1-Piperidine Propionic Acid Ameliorates Experimental Crystal-induced Arthritis and Carrageenan-induced Hyperalgesia

Objective Musculoskeletal diseases, particularly arthritis, are a leading cause of disability worldwide. Current treatments have limitations, prompting the search for new therapeutic targets. This study investigated the anti-inflammatory and analgesic effects of 1-Piperidine Propionic Acid (1-PPA), a novel proteinase-activated receptor-2 (PAR2) antagonist, in two mouse models of joint inflammation and pain. Methods Inflammation and pain were induced by injecting monosodium urate (MSU) crystals into ankle joints or carrageenan into the hind paws. Mice were treated with 1-PPA (0.5 ng or 0.15 µg) or vehicle and clinical evaluations and histological analysis were performed. Mechanical allodynia and gene expression of inflammation and pain mediators were evaluated. Results In the MSU-induced arthritis model, 1-PPA reduced joint swelling, mechanical allodynia, leukocyte infiltration, synovitis, and edema. It also decreased pro-inflammatory cytokine expression (IL-6, IL-1β, TNF-α) and increased anti-inflammatory IL-10. PAR2 and substance P mRNA levels were reduced by 1-PPA treatment. In the carrageenan-induced hyperalgesia model, 1-PPA reduced paw edema and inflammatory cell infiltration in a dose-dependent manner. It also decreased IL-6 and substance P expression. Both doses of 1-PPA improved mechanical hyperalgesia. This study demonstrates that 1-PPA attenuates inflammation and pain in two distinct mouse models. 1-PPA reduced edema, inflammatory cell infiltration, and pro-inflammatory mediator expression while improving pain-related behaviors. Conclusions These results indicate 1-PPA's therapeutic potential for inflammatory joint conditions. Its dual anti-inflammatory and analgesic properties, combined with good local tolerability, position 1-PPA as a promising candidate for treating arthritis and related musculoskeletal disorders.