The 5-HT4 receptor agonist, Velusetrag, rescues GI dysfunction, gut inflammation and dysbiosis in the A53T αS mouse model of Parkinson’s Disease.

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 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 IL-1β and TNFα and by decreasing the number of GFAP-positive glia cells in the colon of treated mice. No downregulation of the 5-HT4 receptor was observed but instead Velusetrag seemed to induce axonal regeneration in the colon, stimulating the AKT pathway. Ultimately, Velusetrag restored a well-balanced intestinal microbial composition comparable to non transgenic mice. Based on these promising data, we are confident that Velusetrag is potentially eligible for clinical studies to treat constipation in PD patients.