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

Abstract

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.

The kynurenine pathway presents multi-faceted metabolic vulnerabilities in cancer

“…To date, a few kynurenine analogues have been developed that selectively inhibit KYNU enzymatic activity ( 158 ). Additional molecules reported to inhibit KYNU include S-phenyl-l-cysteine sulfoxide ( 159 , 160 ), oestrone sulphate ( 161 ), O-methoxybenzoylalanine ( 162 ), and benserazide hydrochloride ( 163 ).…”

An injectable refrigerated hydrogel for inducing local hypothermia and neuroprotection against traumatic brain injury in mice

“…If the initial damage is extensive, secondary TBI occurs, which can result in the initiation of an acute inflammatory response, edema and swelling, continuous breakdown of the blood–brain barrier (BBB), local electrolyte imbalance, and persistent neurological impairment in many patients [ 6 , 7 ]. In TBI, the activation of various metabolic pathways induced by inflammation and oxidative stress can lead to an excess of neurotoxic metabolic byproducts [ 8 ]. Following TBI, oxidative stress triggers the activation of the brain's immune system, resulting in the production of various inflammatory factors and the onset of neuroinflammation.…”