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.
Highlights
Traumatic brain injury (TBI) is one of the leading causes of morbidity and mortality in healthy individuals
The exceeding production of quinolinic acid (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 kynurenine pathway (KP) pathway
In vitro studies on cultured microglia have demonstrated IFN-γ-independent activation of IDO1 by TNF-α and IL-1β [45]. This point is pertinent to our study as we have previously shown a fourfold elevation of TNF-α at protein/mRNA levels in the same post-mortem brains harvested within 17 min post-injury while a nonsignificant increase of IL-1β mRNA was observed early (17 min) which was followed by a substantial and significant upregulation of over fivefold in the delayed group dying beyond 6 h from TBI [36]
Summary
Traumatic brain injury (TBI) is one of the leading causes of morbidity and mortality in healthy individuals. Epidemiologic studies reported that TBI occurs more frequently in young adults due to motor vehicle accidents, sport activities and assaults as major causes of injury. TBI is distinguished in two phases, namely primary and secondary injury. Long-lasting secondary injury processes commence lasting for minutes, hours and days following a TBI. The combination of such pathological changes in the brain’s intrinsic physiology and biochemistry aggravates brain damage and possibly underlies the causes of death. Over the past decades, compelling evidence has shown that such delayed processes represent the most destructive phase of TBI; the complexity and the mechanisms of secondary brain injury require further elucidation. There are few well-defined secondary pathways including inflammation, oxidative stress and excitotoxicity that terminate with the release of neurotoxins, leading to delayed cell death
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