Traumatic Injury Leads to Inflammation and Altered Tryptophan Metabolism in the Juvenile Rabbit Brain.

Neuroinflammation after traumatic brain injury (TBI) contributes to widespread cell death and tissue loss. Here, we evaluated sequential inflammatory response in the brain, as well as inflammation-induced changes in brain tryptophan metabolism over time, in a rabbit pediatric TBI model. On post-natal days 5-7 (P5-P7), New Zealand white rabbit littermates were randomized into three groups: naïve (no injury), sham (craniotomy alone), and TBI (controlled cortical impact). Animals were sacrificed at 6 h and 1, 3, 7, and 21 days post-injury for evaluating levels of pro- and anti-inflammatory cytokines, as well as the major components in the tryptophan-kynurenine pathway. We found that 1) pro- and anti-inflammatory cytokine levels in the brain injury area were differentially regulated in a time-dependent manner post-injury; 2) indoleamine 2,3 dioxygeenase 1 (IDO1) was upregulated around the injury area in TBI kits that persisted at 21 days post-injury; 3) mean length of serotonin-staining fibers was significantly reduced in the injured brain region in TBI kits for at least 21 days post-injury; and 4) kynurenine level significantly increased at 7 days post-injury. A significant decrease in serotonin/tryptophan ratio and melatonin/tryptophan ratio at 21 days post-injury was noted, suggesting that tryptophan metabolism is altered after TBI. A better understanding of the temporal evolution of immune responses and tryptophan metabolism during injury and repair after TBI is crucial for the development of novel therapeutic strategies targeting these pathways.