Toward a Therapy for Autism Spectrum Disorder: The Formyl Peptide Receptor 2 Agonist MR-39 Supports Synaptic Health in the BTBR Mouse and Features a Favorable Safety Profile.

Abstract

Chronic unresolved inflammation is a common feature of several Central Nervous System (CNS) disorders, including autism spectrum disorder (ASD). We previously demonstrated that Formyl Peptide Receptor 2 (FPR2) activation by our agonist MR-39 reduced several inflammatory markers and improved social behavior in two validated animal models of ASD. Therefore, we decided to delve deeper into the potential of MR-39 as a drug for treating ASD. We first investigated the molecular mechanisms underlying the beneficial effects of MR-39 in BTBR mice. MR-39 significantly normalized pro-inflammatory cytokine release and NF-κB expression in the hippocampus and cortex, resulting in upregulation of synaptophysin protein levels, which, in turn, promote plasticity and correct abnormalities in dendritic spine morphology. Next, we characterized the safety and pharmacokinetic profile of MR-39 with respect to potential advancement for further pre- and clinical studies. We found that MR-39 was not genotoxic and safe to use since it had limited interaction with the majority of the targets associated with the adverse drug reaction. Consistently, a repeated-dose administration study evidenced no clinical signs attributable to treatment-related toxicity. On the other hand, MR-39 exhibited rapid hepatocyte clearance and interaction with efflux systems in vitro, suggesting possible limitations due to its pharmacokinetic properties. Finally, we explored multiple strategies to overcome MR-39's low aqueous solubility, finding that the cosolvent approach can greatly enhance solubility and wettability. Overall, our study confirmed that promoting inflammation resolution with MR-39 can open new therapeutic options for ASD and that this compound has potential as a drug.