Protective and Pain-Killer Effects of AMC3, a Novel N-Formyl Peptide Receptors (FPRs) Modulator, in Experimental Models of Rheumatoid Arthritis
Valentina Ferrara,
Alessandra Toti,
Elena Lucarini,
Carmen Parisio,
Laura Micheli,
Clara Ciampi,
Francesco Margiotta,
Letizia Crocetti,
Claudia Vergelli,
Maria Paola Giovannoni,
Lorenzo Di Cesare Mannelli,
Carla Ghelardini
Affiliations
Valentina Ferrara
Department of Neuroscience, Psychology, Drug Research and Child Health—NEUROFARBA—Pharmacology and Toxicology Section, University of Florence, 50139 Florence, Italy
Alessandra Toti
Department of Neuroscience, Psychology, Drug Research and Child Health—NEUROFARBA—Pharmacology and Toxicology Section, University of Florence, 50139 Florence, Italy
Elena Lucarini
Department of Neuroscience, Psychology, Drug Research and Child Health—NEUROFARBA—Pharmacology and Toxicology Section, University of Florence, 50139 Florence, Italy
Carmen Parisio
Department of Neuroscience, Psychology, Drug Research and Child Health—NEUROFARBA—Pharmacology and Toxicology Section, University of Florence, 50139 Florence, Italy
Laura Micheli
Department of Neuroscience, Psychology, Drug Research and Child Health—NEUROFARBA—Pharmacology and Toxicology Section, University of Florence, 50139 Florence, Italy
Clara Ciampi
Department of Neuroscience, Psychology, Drug Research and Child Health—NEUROFARBA—Pharmacology and Toxicology Section, University of Florence, 50139 Florence, Italy
Francesco Margiotta
Department of Neuroscience, Psychology, Drug Research and Child Health—NEUROFARBA—Pharmacology and Toxicology Section, University of Florence, 50139 Florence, Italy
Letizia Crocetti
Department of Neuroscience, Psychology, Drug Research and Child Health—NEUROFARBA—Pharmaceutical and Nutraceutical Section, University of Florence, 50139 Florence, Italy
Claudia Vergelli
Department of Neuroscience, Psychology, Drug Research and Child Health—NEUROFARBA—Pharmaceutical and Nutraceutical Section, University of Florence, 50139 Florence, Italy
Maria Paola Giovannoni
Department of Neuroscience, Psychology, Drug Research and Child Health—NEUROFARBA—Pharmaceutical and Nutraceutical Section, University of Florence, 50139 Florence, Italy
Lorenzo Di Cesare Mannelli
Department of Neuroscience, Psychology, Drug Research and Child Health—NEUROFARBA—Pharmacology and Toxicology Section, University of Florence, 50139 Florence, Italy
Carla Ghelardini
Department of Neuroscience, Psychology, Drug Research and Child Health—NEUROFARBA—Pharmacology and Toxicology Section, University of Florence, 50139 Florence, Italy
Rheumatoid arthritis is an autoimmune disorder that causes chronic joint pain, swelling, and movement impairment, resulting from prolonged inflammation-induced cartilage and bone degradation. The pathogenesis of RA, which is still unclear, makes diagnosis and treatment difficult and calls for new therapeutic strategies to cure the disease. Recent research has identified FPRs as a promising druggable target, with AMC3, a novel agonist, showing preclinical efficacy in vitro and in vivo. In vitro, AMC3 (1–30 µM) exhibited significant antioxidant effects in IL-1β (10 ng/mL)-treated chondrocytes for 24 h. AMC3 displayed a protective effect by downregulating the mRNA expression of several pro-inflammatory and pro-algic genes (iNOS, COX-2, and VEGF-A), while upregulating genes essential for structural integrity (MMP-13, ADAMTS-4, and COLIAI). In vivo, AMC3 (10 mg kg−1) prevented hypersensitivity and restored postural balance in CFA-injected rats after 14 days. AMC3 attenuated joint alterations, reduced joint inflammatory infiltrate, pannus formation, and cartilage erosion. Chronic AMC3 administration reduced transcriptional changes of genes causing excitotoxicity and pain (EAATs and CCL2) and prevented morphological changes in astrocytes, including cell body hypertrophy, processes length, and thickness, caused by CFA in the spinal cord. This study demonstrates the usefulness of AMC3 and establishes the groundwork for further research.
