1 Department of Bioengineering, Clemson University , Clemson, South Carolina.
2 Department of Neurosurgery, Greenville Health System , Greenville, South Carolina.
J Neurotrauma. 2018 Feb 1;35(3):582-592. doi: 10.1089/neu.2017.5092. Epub 2018 Jan 3.
Among the complex pathophysiological events following spinal cord injury (SCI), one of the most important molecular level consequences is a dramatic reduction in neuronal cyclic adenosine monophosphate (cAMP) levels. Many studies shown that rolipram (Rm), a phosphodiesterase IV inhibitor, can protect against secondary cell death, reduce inflammatory cytokine levels and immune cell infiltration, and increase white matter sparing and functional improvement. Previously, we developed a polymeric micelle nanoparticle, poly(lactide-co-glycolide)-graft-polyethylenimine (PgP), for combinatorial delivery of therapeutic nucleic acids and drugs for SCI repair. In this study, we evaluated PgP as an Rm delivery carrier for SCI repair. Rolipram's water solubility was increased ∼6.8 times in the presence of PgP, indicating drug solubilization in the micelle hydrophobic core. Using hypoxia as an in vitro SCI model, Rm-loaded PgP (Rm-PgP) restored cAMP levels and increased neuronal cell survival of cerebellar granular neurons. The potential efficacy of Rm-PgP was evaluated in a rat compression SCI model. After intraspinal injection, 1,1'-dioctadecyl-3,3,3',3'-tetramethyl indotricarbocyanine Iodide-loaded PgP micelles were retained at the injection site for up to 5 days. Finally, we show that a single injection of Rm-PgP nanoparticles restored cAMP in the SCI lesion site and reduced apoptosis and the inflammatory response. These results suggest that PgP may offer an efficient and translational approach to delivering Rm as a neuroprotectant following SCI.
在脊髓损伤 (SCI) 后的复杂病理生理事件中，最重要的分子水平后果之一是神经元环磷酸腺苷 (cAMP) 水平的急剧下降。许多研究表明，磷酸二酯酶 4 抑制剂罗利普兰 (Rm) 可以防止继发性细胞死亡，降低炎症细胞因子水平和免疫细胞浸润，并增加白质保留和功能改善。此前，我们开发了一种聚合物胶束纳米颗粒，聚（乳酸-共-乙醇酸）-接枝-聚乙烯亚胺（PgP），用于治疗性核酸和药物联合递送至 SCI 修复。在这项研究中，我们评估了 PgP 作为 SCI 修复的 Rm 递送载体。在 PgP 的存在下，罗利普兰的水溶性提高了约 6.8 倍，表明药物溶解在胶束疏水核中。使用缺氧作为体外 SCI 模型，载有 Rm 的 PgP（Rm-PgP）恢复了 cAMP 水平并增加了小脑颗粒神经元的神经元细胞存活率。在大鼠压迫性 SCI 模型中评估了 Rm-PgP 的潜在疗效。在脊髓内注射后，1,1'-十八烷基-3,3,3',3'-四甲基吲哚羰花青碘负载的 PgP 胶束在注射部位保留长达 5 天。最后，我们表明，单次注射 Rm-PgP 纳米粒可恢复 SCI 损伤部位的 cAMP，并减少细胞凋亡和炎症反应。这些结果表明，PgP 可能为 Rm 作为 SCI 后神经保护剂的递送提供一种高效且可转化的方法。
