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Velusetrag rescues GI dysfunction, gut inflammation and dysbiosis in a mouse model of Parkinson’s disease

Velusetrag rescues GI dysfunction, gut inflammation and dysbiosis in a mouse model of Parkinson’s disease

Authors :
Jessica Grigoletto
Fabiana Miraglia
Laura Benvenuti
Carolina Pellegrini
Sara Soldi
Serena Galletti
Antonino Cattaneo
Emilio Merlo Pich
Maria Grimaldi
Emanuela Colla
Loredana Vesci
Source :
npj Parkinson's Disease, Vol 9, Iss 1, Pp 1-15 (2023)
Publication Year :
2023
Publisher :
Nature Portfolio, 2023.

Abstract

Abstract In patients with Parkinson’s disease (PD), constipation is common, and it appears in a prodromal stage before the hallmark motor symptoms. The present study aimed to investigate whether Velusetrag, a selective 5‑HT4 receptor agonist, may be a suitable candidate to improve intestinal motility in a mouse model of PD. Five months old PrP human A53T alpha-synuclein transgenic (Tg) mice, which display severe constipation along with decreased colonic cholinergic transmission already at 3 months, were treated daily with the drug for 4 weeks. Velusetrag treatment reduced constipation by significantly stimulating both the longitudinal and circular-driven contractions and improved inflammation by reducing the level of serum and colonic IL1β and TNF-α and by decreasing the number of GFAP-positive glia cells in the colon of treated mice. No significant downregulation of the 5-HT4 receptor was observed but instead Velusetrag seemed to improve axonal degeneration in Tgs as shown by an increase in NF-H and VAChT staining. Ultimately, Velusetrag restored a well-balanced intestinal microbial composition comparable to non-Tg mice. Based on these promising data, we are confident that Velusetrag is potentially eligible for clinical studies to treat constipation in PD patients.

Details

Language :
English
ISSN :
23738057
Volume :
9
Issue :
1
Database :
Directory of Open Access Journals
Journal :
npj Parkinson's Disease
Publication Type :
Academic Journal
Accession number :
edsdoj.033f9b868f44b3b9f1b3b747ced7510
Document Type :
article
Full Text :
https://doi.org/10.1038/s41531-023-00582-1