- Christian Alzheimer
- Christian P Müller
- Kristina Friedland
- Autoren-URL
- https://www.ncbi.nlm.nih.gov/pubmed/36224261
- DOI
- 10.1038/s41380-022-01804-3
- eISSN
- 1476-5578
- Externe Identifier
- PubMed Central ID: PMC9763113
- Ausgabe der Veröffentlichung
- 12
- Zeitschrift
- Mol Psychiatry
- Schlüsselwörter
- Animals
- Mice
- Antidepressive Agents
- Hypericum
- TRPC6 Cation Channel
- Phloroglucinol
- Terpenes
- Sprache
- eng
- Country
- England
- Paginierung
- 5070 - 5085
- PII
- 10.1038/s41380-022-01804-3
- Datum der Veröffentlichung
- 2022
- Status
- Published
- Datum, an dem der Datensatz öffentlich gemacht wurde
- 2022
- Titel
- Analysis of hyperforin (St. John's wort) action at TRPC6 channel leads to the development of a new class of antidepressant drugs.
- Sub types
- Journal Article
- Research Support, Non-U.S. Gov't
- Ausgabe der Zeitschrift
- 27
Datenquelle: PubMed
- Author's licence
- CC-BY
- Autoren
- Yamina El Hamdaoui
- Fang Zheng
- Nikolas Fritz
- Lian Ye
- Mai Anh Tran
- Kevin Schwickert
- Tanja Schirmeister
- Albert Braeuning
- Dajana Lichtenstein
- Ute A Hellmich
- Dorothee Weikert
- Markus Heinrich
- Giulia Treccani
- Michael KE Schäfer
- Gabriel Nowak
- Bernd Nürnberg
- Christian Alzheimer
- Christian P Müller
- Kristina Friedland
- Hosting institution
- Universitätsbibliothek Mainz
- Sammlungen
- DFG-491381577-H
- Resource version
- Published version
- DOI
- 10.1038/s41380-022-01804-3
- Funding acknowledgements
- Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 491381577
- File(s) embargoed
- false
- Open access
- true
- ISSN
- 1476-5578
- Zeitschrift
- Molecular psychiatry
- Schlüsselwörter
- 610 Medizin
- 610 Medical sciences
- Sprache
- eng
- Open access status
- Open Access
- Paginierung
- 5070 - 5085
- Datum der Veröffentlichung
- 2022
- Public URL
- https://openscience.ub.uni-mainz.de/handle/20.500.12030/8418
- Herausgeber
- Springer
- Datum der Datenerfassung
- 2023
- Datum, an dem der Datensatz öffentlich gemacht wurde
- 2023
- Zugang
- Public
- Titel
- Analysis of hyperforin (St. John’s wort) action at TRPC6 channel leads to the development of a new class of antidepressant drugs
- Ausgabe der Zeitschrift
- 27
Files
analysis_of_hyperforin_st_joh-20230118131954936.pdf
Datenquelle: OPENSCIENCE.UB
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