PDE7 INHIBITORS AS NEW POTENTIAL DRUGS FOR SPINAL CORD INJURY

Primary traumatic mechanical injury to the spinal cord (SCI) causes the death of a number of neurons that to date can neither be recovered nor regenerated. However, neurons continue to die for hours after SCI, and this represents a potentially avoidable event. Local inflammatory response in the injured spinal cord contributes significantly to the evolution of this secondary damage. Neuroinflammation is modulated by cAMP levels, thus the key role for phosphodiesterases (PDEs), which hydrolyze cAMP, is undoubtedly. PDE7 is expressed simultaneously on leukocytes and on brain, pointing the potential crucial role of PDE7 as drug target for neuroinflammation. Here we present two chemically diverse families of PDE7 inhibitors, designed using computational techniques as virtual screening and neuronal networks, their biological profile, and their efficacy in experimental SCI model in mice induced by the application of vascular clips (force of 24 g) to the dura via a four‐level T5–T8 laminectomy. We have selected two candidates, namely S14 and VP1.15. They are PDE7 inhibitors with IC 50 values in the micromolar range. These compounds increased cAMP production both in macrophage and neuronal cell lines. Moreover, the inflammatory response induced by LPS treatment in both types of cells were reduced after the treatment with these PDE7 inhibitors. SCI in mice resulted in severe trauma characterized by edema, neutrophil infiltration, and production of a range of inflammatory mediators, tissue damage, and apoptosis. Treatment of the mice with S14 and VP.15 significantly reduced the degree of spinal cord inflammation and tissue injury (histological score); and TNF‐α, IL‐6, COX‐2 and iNOS expression. All these data together, led us to propose PDE7 inhibitors, and specifically S14 and VP1.15, as useful in the therapy of spinal cord injury, trauma and inflammation.