Activation of the kynurenine pathway and increased production of the excitotoxin quinolinic acid following traumatic brain injury in humans

Abstract

During inflammation, the kynurenine pathway (KP) metabolises the essential amino acid tryptophan (TRP) potentially contributing to excitotoxicity via the release of quinolinic acid (QUIN) and 3-hydroxykynurenine (3HK). Despite the importance of excitotoxicity in the development of secondary brain damage, investigations on the KP in TBI are scarce. In this study, we comprehensively characterised changes in KP activation by measuring numerous metabolites in cerebrospinal fluid (CSF) from TBI patients and assessing the expression of key KP enzymes in brain tissue from TBI victims. Acute QUIN levels were further correlated with outcome scores to explore its prognostic value in TBI recovery.MethodsTwenty-eight patients with severe TBI (GCS ≤ 8, three patients had initial GCS = 9–10, but rapidly deteriorated to ≤8) were recruited. CSF was collected from admission to day 5 post-injury. TRP, kynurenine (KYN), kynurenic acid (KYNA), QUIN, anthranilic acid (AA) and 3-hydroxyanthranilic acid (3HAA) were measured in CSF. The Glasgow Outcome Scale Extended (GOSE) score was assessed at 6 months post-TBI. Post-mortem brains were obtained from the Australian Neurotrauma Tissue and Fluid Bank and used in qPCR for quantitating expression of KP enzymes (indoleamine 2,3-dioxygenase-1 (IDO1), kynurenase (KYNase), kynurenine amino transferase-II (KAT-II), kynurenine 3-monooxygenase (KMO), 3-hydroxyanthranilic acid oxygenase (3HAO) and quinolinic acid phosphoribosyl transferase (QPRTase) and IDO1 immunohistochemistry.ResultsIn CSF, KYN, KYNA and QUIN were elevated whereas TRP, AA and 3HAA remained unchanged. The ratios of QUIN:KYN, QUIN:KYNA, KYNA:KYN and 3HAA:AA revealed that QUIN levels were significantly higher than KYN and KYNA, supporting increased neurotoxicity. Amplified IDO1 and KYNase mRNA expression was demonstrated on post-mortem brains, and enhanced IDO1 protein coincided with overt tissue damage. QUIN levels in CSF were significantly higher in patients with unfavourable outcome and inversely correlated with GOSE scores.ConclusionTBI induced a striking activation of the KP pathway with sustained increase of QUIN. The exceeding production of QUIN together with increased IDO1 activation and mRNA expression in brain-injured areas suggests that TBI selectively induces a robust stimulation of the neurotoxic branch of the KP pathway. QUIN’s detrimental roles are supported by its association to adverse outcome potentially becoming an early prognostic factor post-TBI.

Are Kynurenines Accomplices or Principal Villains in Dementia? Maintenance of Kynurenine Metabolism

“…A significant reduction in TRP levels was found at several days after stroke onset, and the KYN/TRP ratio was elevated much higher in stroke patients [65]. KYNA levels were higher in patients who died within 21 days after stroke [66].…”

Exploring the Etiological Links behind Neurodegenerative Diseases: Inflammatory Cytokines and Bioactive Kynurenines

“…Flow diagram of qualitative synthesis regarding kynurenines in neurodegenerative diseases, adopted from Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). [184] Case-control study 28/20,11 Serum, CSF…”

Quantifying the cellular NAD+ metabolome using a tandem liquid chromatography mass spectrometry approach

“…1. Trp is converted to the N -methyl-D-aspartate (NMDA) agonist, quinolinic acid (QUIN), which is subsequently converted to nicotinic acid mononucleotide (NAMN) by the enzyme quinolinic acid phosphoribosyl transferase (QPRT) (Yan et al 2015). NAMN synthesis is catalysed by nicotinamide mononucleotide adenylyltransferase (NMNAT) in the presence of ATP to produce nicotinic acid adenine dinucleotide (NAAD) (Musiek et al 2016).…”