Evaluation of a 5-HT 2B receptor agonist in a murine model of amyotrophic lateral sclerosis
Degeneration of brainstem serotonin neurons has been demonstrated in ALS patients and mouse models and was found responsible for the development of spasticity. Consistent with involvement of central serotonin pathways, 5-HT receptor (5-HT R) was upregulated in microglia of ALS mice. Its deletion wor...
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| Veröffentlicht in: | Scientific reports 2021-12, Vol.11 (1), p.23582 |
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| creator | Arnoux, Alizée Ayme-Dietrich, Estelle Dieterle, Stéphane Goy, Marc-Antoine Schann, Stephan Frauli, Mélanie Monassier, Laurent Dupuis, Luc |
| description | Degeneration of brainstem serotonin neurons has been demonstrated in ALS patients and mouse models and was found responsible for the development of spasticity. Consistent with involvement of central serotonin pathways, 5-HT
receptor (5-HT
R) was upregulated in microglia of ALS mice. Its deletion worsened disease outcome in the Sod1
mouse model and led to microglial degeneration. In ALS patients, a polymorphism in HTR2B gene leading to higher receptor expression in CNS, was associated with increased survival in patients as well as prevention of microglial degeneration. Thus, the aim of our study was to determine the effect of a 5-HT
R agonist : BW723C86 (BW), in the Sod1
mouse model. Despite good pharmacokinetic and pharmacological profiles, BW did not ameliorate disease outcome or motor neuron degeneration in a fast progressing mouse model of ALS despite evidence of modulation of microglial gene expression. |
| doi_str_mv | 10.1038/s41598-021-02900-0 |
| format | Article |
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receptor (5-HT
R) was upregulated in microglia of ALS mice. Its deletion worsened disease outcome in the Sod1
mouse model and led to microglial degeneration. In ALS patients, a polymorphism in HTR2B gene leading to higher receptor expression in CNS, was associated with increased survival in patients as well as prevention of microglial degeneration. Thus, the aim of our study was to determine the effect of a 5-HT
R agonist : BW723C86 (BW), in the Sod1
mouse model. Despite good pharmacokinetic and pharmacological profiles, BW did not ameliorate disease outcome or motor neuron degeneration in a fast progressing mouse model of ALS despite evidence of modulation of microglial gene expression.</description><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/s41598-021-02900-0</identifier><identifier>PMID: 34880312</identifier><language>eng</language><publisher>England</publisher><subject>Amyotrophic Lateral Sclerosis - drug therapy ; Amyotrophic Lateral Sclerosis - metabolism ; Animals ; Disease Models, Animal ; Female ; Indoles - pharmacology ; Male ; Mice ; Mice, Transgenic ; Microglia - drug effects ; Microglia - metabolism ; Motor Neurons - drug effects ; Motor Neurons - metabolism ; Nerve Degeneration - drug therapy ; Nerve Degeneration - metabolism ; Receptor, Serotonin, 5-HT2B - metabolism ; Serotonin - metabolism ; Serotonin 5-HT2 Receptor Agonists - pharmacology ; Superoxide Dismutase-1 - metabolism ; Thiophenes - pharmacology</subject><ispartof>Scientific reports, 2021-12, Vol.11 (1), p.23582</ispartof><rights>2021. The Author(s).</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,777,781,861,27905,27906</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34880312$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Arnoux, Alizée</creatorcontrib><creatorcontrib>Ayme-Dietrich, Estelle</creatorcontrib><creatorcontrib>Dieterle, Stéphane</creatorcontrib><creatorcontrib>Goy, Marc-Antoine</creatorcontrib><creatorcontrib>Schann, Stephan</creatorcontrib><creatorcontrib>Frauli, Mélanie</creatorcontrib><creatorcontrib>Monassier, Laurent</creatorcontrib><creatorcontrib>Dupuis, Luc</creatorcontrib><title>Evaluation of a 5-HT 2B receptor agonist in a murine model of amyotrophic lateral sclerosis</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><description>Degeneration of brainstem serotonin neurons has been demonstrated in ALS patients and mouse models and was found responsible for the development of spasticity. Consistent with involvement of central serotonin pathways, 5-HT
receptor (5-HT
R) was upregulated in microglia of ALS mice. Its deletion worsened disease outcome in the Sod1
mouse model and led to microglial degeneration. In ALS patients, a polymorphism in HTR2B gene leading to higher receptor expression in CNS, was associated with increased survival in patients as well as prevention of microglial degeneration. Thus, the aim of our study was to determine the effect of a 5-HT
R agonist : BW723C86 (BW), in the Sod1
