The Role of Tryptophan Catabolism along the Kynurenine Pathway in Acute Ischemic Stroke

Abstract

Post-stroke inflammation may induce upregulation of the kynurenine (KYN) pathway for tryptophan (TRP) oxidation, resulting in neuroprotective (kynurenic acid, KA) and neurotoxic metabolites (3-hydroxyanthranillic acid, 3-HAA). We investigated whether activity of the kynurenine pathway in acute ischemic stroke is related to initial stroke severity, long-term stroke outcome and the ischemia-induced inflammatory response. Plasma concentrations of TRP and its metabolites were measured in 149 stroke patients at admission, at 24 h, at 72 h and at day 7 after stroke onset. We evaluated the relation between the KYN/TRP ratio, the KA/3-HAA ratio and stroke severity, outcome and inflammatory parameters (C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and neutrophil/lymphocyte ratio (NLR)). KYN/TRP but not KA/3-HAA correlated with the NIHSS score and with the infarct volume. Patients with poor outcome had higher mean KYN/TRP ratios than patients with more favourable outcome. The KYN/TRP ratio at admission correlated with CRP levels, ESR and NLR. The activity of the kynurenine pathway for tryptophan degradation in acute ischemic stroke correlates with stroke severity and long-term stroke outcome. Tryptophan oxidation is related to the stroke-induced inflammatory response.

Mechanisms of poststroke fatigue

“…Darlington et al 96 showed increased TRP catabolism after stroke and suggest that oxidative TRP metabolism contributes to oxidative stress and brain damage. Brouns et al 95 showed a correlation between KYN/TRP ratio and stroke severity and long-term stroke outcome that did not correlate with KA/3-hydroxyanthranillic acid ratio. Mo et al 98 showed an upregulation of IDO activation in ischaemic stroke.…”

Tryptophan-kynurenine pathway is dysregulated in inflammation and immune activation

“…Following its synthesis by IDO, Kyn can be further metabolized by various enzymes (Figure 1)(1, 32–34). Kynureninase produces anthranilic acid (AA) from Kyn(35, 36).…”

Mitochondrial disturbances, excitotoxicity, neuroinflammation and kynurenines: Novel therapeutic strategies for neurodegenerative disorders

“…The accumulation of microglial cells has been demonstrated in the HD brain [37], but the number of T-cells is not altered [38]. There is an increasing evidence of the involvement of activation of the kynurenine pathway in relation to inflammatory processes in both ischemic stroke ( [39]) and HD ( [40]). …”