FPR2 agonist MR-39 normalizes inflammation, boosts synaptic health in BTBR mouse model of ASD.

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder characterized by impaired social interactions and communication, with limited effective pharmacological treatments. Chronic unresolved inflammation is a common feature in CNS disorders like ASD, contributing to its pathophysiology. Targeting inflammation resolution, particularly via Formyl Peptide Receptor 2 (FPR2) activation, presents a novel therapeutic avenue to address the underlying neuroinflammation and synaptic dysfunction observed in ASD.

Researchers investigated the molecular mechanisms and safety profile of MR-39, an FPR2 agonist, in BTBR mice, a validated animal model of ASD. They assessed pro-inflammatory cytokine release and NF-κB expression in the hippocampus and cortex. Synaptic health was evaluated by measuring synaptophysin protein levels and dendritic spine morphology. Furthermore, the study characterized MR-39's genotoxicity, pharmacokinetic profile (hepatocyte clearance, efflux systems), and explored strategies like the cosolvent approach to enhance its aqueous solubility.

MR-39 significantly normalized pro-inflammatory cytokine release and NF-κB expression in both the hippocampus and cortex of BTBR mice. This anti-inflammatory effect led to a beneficial upregulation of synaptophysin protein levels, which are crucial for synaptic plasticity. Consistently, MR-39 corrected abnormalities in dendritic spine morphology, indicating improved synaptic health. Importantly, MR-39 demonstrated a favorable safety profile: it was not genotoxic and showed limited interaction with targets associated with adverse drug reactions. A repeated-dose administration study evidenced no clinical signs attributable to treatment-related toxicity. However, MR-39 exhibited rapid hepatocyte clearance and interaction with efflux systems in vitro, suggesting potential pharmacokinetic limitations. The cosolvent approach was found to greatly enhance MR-39's solubility and wettability.

MR-39 significantly normalized pro-inflammatory cytokine release and NF-κB expression in the hippocampus and cortex, resulting in upregulation of synaptophysin protein levels and corrected abnormalities in dendritic spine morphology.