Targeting inflammation to influence mood following spinal cord injury: a randomized clinical trial

David J Allison, David S Ditor, David J Allison, David S Ditor

Abstract

Background: The purpose of the present study was to examine the efficacy of targeting inflammation as a means of improving mood following spinal cord injury (SCI) and explore the potential mechanisms of action.

Methods: The study was a randomized, parallel-group, controlled, clinical trial (NCT02099890) whereby 20 participants with varying levels and severities of SCI were randomized (3:2) to either the treatment group, consisting of a 12-week anti-inflammatory diet, or control group. Outcome measures were assessed at baseline, 1 and 3 months, and consisted of CES-D scores of depression, markers of inflammation as assessed by various pro- and anti-inflammatory cytokines and several amino acids related to depression.

Results: A significant group × time interaction was found for CES-D (Center for Epidemiologic studies Depression Scale) score (p = 0.01), the TRP/LNAA (tryptophan/large neutral amino acid) ratio (p = 0.04), the composite score of pro-inflammatory cytokines (p = 0.04), IL-1β (interleukin-1 beta) (p = 0.04), and IFN-γ (interferon gamma) (p = 0.03). Pearson's r correlation showed significance between the ∆IL-1β and both the ∆CES-D score (r = 0.740, p < 0.01) and the ∆KYN/TRP (kynurenine/tryptophan) ratio (r = 0.536, p = 0.02). The ∆KYN/TRP ratio was also significantly correlated with the ∆CES-D score (r = 0.586, p = 0.01). Mediation analysis showed that the relationship between the ∆KYN/TRP ratio and the ∆CES-D score was mediated by the ∆IL-1β. Subgroup analysis showed that participants with high CES-D scores had significantly higher concentrations of IL-1β, and all correlations were maintained or strengthened within this subgroup.

Conclusions: Overall, the results demonstrated the effectiveness of targeting inflammation as a means of improving mood in SCI, with potential mechanisms relating to the reduction in IL-1β and improvements in levels of neuroactive compounds related to the kynurenine pathway. Due to the limited sample size, results should be interpreted with caution; however, they are worthy of further examination due to the potential impact of inflammation on depression.

Trial registration: ClinicalTrials.gov ID: NCT02099890 .

Figures

Fig. 1
Fig. 1
Tryptophan Metabolism along the kynurenine pathway. a The kynurenine pathway within the periphery and brain under healthy conditions. Proper enzyme regulation results in a healthy balance of TRP and TRP metabolites. As a result, adequate levels of TRP are available for 5-HT synthesis and properly regulated SERT proteins ensure that extra-cellular concentrations of 5-HT are not depleted. Healthy levels of TRP metabolites within the brain (e.g., QUIN) ensure normal activation of NMDA receptors thereby maintaining healthy hippocampal function and proper regulation of the HPA axis. b The kynurenine pathway within the periphery and brain in a state of chronic inflammation. Elevated levels of pro-inflammatory cytokines cause upregulation of enzymes such as IDO thereby resulting in an increased breakdown of TRP and production of TRP metabolites. As a result, reduced levels of TRP are available for the synthesis of 5-HT. Pro-inflammatory cytokines also upregulate SERT proteins causing further depletion of extra-cellular 5-HT. Elevated levels of TRP metabolites within the brain such as QUIN (potent NMDA agonist) result in over-activation of NMDA receptors, neuronal damage, and potential atrophy. This may also lead to a loss of inhibition of the HPA axis and excessive production of stress hormones

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