Treatment with Ureidopropanamide Formyl Peptide Receptor 2 Agonists Attenuates Brain Changes Induced by Systemic...

Multiple lines of evidence highlight the impact of the resolution of inflammation (RoI) on mitigating the inflammatory response and restoring homeostasis in the brain. Recently, the significance of formyl peptide receptor 2 (FPR2) in this process has been emphasized due to its remarkable ability to interact with a wide range of ligands, including specialized proresolving mediators (SPMs). Although these endogenous molecules, such as lipoxin A₄ (LXA₄), exhibit beneficial effects, their unfavorable pharmacokinetic properties result in rapid chemical inactivation. Hence, in the present study, we examined the proresolving and anti-inflammatory properties of LXA₄ and two potent FPR2 agonists, namely, compounds CMC23 and MR-39. For this purpose, we conducted time-dependent behavioral and biochemical studies in selected brain areas of adult male rats by using a systemic immunoactivation model. We reported that LXA₄ and CMC23 abolished behavioral disturbances evoked by lipopolysaccharide (LPS) administration; however, only CMC23 exhibited long-lasting beneficial properties on these impairments. In the biochemical part of our study, endogenous LXA₄ showed beneficial effects but mostly 1 h after i.c.v. administration. The strong and prolonged proresolving potency of CMC23 was evidenced by the attenuation of proinflammatory cytokine release (IL-1β, IL-6, TNF-α) in both examined structures. Moreover, the proresolving effect of MR-39 administration was evident only in the biochemical part of the experiments. These findings provide new in vivo evidence that ureidopropanamide FPR2 agonists, especially CMC23, exert protective and anti-inflammatory actions; thus, FPR2 may be proposed as a promising target for RoI improvement.