PDE 7 inhibitors: New potential drugs for the therapy of spinal cord injury

Irene Paterniti, Emanuela Mazzon, Carmen Gil, Daniela Impellizzeri, Valle Palomo, Myriam Redondo, Daniel I. Perez, Emanuela Esposito, Ana Martinez, Salvatore Cuzzocrea

Research output: Contribution to journalArticle

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. Methodology/Principal Findings: 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/Significance: 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.

Original languageEnglish
Article numbere15937
JournalPLoS One
Volume6
Issue number1
DOIs
Publication statusPublished - 2011

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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    Paterniti, I., Mazzon, E., Gil, C., Impellizzeri, D., Palomo, V., Redondo, M., Perez, D. I., Esposito, E., Martinez, A., & Cuzzocrea, S. (2011). PDE 7 inhibitors: New potential drugs for the therapy of spinal cord injury. PLoS One, 6(1), [e15937]. https://doi.org/10.1371/journal.pone.0015937