Systemic Inhibition of Soluble Tumor Necrosis Factor with XPro1595 Exacerbates a Post-Spinal Cord Injury Depressive Phenotype in Female Rats

Spinal cord injury (SCI) is associated with a three-fold risk of major depressive disorder compared with the general population. Current antidepressant therapy is often not as effective in this patient population, suggesting the need for a more efficacious therapeutic target. The goal of this study was to elucidate the role of inflammatory cytokine tumor necrosis factor (TNF) in the dorsal raphe nucleus (DRN, the principle source of serotonin to the brain) in the development and possible treatment of depression after SCI. A depressive phenotype following moderate T9 contusion was identified in adult female rats using a battery of behavioral tests (forced swim test, sucrose preference test, novel object recognition test, open field locomotion, and social exploration). Data revealed two clusters of injured rats (58%) that exhibit increased immobility in the forced swim test, indicating depressive phenotype or a melancholic-depressive phenotype with concomitant decrease in sucrose preference. ElevatedTNF levels in the DRN of these two clusters correlated with increased immobility in the forced swim test. We then tested the efficacy of soluble TNF inhibition with XPro1595 treatment to prevent the depressive phenotype after SCI. Subcutaneous (s.c.) delivery of XPro1595 caused an exacerbation of depressive phenotype, with all treated clusters exhibiting increased forced swim immobility compared with saline-treated non-depressed rats. Intracerebroventricular (i.c.v.) administration of the drug did not prevent or enhance the development of depression after injury. These results suggest a complex role for TNF-based neuroinflammation in SCI-induced depression that needs to be further explored, perhaps in conjunction with a broader targeting of additional post-SCI inflammatory cytokines.