Blast-related traumatic brain injury is mediated by the kynurenine pathway

Objectives The overactivation of the kynurenine pathway, the major metabolic pathway of tryptophan, induced by inflammation and oxidative stress, might bring about excessive neurotoxic metabolites. This study aimed to investigate whether kynurenine pathway is overactivated in blast-related traumatic brain injury (bTBI) and whether inhibitors of kynureninase and kynurenine-3-monooxygenase (KMO), important enzymes in kynurenine pathway, could alleviate bTBI in rats. Methods A shock tube was used to establish the bTBI animal models. Pathological changes in the hippocampus were observed using Nissl, propidium iodide and TdT-mediated dUTP Nick-End Labeling (TUNEL) staining. Immunohistochemistry was used to evaluate the expression levels of kynureninase and KMO. After the establishment of bTBI rat models, they were treated with KMO inhibitor (Ro 61-8048) and kynureninase inhibitor (benserazide hydrochloride), and the animals' behavioral performance was assessed using an elevated plus maze (EPM). Results After blast exposure, the number of neurons decreased, whereas the expression of kynureninase and KMO increased in the CA1 area of the rat hippocampus. In vitro, KMO inhibitor (Ro) and kynureninase inhibitor (benserazide hydrochloride) intervention could reduce the proportion of TUNEL-positive neurons in the hippocampus. In vivo, after Ro treatment, the behavior of the bTBI rats was significantly improved, and more neurons survived in the hippocampus CA1 region; however, following benserazide hydrochloride treatment, the behavior of bTBI rats was not significantly improved, and neuron survival could not be improved in the hippocampal CA1 region. Conclusion The expression levels of KMO and kynureninase were increased in the hippocampus of the bTBI rats, suggesting that these factors might mediate the bTBI damage. Furthermore, the KMO inhibitor showed a significant protective effect on bTBI.

Automated summary

The overactivation of the kynurenine pathway is observed in blast-related traumatic brain injury, and inhibitors of key enzymes in this pathway show a protective effect in reducing the damage. Specifically, the KMO inhibitor exhibits significant neuroprotective properties in this type of brain injury.