Altered kynurenine metabolism correlates with infarct volume in stroke.
Inflammation and oxidative stress are involved in brain damage following stroke, and tryptophan oxidation along the kynurenine pathway contributes to the modulation of oxidative stress partly via the glutamate receptor agonist quinolinic acid and antagonist kynurenic acid, and via redox-active compounds such as 3-hydroxyanthranilic acid. We have confirmed that following a stroke, patients show early elevations of plasma neopterin, S100B and peroxidation markers, the latter two correlating with infarct volume assessed from computed tomography (CT) scans, and being consistent with a rapid inflammatory response. We now report that the kynurenine pathway of tryptophan metabolism was also activated, with an increased kynurenine : tryptophan ratio, but with a highly significant decrease in the ratio of 3-hydroxyanthranilic acid : anthranilic acid, which was strongly correlated with infarct volume. Levels of kynurenic acid were significantly raised in patients who died within 21 days compared with those who survived. The results suggest that increased tryptophan catabolism is initiated before or immediately after a stroke, and is related to the inflammatory response and oxidative stress, with a major change in 3-hydroxyanthranilic acid levels. Together with previous evidence that inhibiting the kynurenine pathway reduces brain damage in animal models of stroke and cerebral inflammation, and that increased kynurenine metabolism directly promotes oxidative stress, it is proposed that oxidative tryptophan metabolism may contribute to the oxidative stress and brain damage following stroke. Some form of anti-inflammatory intervention between the rise of S100B and the activation of microglia, including inhibition of the kynurenine pathway, may be valuable in modifying patient morbidity and mortality.
Darlington
L G
LG
Epsom General Hospital, Epsom, Surrey KT18 7EG, UK.
Mackay
G M
GM
Forrest
C M
CM
Stoy
N
N
George
C
C
Stone
T W
TW
D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D020520:Brain Infarction / Q000209:etiology / Q000473:pathology*; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D005260:Female; D006801:Humans; D007737:Kynurenine / Q000378:metabolism*; D015227:Lipid Peroxidation / Q000502:physiology; D008297:Male; D008954:Models, Biological; D019798:Neopterin / Q000378:metabolism; D009414:Nerve Growth Factors / Q000378:metabolism; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000378:metabolism; D013223:Statistics as Topic; D020521:Stroke / Q000150:complications / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D013997:Time Factors; D014057:Tomography, X-Ray Computed / Q000379:methods; D014364:Tryptophan / Q000378:metabolism
D009414:Nerve Growth Factors; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; C579160:S100B protein, human; D007737:Kynurenine; D019798:Neopterin; D014364:Tryptophan