ADENOSINE RECEPTORS AS STRATEGIC TARGETS FOR THE DESIGN AND DEVELOPMENT OF INNOVATIVE DRUGS FOR THE MANAGEMENT OF SPINAL CORD INJURY

Among the many molecular mechanisms regulating tissues homeostasis, the purinergic signalling assumes an important role and in the last few years adenosine receptors have been studied as a target for many diseases including neurodegenerative conditions. Spinal cord injury (SCI) is a complex clinical and progressive condition characterized by neuronal loss, axonal destruction and demyelination, in particular at the site of impact. A “secondary” phase generally follows the mechanical injury which is characterized by microvascular dysfunction and enrolment of inflammatory cells, thus contributing to further spinal cord damage. The aims of this study were to investigate the mode of action of an adenosine receptor agonist, PDRN, in an experimental model of SCI. Moreover, since adenosine receptors stimulation may also activate Wnt pathway, we wanted to study PDRN effects on Wnt signalling during spinal cord injury. Spinal trauma was induced by extradural compression of SC exposed via a four-level T5-T8 laminectomy in adult male C57BL6/J mice. Animals were randomly assigned to the following groups: Sham (n=7), SCI (n=7), SCI+PDRN (8 mg/kg/i.p.; n=7). PDRN systemically administered 1 hour following spinal cord injury, protected from tissue damage, demyelination, and reduced motor deficits in addition to the release of the pro-inflammatory cytokines TNF-α and IL-1beta. Furthermore, PDRN stimulated Wnt/beta-catenin pathway and decreased apoptotic process 24 hours following SCI. These results confirm PDRN anti-inflammatory activity and demonstrate that a crosstalk between Wnt/beta-catenin signalling is possible by adenosine receptors activation. Moreover, these data let us hypothesize that PDRN might promote neural repair through axonal regeneration and/or neurogenesis. However, further studies are required to elucidate PDRN mechanism of action in neurological disorders.