Evaluation of a 5-HT2B receptor agonist in a murine model of amyotrophic lateral sclerosis

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-HT2B receptor (5-HT2BR) was upregulated in microglia of ALS mice. Its...

Full description

Bibliographic Details
Main Authors: Alizée Arnoux, Estelle Ayme-Dietrich, Stéphane Dieterle, Marc-Antoine Goy, Stephan Schann, Mélanie Frauli, Laurent Monassier, Luc Dupuis
Format: Article
Language:English
Published: Nature Portfolio 2021-12-01
Series:Scientific Reports
Online Access:https://doi.org/10.1038/s41598-021-02900-0
_version_ 1818337581335576576
author Alizée Arnoux
Estelle Ayme-Dietrich
Stéphane Dieterle
Marc-Antoine Goy
Stephan Schann
Mélanie Frauli
Laurent Monassier
Luc Dupuis
author_facet Alizée Arnoux
Estelle Ayme-Dietrich
Stéphane Dieterle
Marc-Antoine Goy
Stephan Schann
Mélanie Frauli
Laurent Monassier
Luc Dupuis
author_sort Alizée Arnoux
collection DOAJ
description 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-HT2B receptor (5-HT2BR) was upregulated in microglia of ALS mice. Its deletion worsened disease outcome in the Sod1 G86R 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-HT2BR agonist : BW723C86 (BW), in the Sod1 G86R 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.
first_indexed 2024-12-13T14:57:29Z
format Article
id doaj.art-78eb463cf7e84a3299345d8d48c1867d
institution Directory Open Access Journal
issn 2045-2322
language English
last_indexed 2024-12-13T14:57:29Z
publishDate 2021-12-01
publisher Nature Portfolio
record_format Article
series Scientific Reports
spelling doaj.art-78eb463cf7e84a3299345d8d48c1867d2022-12-21T23:41:12ZengNature PortfolioScientific Reports2045-23222021-12-0111111110.1038/s41598-021-02900-0Evaluation of a 5-HT2B receptor agonist in a murine model of amyotrophic lateral sclerosisAlizée Arnoux0Estelle Ayme-Dietrich1Stéphane Dieterle2Marc-Antoine Goy3Stephan Schann4Mélanie Frauli5Laurent Monassier6Luc Dupuis7Mécanismes Centraux et Périphériques de la Neurodégénérescence, U1118, Inserm, UMR-S1118, CRBS, Université de StrasbourgLaboratoire de Pharmacologie et Toxicologie Neurocardiovasculaire, UR7296, Université de StrasbourgMécanismes Centraux et Périphériques de la Neurodégénérescence, U1118, Inserm, UMR-S1118, CRBS, Université de StrasbourgMécanismes Centraux et Périphériques de la Neurodégénérescence, U1118, Inserm, UMR-S1118, CRBS, Université de StrasbourgDomain TherapeuticsDomain TherapeuticsLaboratoire de Pharmacologie et Toxicologie Neurocardiovasculaire, UR7296, Université de StrasbourgMécanismes Centraux et Périphériques de la Neurodégénérescence, U1118, Inserm, UMR-S1118, CRBS, Université de StrasbourgAbstract 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-HT2B receptor (5-HT2BR) was upregulated in microglia of ALS mice. Its deletion worsened disease outcome in the Sod1 G86R 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-HT2BR agonist : BW723C86 (BW), in the Sod1 G86R 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.https://doi.org/10.1038/s41598-021-02900-0
spellingShingle Alizée Arnoux
Estelle Ayme-Dietrich
Stéphane Dieterle
Marc-Antoine Goy
Stephan Schann
Mélanie Frauli
Laurent Monassier
Luc Dupuis
Evaluation of a 5-HT2B receptor agonist in a murine model of amyotrophic lateral sclerosis
Scientific Reports
title Evaluation of a 5-HT2B receptor agonist in a murine model of amyotrophic lateral sclerosis
title_full Evaluation of a 5-HT2B receptor agonist in a murine model of amyotrophic lateral sclerosis
title_fullStr Evaluation of a 5-HT2B receptor agonist in a murine model of amyotrophic lateral sclerosis
title_full_unstemmed Evaluation of a 5-HT2B receptor agonist in a murine model of amyotrophic lateral sclerosis
title_short Evaluation of a 5-HT2B receptor agonist in a murine model of amyotrophic lateral sclerosis
title_sort evaluation of a 5 ht2b receptor agonist in a murine model of amyotrophic lateral sclerosis
url https://doi.org/10.1038/s41598-021-02900-0
work_keys_str_mv AT alizeearnoux evaluationofa5ht2breceptoragonistinamurinemodelofamyotrophiclateralsclerosis
AT estelleaymedietrich evaluationofa5ht2breceptoragonistinamurinemodelofamyotrophiclateralsclerosis
AT stephanedieterle evaluationofa5ht2breceptoragonistinamurinemodelofamyotrophiclateralsclerosis
AT marcantoinegoy evaluationofa5ht2breceptoragonistinamurinemodelofamyotrophiclateralsclerosis
AT stephanschann evaluationofa5ht2breceptoragonistinamurinemodelofamyotrophiclateralsclerosis
AT melaniefrauli evaluationofa5ht2breceptoragonistinamurinemodelofamyotrophiclateralsclerosis
AT laurentmonassier evaluationofa5ht2breceptoragonistinamurinemodelofamyotrophiclateralsclerosis
AT lucdupuis evaluationofa5ht2breceptoragonistinamurinemodelofamyotrophiclateralsclerosis