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

Claudia Cristiano,Carla Perrone-Capano,Marianna Crispino,Roberto Russo,Antonio Calignano,Enza Lacivita,Floriana Volpicelli,Marcello Leopoldo

doi:10.3390/ph15020161

Abstract

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.

Highlights

Publisher’s Note: MDPI stays neutralAutism spectrum disorders (ASD) are a heterogeneous set of childhood neurodevelopmental disorders characterized by persistent deficits in social communication and interactions, as well as restricted and stereotyped behavior and interests [1,2,3,4]
We investigated for the first time the potential effects of the formyl peptide receptor 2 (FPR2) rate in hCMEC/D3 cells, an in vitro model of the blood–brain barrier [57], and alleviates agonist MR-39 in two ASD mouse models: a polygenic model represented by the BTBR
We tested the of neuroplasticity in response to FPR2 activation, we evaluated the MR-39 effect on neuimpact of MR-39 on the hippocampal neuro-inflammatory profile, as well as on stereotyped ritesocial elongation in neuronal cultures obtained fromtothe hippocampus of the BTBR

Summary

Introduction

Publisher’s Note: MDPI stays neutralAutism spectrum disorders (ASD) are a heterogeneous set of childhood neurodevelopmental disorders characterized by persistent deficits in social communication and interactions, as well as restricted and stereotyped behavior and interests [1,2,3,4]. ASD have complex and still controversial pathogenesis, the consensus is that these disorders are linked to both genetic and environmental risk factors [5]. Recent studies repeatedly reported that one of the most common risk environmental factors associated with ASD is ongoing neuroinflammation in various brain regions [6,7]. ASD patients display altered inflammatory states and immune abnormalities throughout their life [8,9], and post-mortem studies on the brains of autistic subjects have shown increased levels of pro-inflammatory cytokines and microglia activation [10,11]. ASD symptoms seem to be linked to an inflammatory state and altered immune functions. Due to the bidirectional communication between the immune system and the brain [13], cytokine with regard to jurisdictional claims in published maps and institutional affiliations

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