Preclinical evaluation of the urokinase receptor-derived peptide UPARANT as an anti-inflammatory drug
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Inflammation plays a key role in the pathogenesis of several chronic diseases. The urokinase plasminogen activator receptor (uPAR) exerts a plethora of functions in both physiological and pathological processes, including inflammation.
Objective and design
In this study, we evaluated the anti-inflammatory effect of a novel peptide ligand of uPAR, UPARANT, in different animal models of inflammation.
Subjects and treatment
Rats and mice were divided in different groups (n = 5) for single or repeated administration of vehicle (9% DMSO in 0.9% NaCl), UPARANT (6, 12 and 24 mg/kg) or dexamethasone (2 mg/kg). Animals were subjected to carrageenan-induced paw oedema or zymosan-induced peritonitis.
UPARANT effects were tested on: (1) the carrageenan-induced paw oedema volume, (2) the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) and the nitrite/nitrate (NOx) levels in the paw exudates, (3) cells recruitment into the peritoneal cavity after zymosan injection and (4) NOx levels in the peritoneal lavage.
UPARANT (12 and 24 mg/kg) reduced inflammation in both experimental paradigms. Analysis of pro-inflammatory enzymes revealed that administration of UPARANT reduced iNOS, COX2 and NO over-production.
Our study provides a solid evidence that UPARANT reduces the severity of inflammation in diverse animal models, thus representing a novel anti-inflammatory drug with potential advantages with respect to the typical steroidal agents.
KeywordsInflammation Urokinase-type plasminogen activator receptor UPARANT
- 7.Gyetko MR, Aizenberg D, Mayo-Bond L, Pu J. Urokinase deficient and urokinase receptor-deficient mice have impaired neutrophil antimicrobial activation in vitro. LeukocBiol. 2004;76:648–56.Google Scholar
- 17.Dufton N, Hannon R, Brancaleone V, Dalli J, Patel HB, Gray M, D’Acquisto F, Buckingham JC, Perretti M, Flower RJ. Anti-inflammatory role of the murine formyl-peptide receptor 2: ligand-specific effects on leukocyte responses and experimental inflammation. J Immunol. 2010;184:2611–9.CrossRefPubMedPubMedCentralGoogle Scholar
- 18.Bifulco K, Longanesi-Cattani I, Franco P, Pavone V, Mugione P, Di Carluccio G, Masucci MT, Arra C, Pirozzi G, Stoppelli MP, Carriero MV. Single amino acid substitutions in the chemotactic sequence of urokinase receptor modulate cell migration and invasion. PLoS One. 2012;7:44806.CrossRefGoogle Scholar
- 19.Carriero MV, Longanesi-Cattani I, Bifulco K, Maglio O, Lista L, Barbieri A, Votta G, Masucci MT, Arra C, Franco R, De Rosa M, Stoppelli MP, Pavone V. Structure-based design of an urokinase-type plasminogen activator receptor-derived peptide inhibiting cell migration and lung metastasis. Mol Cancer Ther. 2009;8:2708–17.CrossRefPubMedGoogle Scholar
- 21.Dal Monte M, Rezzola S, Cammalleri M, Belleri M, Locri F, Morbidelli L, Corsini M, Paganini G, Semeraro F, Cancarini A, Rusciano D, Presta M, Bagnoli P. Antiangiogenic effectiveness of the urokinase receptor-derived peptide UPARANT in a model of oxygen-induced retinopathy. Invest Ophthalmol Vis Sci. 2015;56:2392–407.CrossRefGoogle Scholar
- 22.Carriero MV, Bifulco K, Minopoli M, Lista L, Maglio O, Mele L, Di Carluccio G, De Rosa M, Pavone V. UPARANT: a urokinase receptor-derived peptide inhibitor of VEGF-driven angiogenesis with enhanced stability and in vitro and in vivo potency. Mol Cancer Ther. 2014;13:1092–104.CrossRefPubMedGoogle Scholar
- 26.Palazzo E, Marabese I, Soukupova M, Luongo L, Boccella S, Giordano C, de Novellis V, Rossi F, Maione S. Metabotropic glutamate receptor subtype 8 in the amygdala modulates thermal threshold, neurotransmitter release, and rostral ventromedial medulla cell activity in inflammatory pain. J Neurosci. 2011;31:4687–97.CrossRefPubMedGoogle Scholar