Development of Rolipram Loaded PgP Nanoparticles for Spinal Cord Injury Repair

Spinal cord injury (SCI) leads to devastating neurological deficits due to primary mechanical damage and secondary injury mechanisms, including inflammation, oxidative stress, excitotoxicity, and inhibitory scarring, which collectively impede neural regeneration. One key aspect of SCI pathology is a significant reduction in cyclic adenosine monophosphate (cAMP) levels, primarily due to increased phosphodiesterase (PDE 4) activity. As a ubiquitous second messenger, cAMP regulates key signaling pathways, including protein kinase A (PKA) / cAMP response element-binding protein (CREB) and exchange protein activated by cAMP 2 (EPAC2). Therefore, restoring/increasing cAMP level is one of the major therapeutic strategies to reduce neurotrauma and restore function. Rolipram, a selective PDE4 inhibitor, prevents cAMP degradation and enhances downstream signaling, promoting axonal regeneration and neuroprotection. However, its poor solubility, rapid clearance, and systemic side effects limit clinical application. Thus, there is a clear need for improved therapeutic strategies to safely deliver rolipram to the injured spinal cord. Our lab developed a proprietary cationic amphiphilic graft copolymer, poly (lactide-co-glycolide)-graft-polyethylenimine (PLGA-graft-PEI or PgP, US Patent 10,232,050 B1) as a nanocarrier for hydrophobic drugs. In previous studies, we successfully loaded rolipram (Rm) in PgP (Rm-PgP) and demonstrated that Rm-PgP can inhibit secondary injury in a rat severe compression SCI model. The objective of this project was to investigate the therapeutic efficacy of Rm-PgP administered by 1) local intraspinal injection immediately after injury, 2) single and repeat intrathecal injection, a minimally invasive and clinically relevant administration route, immediately after injury, and 3) determine the treatment time window of Rm-PgP by delayed treatment (1 day and 4 weeks post injury) in a rat moderate contusion SCI model. We observed first that local intraspinal administration of Rm-PgP immediately after injury reduced secondary injury (inflammatory response, apoptosis, astrogliosis, and neuronal cell death), improved motor function, and delayed neuropathic pain induction. Second, we observed that both single and repeated treatment of Rm-PgP by intrathecal administration significantly reduced secondary injury, improved motor function recovery, and mitigated neuropathic pain compared to untreated SCI animal group. Finally, we observed that Rm-PgP delayed treatment at 1 day post injury in acute phase significantly reduced cavity volume and apoptosis and improved motor function recovery compared to untreated SCI animal group. For 4 weeks delayed treatment in chronic phase, we did not observe the improvement of motor function, but mitigation of neuropathic pain as well as reduced secondary injury were observed, although the changes were not significantly different. In conclusion, these findings establish nanoparticle-mediated rolipram delivery as a promising therapeutic strategy for SCI, offering targeted, sustained drug release and improved functional outcomes. This work advances the development of translational neuroprotective and regenerative approaches for SCI treatment.