The N-Formyl Peptide Receptor 2 (FPR2) Agonist MR-39 Improves Ex Vivo and In Vivo Amyloid Beta (1–42)-Induced Neuroinflammation in Mouse Models of Alzheimer’s Disease

Abstract

The major histopathological hallmarks of Alzheimer’s disease (AD) include β-amyloid (Aβ) plaques, neurofibrillary tangles, and neuronal loss. Aβ 1–42 (Aβ1-42) has been shown to induce neurotoxicity and secretion of proinflammatory mediators that potentiate neurotoxicity. Proinflammatory and neurotoxic activities of Aβ1-42 were shown to be mediated by interactions with several cell surface receptors, including the chemotactic G protein-coupled N-formyl peptide receptor 2 (FPR2). The present study investigated the impact of a new FPR2 agonist, MR-39, on the neuroinflammatory response in ex vivo and in vivo models of AD. To address this question, organotypic hippocampal cultures from wild-type (WT) and FPR2-deficient mice (knockout, KO, FPR2−/−) were treated with fibrillary Aβ1-42, and the effect of the new FPR2 agonist MR-39 on the release of pro- and anti-inflammatory cytokines was assessed. Similarly, APP/PS1 double-transgenic AD mice were treated for 20 weeks with MR-39, and immunohistological staining was performed to assess neuronal loss, gliosis, and Aβ load in the hippocampus and cortex. The data indicated that MR-39 was able to reduce the Aβ1-42-induced release of proinflammatory cytokines and to improve the release of anti-inflammatory cytokines in mouse hippocampal organotypic cultures. The observed effect was apparently related to the inhibition of the MyD88/TRAF6/NFкB signaling pathway and a decrease in NLRP3 inflammasome activation. Administration of MR-39 to APP/PS1 mice improved neuronal survival and decreased microglial cell density and plaque load.These results suggest that FPR2 may be a promising target for alleviating the inflammatory process associated with AD and that MR-39 may be a useful therapeutic agent for AD.

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

“…Recently, we have identified a series of ureidopropanamide FPR2 agonists with favorable pharmacokinetic characteristics and, among them, we selected for this study the compound MR-39 for its good metabolic stability, passive diffusion, and permeation rates in an in vitro model of the blood-brain barrier. In addition, the MR-39 shows anti-inflammatory and pro-resolving properties in primary microglial cells [57] and in a mouse model of Alzheimer's disease [58]. To evaluate the effect of FPR2 stimulation, hippocampal neurons from B6 and BTBR mice were treated for 4 h and 72 h with MR-39 (10 µM) and the neurite outgrowth was estimated.…”

“…To circumvent this problem, we have recently synthesized different FPR2 agonists [55,56] and selected one of them, named MR-39, for our current study. MR-39 shows favorable pharmacokinetic characteristics and displays strong anti-inflammatory activities in lipopolysaccharide (LPS)-stimulated rat primary microglial cells, reducing interleukin-1β (Il-1β) and Tumor necrosis factor-α (Tnf-α) levels; in addition, it has a good permeation rate in hCMEC/D3 cells, an in vitro model of the blood-brain barrier [57], and alleviates the inflammatory process associated with Alzheimer diseases [58].…”

Design, Synthesis, Biological Evaluation, and Computational Studies of Novel Ureidopropanamides as Formyl Peptide Receptor 2 (FPR2) Agonists to Target the Resolution of Inflammation in Central Nervous System Disorders

“…In fact, compound 2 reduced cell death and the release of proinflammatory mediators (IL-1β, IL-6, and TNF-α) induced by β-amyloid and improved the release of anti-inflammatory mediators (IL-4 and TGF-β). 28 Finally, compound 2 improved neuronal survival and decreased microglial cell density and plaque load after systemic administration to the APP/PS1 mouse model of Alzheimer's disease, suggesting that activation of FPR2 may be a therapeutic strategy for Alzheimer's Disease. 28 However, compound 2 produced anti-inflammatory and proresolving effects at micromolar concentrations, contrary to LXA4 and the epimer aspirin-triggered LXA4, which had such effects at the nanomolar range.…”

“…28 Finally, compound 2 improved neuronal survival and decreased microglial cell density and plaque load after systemic administration to the APP/PS1 mouse model of Alzheimer's disease, suggesting that activation of FPR2 may be a therapeutic strategy for Alzheimer's Disease. 28 However, compound 2 produced anti-inflammatory and proresolving effects at micromolar concentrations, contrary to LXA4 and the epimer aspirin-triggered LXA4, which had such effects at the nanomolar range. 26 This can translate in high in vivo dosage and potential unwanted off-target side effects.…”

Stimulation of Formyl Peptide Receptor-2 by the New Agonist CMC23 Protects against Endotoxin-Induced Neuroinflammatory Response: A Study in Organotypic Hippocampal Cultures

“…Thus, OHCs are an exciting tool for investigating the neuroimmune processes of the brain ex vivo. 27,29 To induce the neuroinflammatory condition, we used a OHCs were pretreated with the FPR2 antagonist WRW4 (10 μM) for 30 min. Subsequently, OHCs were treated with CMC23 (0.1 μM) for 1 h and finally with lipopolysaccharide (LPS; 1 μg/mL) for 24 h. Control slices were treated with the appropriate vehicle.…”