Propentofylline and Interleukin-4 Modulate Lesion-Associated Myeloid Responses and Improve Functional Recovery After Spinal Cord Injury

Spinal cord injury (SCI) triggers a secondary injury cascade characterized by persistent innate immune activation, chronic neuroinflammation, and progressive tissue loss that limits functional recovery. Here, we evaluated a systemic combination treatment using propentofylline (PPF), a glial modulator, together with interleukin-4 (IL-4), a cytokine associated with repair-related myeloid responses. In vitro, PPF enhanced IL-4-dependent induction of arginase-1 (ARG1) in TNFα-primed BV2 microglia. In vivo, adult Fischer rats of both sexes received vehicle, PPF, IL-4, or combined PPF + IL-4 beginning within 1 h after moderate T8 contusive SCI and continuing daily for 14 days. Locomotor recovery was assessed longitudinally for 8 weeks, followed by histological and immunohistochemical analyses. Combined PPF + IL-4 treatment produced the greatest improvement in gross and skilled locomotor recovery compared with vehicle, or either monotherapy. At 8 weeks post-SCI, the combined therapy aligned with a reduction in chronic lesion-associated p-p38 MAPK, decreased pP65 NFkB (RelA) activation, increased expression of reparative factors ARG1 and CD206, as well as reduced lesion cavitation and trends toward greater gray and white matter preservation. Stratification of functional data by sex showed BBB improvements with combined PPF + IL-4 in both males and females after SCI. Together, these findings show that combined systemic PPF and IL-4 treatment was associated with improved functional recovery, reduced lesion cavitation, and changes in lesion-associated molecular and histological endpoints after SCI, supporting further preclinical investigation.