Behavioral, Anti-Inflammatory, and Neuroprotective Effects of a Novel FPR2 Agonist in Two Mouse Models of Autism

Autism spectrum disorders (ASD) are a group of heterogeneous neurodevelopmental conditions characterized by social deficits, repetitive stereotyped behaviors, and altered inflammatory responses. Accordingly, children with ASD show decreased plasma levels of lipoxin A4 (LXA4), a mediator involved in the resolution of inflammation, which is the endogenous ligand of the formyl peptide receptor 2 (FPR2). To investigate the role of FPR2 in ASDs, we have used a new ureidopropanamide derivative able to activate the receptor, named MR-39. The effects of MR-39 (10 mg/kg, for 8 days) on hippocampal pro-inflammatory profile, neuronal plasticity, and social behavior were evaluated in two validated animal models of ASD: BTBR mouse strain and mice prenatally exposed to valproic acid (VPA). Primary cultures of hippocampal neurons from BTBR mice were also used to evaluate the effect of MR-39 on neurite elongation. Our results show that MR-39 treatment reduced several inflammatory markers, restored the low expression of LXA4, and modulated FPR2 expression in hippocampal tissues of both ASD animal models. These findings were accompanied by a significant positive effect of MR-39 on social behavioral tests of ASD mice. Finally, MR-39 stimulates neurite elongation in isolated hippocampal neurons of BTBR mice. In conclusion, these data indicate FPR2 as a potential target for an innovative therapeutical approach for the cure of ASD.