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Rolipram, a phosphodiesterase\u20104 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\u2010loaded poly(lactide\u2010co\u2010glycolide)\u2010graft\u2010polyethylenimine (PgP) nanoparticles (Rm\u2010PgP) to enable localized and sustained drug delivery. In our previous findings, Rm\u2010PgP 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\u2010PgP by the clinically relevant intrathecal route immediately after injury. We observed that the hydrophobic dye, DiR\u2010loaded PgP (DiR\u2010PgP) was retained in the CNS over 7\u2009days post\u2010injury (DPI). In addition, we observed that both single and repeat Rm\u2010PgP 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\u2010PgP treatment groups showed higher levels of activated cAMP\u2010response element\u2010binding protein (pCREB) relative to the untreated control. We also observed that both Rm\u2010PgP 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\u2010PgP by intrathecal administration in mitigating secondary injury during the critical early phase of recovery after SCI.<\/jats:p>","DOI":"10.1002\/jnr.70091","type":"journal-article","created":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T01:58:52Z","timestamp":1762394332000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Rolipram\u2010Loaded\n                    <scp>PgP<\/scp>\n                    Nanotherapeutics via Intrathecal Administration Reduces Secondary Injury in a Rat Acute Moderate Contusion\n                    <scp>SCI<\/scp>\n                    Model"],"prefix":"10.1002","volume":"103","author":[{"given":"Zhen","family":"Liao","sequence":"first","affiliation":[{"name":"Drug Design, Development, and Delivery (4D) Laboratory, Department of Bioengineering, Clemson University  Clemson South Carolina 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Philadelphia Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6277-0922","authenticated-orcid":false,"given":"Jeoung Soo","family":"Lee","sequence":"additional","affiliation":[{"name":"Drug Design, Development, and Delivery (4D) Laboratory, Department of Bioengineering, Clemson University  Clemson South Carolina 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