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

Autor: Grigoletto J; Bio@SNS Laboratory, Scuola Normale Superiore, Piazza dei Cavalieri 7, 56126, Pisa, Italy., Miraglia F; Bio@SNS Laboratory, Scuola Normale Superiore, Piazza dei Cavalieri 7, 56126, Pisa, Italy., Benvenuti L; Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, 56126, Pisa, Italy., Pellegrini C; Unit of Histology and Medical Embryology, Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, 56126, Pisa, Italy., Soldi S; AAT Advanced Analytical Technologies Srl, via P. Majavacca 12 - 29017, Fiorenzuola d'Arda (PC), Italy., Galletti S; AAT Advanced Analytical Technologies Srl, via P. Majavacca 12 - 29017, Fiorenzuola d'Arda (PC), Italy., Cattaneo A; Bio@SNS Laboratory, Scuola Normale Superiore, Piazza dei Cavalieri 7, 56126, Pisa, Italy.; Neurotrophins and Neurodegenerative Diseases Laboratory, Rita Levi-Montalcini European Brain Research Institute, Viale Regina Elena 295, Rome, 00161, Italy., Pich EM; Corporate R&D, Alfasigma S.p.A., Via Pontina km 30.400, 00071, Pomezia (Rome), Italy., Grimaldi M; Corporate R&D, Alfasigma S.p.A., Via Pontina km 30.400, 00071, Pomezia (Rome), Italy., Colla E; Bio@SNS Laboratory, Scuola Normale Superiore, Piazza dei Cavalieri 7, 56126, Pisa, Italy. emanuela.colla@sns.it.; Department of Human Sciences and Promotion of Quality of Life, San Raffaele Open University, Via Val Cannuta 247, 00166, Rome, Italy. emanuela.colla@sns.it., Vesci L; Corporate R&D, Alfasigma S.p.A., Via Pontina km 30.400, 00071, Pomezia (Rome), Italy. loredana.vesci@alfasigma.com.
Jazyk: angličtina
Zdroj: NPJ Parkinson's disease [NPJ Parkinsons Dis] 2023 Oct 02; Vol. 9 (1), pp. 140. Date of Electronic Publication: 2023 Oct 02.
DOI: 10.1038/s41531-023-00582-1
Abstrakt: 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.
(© 2023. Springer Nature Limited.)
Databáze: MEDLINE
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