Are formyl peptide receptors novel targets for therapeutic intervention in ischaemia–reperfusion injury?

Abstract

Ischaemia-reperfusion (I/R) injury is a common feature of several diseases associated with high morbidity and mortality, such as stroke and myocardial infarction. The damaged tissue displays cardinal signs of inflammation and microvascular injury that, unless resolved, lead to long-term tissue damage with associated dysfunction. Current therapies are limited and are often associated with many side effects. Increasing evidence suggests that members of the formyl peptide receptor (FPR) family, in particular human FPR2/ALX, might have an important role in the pathophysiology of I/R injury. It was recently demonstrated that several peptides and non-peptidyl small-molecule compounds have anti-inflammatory and pro-resolving properties via their action on members of the FPR family. Here I review this evidence and suggest that FPR ligands, particularly in the brain, could be novel and exciting anti-inflammatory therapeutics for the treatment of a variety of clinical conditions, including stroke.

Hydroalcoholic crude extract of Casearia sylvestris Sw. reduces chronic post-ischemic pain by activation of pro-resolving pathways

“…Considering the present model of CPIP induced by I/R, these founds are also in agreement with the idea that targeting ALX/FPR2 receptors in both types of cells can be useful to treat symptoms of diseases in which pathophysiology relies importantly on vascular disturbances Dufton & Perretti, 2010), specially those involving I/R-induced injuries (Gavins, 2010).…”

A Urokinase Receptor–Derived Peptide Inhibiting VEGF-Dependent Directional Migration and Vascular Sprouting

“…Furthermore, FPRs are documented to regulate innate inflammatory responses and mediate cell migration in response to a variety of chemotactic factors by facilitating the trafficking of phagocytes to the site of bacterial invasion (44). Given the finding that RERF interferes with the complex cross-talk involving uPAR, FPR, and integrins, it is reasonable to foresee that this peptide may be also used to develop new drugs for the treatment of diseases that are sustained by a chronic excess of cell migration such as inflammatory diseases.…”

Gastrin-Releasing Peptide/Neuromedin B Receptor Antagonists PD176252, PD168368, and Related Analogs Are Potent Agonists of Human Formyl-Peptide Receptors

“…For example, mouse FPRs have been reported to be candidate chemosensory receptors in the vomeronasal organ (Liberles et al, 2009). Likewise, several studies have suggested that FPR2 agonists exhibit protective effects in ischemia-reperfusion models (for review, see Gavins, 2010). Overall, the demonstrated role of FPRs in orchestrating acute-phase inflammation supports the development of FPR agonists as novel anti-inflammatory therapeutics (Dufton and Perretti, 2010).…”

“…N-Formyl peptides activate cells through formyl peptide receptors (FPRs), which are G protein-coupled receptors (GPCRs) (for review, see Ye et al, 2009). The three human FPRs (FPR1, FPR2, and FPR3) are expressed on a variety of cell types, including neutrophils, macrophages, T lymphocytes, epithelial cells, hepatocytes, fibroblasts, astrocytes, and other cells that serve a variety of regulatory functions during the host defense response (for review, see Ye et al, 2009;Gavins, 2010). For example, FPR1 and FPR2 have been implicated in control of endogenous inflammatory processes and initiation of proinflammatory neutrophil responses to pathogenic bacteria (Kretschmer et al, 2010).…”