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Abstract: 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 SCI. Pro-inflammatory cytokines IL-1β, IL-6 and TNFα were investigated at 6h 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 100ng) or received an intraperitoneal injection of RA (15mg/kg bodyweight). Surprisingly intrathecal RA up to amounts of 100ng 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-1β, IL-6 and TNFα mRNA levels, respectively. Although local doses higher than 100ng 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 100ng 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. [ABSTRACT FROM AUTHOR]

Patients suffering from major depression (MD) have been shown to have higher levels of circulating cytokines, and patients undergoing cytokine therapy frequently develop MD. The current hypothesis underlying how this might affect MD development states that these cytokines affect the expression of indoleamine-2,3-monooxygenase (IDO). With this in mind we used a robust and validated model of depression in mice – chronic mild stress (CMS). In order to determine the impact of peripheral inflammation on mood under conditions of stress, we also challenged mice which had undergone CMS with the bacterial endotoxin lipopolysaccharide (LPS). Animals which underwent CMS showed increased immobility in the forced swim test and decreased preference for a sucrose solution. LPS alone did not induce any significant behavioural phenotype. However, when combined with CMS, LPS significantly exacerbated the behavioural responses measured. CNS expression of the 5-HT transporter (SERT) and 5-HT2A receptor mRNA, as well as the mRNA for a number of proinflammatory cytokines was also significantly different between groups receiving CMS, CMS and LPS, and LPS alone. These data clearly indicate that a number of molecular changes occur in the serotonergic system, and these changes are exacerbated by a concomitant inflammatory challenge. This work highlights the relationship that exists between the innate immune system and chronic stress. [ABSTRACT FROM AUTHOR]