Rolipram-Loaded PgP Nanotherapeutics via Intrathecal Administration Reduces Secondary Injury in a Rat Acute Moderate Contusion SCI Model

Abstract

Spinal cord injury (SCI) triggers complex secondary injury mechanisms, resulting in long-term impacts on sensory and motor function. Rolipram, a phosphodiesterase-4 inhibitor, has shown promise in preserving/restoring cyclic adenosine monophosphate (cAMP) to reduce secondary injury responses, but its clinical application is hindered by poor solubility and systemic side effects. To overcome these challenges, we developed rolipram-loaded poly(lactide-co-glycolide)-graft-polyethylenimine (PgP) nanoparticles (Rm-PgP) to enable localized and sustained drug delivery. In our previous findings, Rm-PgP administered via intraspinal injection restored cAMP levels at the lesion site, and reduced secondary injury after moderate, contusive SCI. In this study, we investigated the effect of single and repeat administration of Rm-PgP by the clinically relevant intrathecal route immediately after injury. We observed that the hydrophobic dye, DiR-loaded PgP (DiR-PgP) was retained in the CNS over 7 days post-injury (DPI). In addition, we observed that both single and repeat Rm-PgP treatment groups showed higher cAMP levels compared to those in the untreated SCI group and only the single treatment group showed a significant difference compared to the untreated SCI group. Lastly, we observed that cAMP restoration in both single and repeat Rm-PgP treatment groups showed higher levels of activated cAMP-response element-binding protein (pCREB) relative to the untreated control. We also observed that both Rm-PgP treatment groups showed reduced inflammatory response, reduced astrogliosis and apoptosis, and increased neuronal survival and spared tissue volume. These findings highlight the neuroprotective efficacy of Rm-PgP by intrathecal administration in mitigating secondary injury during the critical early phase of recovery after SCI.