Roberto Carlos Coll1, Patricia María Vargas1, María Laura Mariani1, Alicia Beatriz Penissi2. 1. Instituto de Histología Y Embriología "Dr. Mario H. Burgos" (IHEM-CONICET), Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Casilla de Correo 56. (5500), Mendoza, Argentina. 2. Instituto de Histología Y Embriología "Dr. Mario H. Burgos" (IHEM-CONICET), Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, Casilla de Correo 56. (5500), Mendoza, Argentina. apenissi@fcm.uncu.edu.ar.
Abstract
INTRODUCTION: Mast cells are involved in not only inducing, but also maintaining neurogenic inflammation and neuropathic pain. In previous work, we have demonstrated that dehydroleucodine, xanthatin and 3-benzyloxymethyl-5H-furan-2-one inhibit rat peritoneal and human LAD2 mast cell degranulation induced by compound 48/80 and calcium ionophore A23187. However, the effect of these molecules on neuropeptide-induced mast cell activation has not been studied so far. OBJECTIVE: The aim of this study was to determine whether dehydroleucodine, xanthatin, and 3-benzyloxymethyl-5H-furan-2-one inhibit neuropeptide-induced mast cell activation. METHODS: This work is based on in vitro simulation of a neurogenic inflammation scenario involving neuropeptides and mast cells, to subsequently analyze potential therapeutic strategies for neuropathic pain. RESULTS: Neuromedin-N did not stimulate mast cell serotonin release but substance P and neurotensin did induce serotonin release from peritoneal mast cells in a dose-dependent manner. Mast cell serotonin release induced by substance P and neurotensin was inhibited by dehydroleucodine and xanthatin, but not by 3-benzyloxymethyl-5H-furan-2-one. The inhibitory potency of dehydroleucodine and xanthatin was higher than that obtained with the reference compounds, ketotifen and sodium chromoglycate, when mast cells were preincubated with dehydroleucodine before substance P incubation, and with dehydroleucodine or xanthatin before neurotensin incubation. CONCLUSIONS: These results are the first strong evidence supporting the hypothesis that dehydroleucodine and xanthatin inhibit substance P- and neurotensin-induced serotonin release from rat peritoneal mast cells. Our findings suggest, additionally, that these α,β-unsaturated lactones could be of value in future pharmacological research related to inappropriate mast cell activation conditions such as neurogenic inflammation and neuropathic pain.
INTRODUCTION: Mast cells are involved in not only inducing, but also maintaining neurogenic inflammation and neuropathic pain. In previous work, we have demonstrated that dehydroleucodine, xanthatin and 3-benzyloxymethyl-5H-furan-2-one inhibit rat peritoneal and human LAD2 mast cell degranulation induced by compound 48/80 and calcium ionophore A23187. However, the effect of these molecules on neuropeptide-induced mast cell activation has not been studied so far. OBJECTIVE: The aim of this study was to determine whether dehydroleucodine, xanthatin, and 3-benzyloxymethyl-5H-furan-2-one inhibit neuropeptide-induced mast cell activation. METHODS: This work is based on in vitro simulation of a neurogenic inflammation scenario involving neuropeptides and mast cells, to subsequently analyze potential therapeutic strategies for neuropathic pain. RESULTS: Neuromedin-N did not stimulate mast cell serotonin release but substance P and neurotensin did induce serotonin release from peritoneal mast cells in a dose-dependent manner. Mast cell serotonin release induced by substance P and neurotensin was inhibited by dehydroleucodine and xanthatin, but not by 3-benzyloxymethyl-5H-furan-2-one. The inhibitory potency of dehydroleucodine and xanthatin was higher than that obtained with the reference compounds, ketotifen and sodium chromoglycate, when mast cells were preincubated with dehydroleucodine before substance P incubation, and with dehydroleucodine or xanthatin before neurotensin incubation. CONCLUSIONS: These results are the first strong evidence supporting the hypothesis that dehydroleucodine and xanthatin inhibit substance P- and neurotensin-induced serotonin release from rat peritoneal mast cells. Our findings suggest, additionally, that these α,β-unsaturated lactones could be of value in future pharmacological research related to inappropriate mast cell activation conditions such as neurogenic inflammation and neuropathic pain.