Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Messina, Italy.
PLoS One. 2011 Jan 31;6(1):e15937. doi: 10.1371/journal.pone.0015937.
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.
原发性创伤性机械性脊髓损伤（SCI）导致许多神经元死亡，迄今为止，这些神经元既不能恢复也不能再生。在过去的几年中，我们的团队一直致力于 PDE7 抑制剂的设计、合成和评估，将其作为几种神经疾病的新型创新药物。我们的工作假设基于两个不同的事实。首先，神经炎症受 cAMP 水平的调节，因此磷酸二酯酶（PDEs）的关键作用，即水解 cAMP，无疑得到了证明。另一方面，PDE7 同时在白细胞和大脑中表达，突出了 PDE7 作为神经炎症药物靶点的潜在关键作用。
方法/主要发现：在这里，我们展示了两种化学结构不同的 PDE7 抑制剂家族，这些抑制剂是使用计算技术，如虚拟筛选和神经元网络设计的。我们报告了它们的生物学特征及其在通过 T5-T8 椎板切除术在硬脑膜上应用血管夹（24g 力）诱导的 SCI 实验模型中的疗效。我们选择了两种候选药物，即 S14 和 VP1.15，作为 PDE7 抑制剂。这些化合物在巨噬细胞和神经元细胞系中都能增加 cAMP 的产生。关于药物特性，使用平行人工膜（PAMPA）方法，这些化合物能够穿过血脑屏障。在 SCI 小鼠中，严重创伤的特征是水肿、中性粒细胞浸润以及一系列炎症介质、组织损伤和细胞凋亡的产生。用两种 PDE7 抑制剂 S14 和 VP1.15 治疗小鼠，显著降低了脊髓炎症、组织损伤（组织学评分）以及 TNF-α、IL-6、COX-2 和 iNOS 表达的程度。
结论/意义：所有这些数据共同促使我们提出 PDE7 抑制剂，特别是 S14 和 VP1.15，作为进一步研究用于治疗 SCI 的潜在药物候选物。
