Table 2.

Humans studies with stroke/ischemia and kynurenine pathway.

References	Study population	Results	Conclusion
Darlington et al. (53)	Patients with symptoms of acute stroke. Performed CY scan and measure kynurenines, neopterin, lipid peroxidation, S100B	KYN pathway of tryptophan metabolism is activated, with an increased KYN:TRP ratio, but with a highly significant decrease in the ratio of 3-HAA: anthranilic acid, which was strongly correlated with infarct volume. Levels of KYNA were significantly raised in patients who died within 21 days compared with those who survived. The results suggest that increased TRP 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-HAA levels.	The results suggest 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
Brouns et al. (54)	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.	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 favorable 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.	The results suggest the activity of the KYN 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.
Gold et al. (55)	Patients were recruited from the acute stroke. Assessments for cognition, stroke severity, and the depressive symptoms. TRP and KYN concentrations were determined by high-performance liquid chromatography.	Higher KYN/TRP ratios were associated with lower post-stroke global cognition. A backward stepwise elimination linear regression showed that the highest KYN/TRP ratio tertile predicted lower sMMSE scores, controlling for age with NIHSS, and lesion volume.	The results suggest an inflammatory response characterized by IDO activation may be relevant to the development of PSCI. Since the neuroactivity of KYN metabolites may be amenable to pharmacotherapeutic intervention, the KYN/TRP ratio may be a clinically important biomarker.
Bensimon et al. (56)	Patients with ischemic stroke divided into high, medium, and low depressive symptom tertiles. Measure concentrations of KYN and TRP and cytokine concentrations.	No differences in KYN/TRP ratios between CES-D for cytokines (n = 53), serum IL-1β concentrations and serum ratios of IL-18/IL-10, IFNγ/IL-10, and IL-1β/IL-10 were elevated in the middle CES-D tertile. Post hoc analyses suggested that serum ratios of IL-18/IL-10, and IL-1β/IL-10, as well as IL-1β, were significantly associated with fatigue.	The results suggest that peripheral KYN/TRP ratios were not associated with depressive symptoms in a post-stroke population. However, in exploratory analyses a pro-inflammatory bias was identified specifically in patients with mild depressive symptoms and associated with post-stroke fatigue, suggesting an avenue for future research.
Mo et al. (57)	A total of 81 patients with ischemic stroke and 35 normal controls were recruited. Measure, concentration of serum hsCRP, apolipoprotein A-1 and apolipoprotein B, triglyceride, cholesterol, high density lipoprotein (HDL). TRP, KYN and KYNA.	Lower TRP, KYNA, HDL, and KAT activity ratio were found in the stroke group compared to the control group. The levels of hsCRP and IDO activity ratio were much higher in the stroke group than the control group. The IDO activity in patients with ischemic stroke showed a positive correlation with hsCRP. In addition, hsCRP and IDO levels were positively associated with the NIHSS score both at admission and 3 weeks post-stroke.	The results suggest an inflammatory response characterized by up-regulated IDO activation in ischemic stroke, which might be closely relevant to its pathophysiology.
Ormstad et al. (58)	Acute serum levels of 5-hydroxytryptamine (5-HT), TRP catabolites (TRYCATs), and competing amino acids, as well as subsequent fatigue and depression, were measured in 45 stroke patients.	TRP index [ = 100 × TRP / (tyrosine + valine + phenylalanine + leucine + isoleucine)] was lower in patients with a Fatigue Severity Scale (FSS) score of ≥4 at 12 months than in those with an FSS score of <4. Furthermore, the serum level of KYNA in the acute stroke phase was higher in patients with an FSS of score ≥4 at 18 months than in those with an FSS score of <4. These findings indicate that stroke patients with PSF have a lower bioavailability of TRP for 5-HT synthesis in the brain in the acute stroke phase.	The findings indicate that stroke patients with PSF have a lower bioavailability of TRP for 5-HT synthesis in the brain in the acute stroke phase. However, they also appear to have greater neuroprotective potential in that phase. In contrast to PSF, no predictors of PSD were found.