Systemic but not local administration of retinoic acid reduces early transcript levels of pro-inflammatory cytokines after experimental spinal cord injury

Early rises of pro-inflammatory cytokines play a key role in tissue damage and has detrimental consequences for functional outcome after spinal cord injury (SCI). All-trans retinoic acid (RA) has been shown to be a therapeutic agent reducing cytokine expression in vitro, but its use may be limited due to adverse side effects associated with systemic delivery. Local delivery of RA may circumvent adverse side effects, but may simultaneously reduce the therapeutic benefits of the therapy. Here, we investigated whether local or systemic RA treatment differentially affected pro-inflammatory cytokine expression early after rat SO. Pro-inflammatory cytokines IL-1 beta, IL-6 and TNF alpha were investigated at 6 h after moderate contusion injury of the thoracic (T9) spinal cord, when mRNA levels are known to peak. Rats were either treated with intrathecal RA (0, 2.5, 10, or 100 ng) or received an intraperitoneal injection of RA (15 mg/kg bodyweight). Surprisingly intrathecal RA up to amounts of 100 ng did not attenuate SCI-induced increases in gene-expression of pro-inflammatory cytokines. In contrast, intraperitoneal RA rendered a 60%, 35% and 58% reduction of IL-1 beta, IL-6 and TNF alpha mRNA levels, respectively. Although local doses higher than 100 ng RA may reduce pro-inflammatory cytokine gene-expression, such doses precipitate and possibly increase risks of adverse side effects. We conclude that in contrast to systemic delivery, intrathecal administration of RA up to doses of 100 ng is ineffective in reducing early pro-inflammatory cytokine gene-expression. Future studies are required to investigate the effects of single intraperitoneal RA treatment on long-term SCI outcome.