mouse model. Despite good pharmacokinetic and pharmacological profiles, BW did not ameliorate disease outcome or motor neuron degeneration in a fast progressing mouse model of ALS despite evidence of modulation of microglial gene expression.</description><subject>Amyotrophic Lateral Sclerosis - drug therapy</subject><subject>Amyotrophic Lateral Sclerosis - metabolism</subject><subject>Animals</subject><subject>Disease Models, Animal</subject><subject>Female</subject><subject>Indoles - pharmacology</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Microglia - drug effects</subject><subject>Microglia - metabolism</subject><subject>Motor Neurons - drug effects</subject><subject>Motor Neurons - metabolism</subject><subject>Nerve Degeneration - drug therapy</subject><subject>Nerve Degeneration - metabolism</subject><subject>Receptor, Serotonin, 5-HT2B - metabolism</subject><subject>Serotonin - metabolism</subject><subject>Serotonin 5-HT2 Receptor Agonists - pharmacology</subject><subject>Superoxide Dismutase-1 - metabolism</subject><subject>Thiophenes - pharmacology</subject><issn>2045-2322</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFjkEKwjAURIMgWtQLuJB_gehP0kK7VSo9gDsXJbZRI0lTklTw9hbRtQPDLN5bDCFrhluGIt-FlGVFTpGzsQUixQlJOKYZ5YLzOVmF8MAxGS9SVszIXKR5joLxhJzLpzSDjNp14K4gIaPVCfgevGpUH50HeXOdDhF0N1I7eN0psK5V5uPbl4ve9XfdgJFReWkgNEZ5F3RYkulVmqBW312QzbE8HSraDxer2rr32kr_qn9vxF_hDVfwRXA</recordid><startdate>20211208</startdate><enddate>20211208</enddate><creator>Arnoux, Alizée</creator><creator>Ayme-Dietrich, Estelle</creator><creator>Dieterle, Stéphane</creator><creator>Goy, Marc-Antoine</creator><creator>Schann, Stephan</creator><creator>Frauli, Mélanie</creator><creator>Monassier, Laurent</creator><creator>Dupuis, Luc</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope></search><sort><creationdate>20211208</creationdate><title>Evaluation of a 5-HT 2B receptor agonist in a murine model of amyotrophic lateral sclerosis</title><author>Arnoux, Alizée ; Ayme-Dietrich, Estelle ; Dieterle, Stéphane ; Goy, Marc-Antoine ; Schann, Stephan ; Frauli, Mélanie ; Monassier, Laurent ; Dupuis, Luc</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-pubmed_primary_348803123</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Amyotrophic Lateral Sclerosis - drug therapy</topic><topic>Amyotrophic Lateral Sclerosis - metabolism</topic><topic>Animals</topic><topic>Disease Models, Animal</topic><topic>Female</topic><topic>Indoles - pharmacology</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Microglia - drug effects</topic><topic>Microglia - metabolism</topic><topic>Motor Neurons - drug effects</topic><topic>Motor Neurons - metabolism</topic><topic>Nerve Degeneration - drug therapy</topic><topic>Nerve Degeneration - metabolism</topic><topic>Receptor, Serotonin, 5-HT2B - metabolism</topic><topic>Serotonin - metabolism</topic><topic>Serotonin 5-HT2 Receptor Agonists - pharmacology</topic><topic>Superoxide Dismutase-1 - metabolism</topic><topic>Thiophenes - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Arnoux, Alizée</creatorcontrib><creatorcontrib>Ayme-Dietrich, Estelle</creatorcontrib><creatorcontrib>Dieterle, Stéphane</creatorcontrib><creatorcontrib>Goy, Marc-Antoine</creatorcontrib><creatorcontrib>Schann, Stephan</creatorcontrib><creatorcontrib>Frauli, Mélanie</creatorcontrib><creatorcontrib>Monassier, Laurent</creatorcontrib><creatorcontrib>Dupuis, Luc</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><jtitle>Scientific reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Arnoux, Alizée</au><au>Ayme-Dietrich, Estelle</au><au>Dieterle, Stéphane</au><au>Goy, Marc-Antoine</au><au>Schann, Stephan</au><au>Frauli, Mélanie</au><au>Monassier, Laurent</au><au>Dupuis, Luc</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Evaluation of a 5-HT 2B receptor agonist in a murine model of amyotrophic lateral sclerosis</atitle><jtitle>Scientific reports</jtitle><addtitle>Sci Rep</addtitle><date>2021-12-08</date><risdate>2021</risdate><volume>11</volume><issue>1</issue><spage>23582</spage><pages>23582-</pages><eissn>2045-2322</eissn><abstract>Degeneration of brainstem serotonin neurons has been demonstrated in ALS patients and mouse models and was found responsible for the development of spasticity. Consistent with involvement of central serotonin pathways, 5-HT
receptor (5-HT
R) was upregulated in microglia of ALS mice. Its deletion worsened disease outcome in the Sod1
mouse model and led to microglial degeneration. In ALS patients, a polymorphism in HTR2B gene leading to higher receptor expression in CNS, was associated with increased survival in patients as well as prevention of microglial degeneration. Thus, the aim of our study was to determine the effect of a 5-HT
R agonist : BW723C86 (BW), in the Sod1
mouse model. Despite good pharmacokinetic and pharmacological profiles, BW did not ameliorate disease outcome or motor neuron degeneration in a fast progressing mouse model of ALS despite evidence of modulation of microglial gene expression.</abstract><cop>England</cop><pmid>34880312</pmid><doi>10.1038/s41598-021-02900-0</doi></addata></record> |
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| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Nature Free; PubMed Central; Alma/SFX Local Collection; Springer Nature OA/Free Journals; Free Full-Text Journals in Chemistry |
| subjects | Amyotrophic Lateral Sclerosis - drug therapy Amyotrophic Lateral Sclerosis - metabolism Animals Disease Models, Animal Female Indoles - pharmacology Male Mice Mice, Transgenic Microglia - drug effects Microglia - metabolism Motor Neurons - drug effects Motor Neurons - metabolism Nerve Degeneration - drug therapy Nerve Degeneration - metabolism Receptor, Serotonin, 5-HT2B - metabolism Serotonin - metabolism Serotonin 5-HT2 Receptor Agonists - pharmacology Superoxide Dismutase-1 - metabolism Thiophenes - pharmacology |
| title | Evaluation of a 5-HT 2B receptor agonist in a murine model of amyotrophic lateral sclerosis |
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