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Activation of A2A Receptor by PDRN Reduces Neuronal Damage and Stimulates WNT/β-CATENIN Driven Neurogenesis in Spinal Cord Injury

Affiliation
Department of Clinical and Experimental Medicine, AOU Policlinico G. Martino, University of Messina ,Messina ,Italy
Irrera, Natasha;
Affiliation
Department of Clinical and Experimental Medicine, AOU Policlinico G. Martino, University of Messina ,Messina ,Italy
Arcoraci, Vincenzo;
Affiliation
Department of Clinical and Experimental Medicine, AOU Policlinico G. Martino, University of Messina ,Messina ,Italy
Mannino, Federica;
Affiliation
Department of Biomedical and Dental Sciences and Morphological and Functional Sciences, AOU Policlinico G. Martino, University of Messina ,Messina ,Italy
Vermiglio, Giovanna;
Affiliation
Department of Clinical and Experimental Medicine, AOU Policlinico G. Martino, University of Messina ,Messina ,Italy
Pallio, Giovanni;
Affiliation
Department of Clinical and Experimental Medicine, AOU Policlinico G. Martino, University of Messina ,Messina ,Italy
Minutoli, Letteria;
Affiliation
NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust and Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds ,Leeds ,United Kingdom
Bagnato, Gianluca;
Affiliation
Department of Biomedical and Dental Sciences and Morphological and Functional Sciences, AOU Policlinico G. Martino, University of Messina ,Messina ,Italy
Anastasi, Giuseppe Pio;
Affiliation
IRCCS Centro Neurolesi “Bonino-Pulejo” ,Messina ,Italy
Mazzon, Emanuela;
Affiliation
IRCCS Centro Neurolesi “Bonino-Pulejo” ,Messina ,Italy
Bramanti, Placido;
Affiliation
Department of Clinical and Experimental Medicine, AOU Policlinico G. Martino, University of Messina ,Messina ,Italy
Squadrito, Francesco;
Affiliation
Department of Biomedical and Dental Sciences and Morphological and Functional Sciences, AOU Policlinico G. Martino, University of Messina ,Messina ,Italy
Altavilla, Domenica;
Affiliation
Department of Clinical and Experimental Medicine, AOU Policlinico G. Martino, University of Messina ,Messina ,Italy
Bitto, Alessandra

Spinal cord injury (SCI) is a complex clinical and progressive condition characterized by neuronal loss, axonal destruction and demyelination. In the last few years, adenosine receptors have been studied as a target for many diseases, including neurodegenerative conditions. The aim of this study was to investigate the effects of an adenosine receptor agonist, PDRN, in an experimental model of SCI. Moreover, since adenosine receptors stimulation may also activate the Wnt pathway, we wanted to study PDRN effects on Wnt signaling following SCI. Spinal trauma was induced by extradural compression of spinal cord at T5-T8 level in C57BL6/J mice. Animals were randomly assigned to the following groups: Sham ( n = 10), SCI ( n = 14), SCI+PDRN (8 mg/kg/i.p.; n = 14), SCI+PDRN+DMPX (8 and 10 mg/kg/i.p., respectively; n = 14). DMPX was used as an adenosine receptor antagonist to evaluate whether adenosine receptor block might prevent PDRN effects. PDRN systemically administered 1 h following SCI, protected from tissue damage, demyelination, and reduced motor deficits evaluated after 10 days. PDRN also reduced the release of the pro-inflammatory cytokines TNF-α and IL-1β, reduced BAX expression and preserved Bcl-2. Furthermore, PDRN stimulated Wnt/β-catenin pathway and decreased apoptotic process 24 h following SCI, whereas DMPX administration prevented PDRN effects on Wnt/β-catenin signaling. These results confirm PDRN anti-inflammatory activity and demonstrate that a crosstalk between Wnt/β-catenin signaling is possible by adenosine receptors activation. Moreover, these data let us hypothesize that PDRN might promote neural repair through axonal regeneration and/or neurogenesis.

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License Holder: Copyright © 2018 Irrera, Arcoraci, Mannino, Vermiglio, Pallio, Minutoli, Bagnato, Anastasi, Mazzon, Bramanti, Squadrito, Altavilla and Bitto.

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