title: PDE 7 inhibitors: new potential drugs for the therapy of spinal cord injury.
abstract: BACKGROUND
  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. During the last years our group has been involved in the design, synthesis and evaluation of PDE7 inhibitors as new innovative drugs for several neurological disorders. Our working hypothesis is based on two different facts. Firstly, neuroinflammation is modulated by cAMP levels, thus the key role for phosphodiesterases (PDEs), which hydrolyze cAMP, is undoubtedly demonstrated. On the other hand, PDE7 is expressed simultaneously on leukocytes and on the brain, highlighting the potential crucial role of PDE7 as drug target for neuroinflammation.
  
  
  RESULTS
  Here we present two chemically diverse families of PDE7 inhibitors, designed using computational techniques such as virtual screening and neuronal networks. We report their biological profile and their efficacy in an experimental SCI model 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, as PDE7 inhibitors. These compounds increase cAMP production both in macrophage and neuronal cell lines. Regarding drug-like properties, compounds were able to cross the blood brain barrier using parallel artificial membranes (PAMPA) methodology. 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 VP1.15, two PDE7 inhibitors, significantly reduced the degree of spinal cord inflammation, tissue injury (histological score), and TNF-α, IL-6, COX-2 and iNOS expression.
  
  
  CONCLUSIONS
  All these data together led us to propose PDE7 inhibitors, and specifically S14 and VP1.15, as potential drug candidates to be further studied for the treatment of SCI.
authors.affiliation: Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Messina, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Paterniti
authors.forename: Emanuela
authors.initials: E
authors.lastname: Mazzon
authors.forename: Carmen
authors.initials: C
authors.lastname: Gil
authors.forename: Daniela
authors.initials: D
authors.lastname: Impellizzeri
authors.forename: Valle
authors.initials: V
authors.lastname: Palomo
authors.forename: Myriam
authors.initials: M
authors.lastname: Redondo
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Perez
authors.forename: Emanuela
authors.initials: E
authors.lastname: Esposito
authors.forename: Ana
authors.initials: A
authors.lastname: Martinez
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cuzzocrea
mesh_terms: D000818:Animals; D002460:Cell Line; D000242:Cyclic AMP / Q000096:biosynthesis / Q000378:metabolism; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7 / Q000037:antagonists & inhibitors*; D015195:Drug Design; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use*; D013119:Spinal Cord Injuries / Q000188:drug therapy*; D016896:Treatment Outcome
chemical_list: D010726:Phosphodiesterase Inhibitors; D000242:Cyclic AMP; D054708:Cyclic Nucleotide Phosphodiesterases, Type 7; C517458:PDE7A protein, human