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. 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) LDN193189 HCl to the dura via a four-level T5CT8 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 LDN193189 HCl edema, neutrophil RGS1 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-, 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. Introduction Spinal cord injury (SCI) is a highly debilitating pathology . Although innovative medical care has improved patient outcome, advances in pharmacotherapy for the purpose of decrease neuronal injury and promoting regeneration have been limited. The complex pathophysiology of SCI may explain the difficulty in finding a suitable therapy. An excessive post-traumatic inflammatory reaction may play an important role in the LDN193189 HCl secondary injury processes, which develop after SCI . The primary traumatic mechanical injury to the spinal cord 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 . This secondary neuronal death is determined by a large number of cellular, molecular, and biochemical cascades. One such cascade that has been proposed to contribute significantly to the evolution of the secondary damage is the local inflammatory response in the injured spinal cord. Recent evidence, however, suggests that leukocytes, especially neutrophils which are the first leukocytes to arrive within the injured spinal cord , LDN193189 HCl may also be directly involved in the pathogenesis and extension of spinal cord injury in rats. Several authors have demonstrated that neutrophils are especially prominent in a marginal zone around the main area of injury and infarction at 24 h . The cardinal features of inflammation, namely infiltration of inflammatory cells (not only polymorphonuclear neutrophils but also macrophage and lymphocytes), release of inflammatory mediators, and activation of endothelial cells leading to increased vascular permeability, edema formation, and tissue destruction have been widely characterized in animal models of SCI . Both necrotic and apoptotic mechanisms of cell death after SCI then, have been well and extensively described in animal SCI models . Phosphodiesterases (PDEs) are a large family of metallophosphohydrolase enzymes that ubiquitously metabolize the second messengers adenosine and guanosine 3,5-cyclic monophosphates (cAMP and cGMP) to their respective inactive 5-monophosphates. cAMP and cGMP are synthesized by adenylyl and guanylyl cyclases respectively, and mediate the action of hormones, neurotransmitters, and other cellular effectors in many physiologic processes. As elevation of intracellular cAMP level impacts immunosuppressive and anti-inflammatory properties , , selective inhibitors of cAMP-specific PDEs have been widely studied as therapeutics for the treatment of human diseases , predominantly immune disorders such as multiple sclerosis and inflammatory processes , and also disorders of the central nervous system (CNS) such as depression, psychosis, and Alzheimer’s disease. To date, most of the research has been centered on PDE4 inhibitors because PDE4 represents the major isoenzyme in most T-cell preparations and its selective inhibitors are able to decrease inflammatory cytokine production , . PDE4 inhibitors have been widely studied as anti-inflammatory agents for the treatment of inflammatory disease and multiple sclerosis . However, a major drawback of these compounds is the significant side effects such as emesis. To overcome these adverse.