The kynurenine pathway in body and brain : relation with physical exercise and mental health

The kynurenine pathway of tryptophan degradation is the focus in a variety of research fields and several of the metabolites produced along the pathway are suggested as future biomarkers. Growing interest in a better understanding of the physiological and the pathophysiological importance of kynurenine pathway metabolites is followed by the need for a robust, sensitive method that can quantify multiple metabolites simultaneously. In the present thesis, the first aim was to develop and validate robust and sensitive methods for the analysis of kynurenine pathway metabolites in body and brain. Our method thus allows for simultaneous quantification of low concentrations of tryptophan, kynurenine, kynurenic acid (KYNA), 3- hydroxykynurenine (3-HK), xanthurenic acid (XA), 3-hydroxyanthranilic acid (3-HANA), quinolinic acid (QUIN), picolinic acid (PIC), nicotinic acid (NA) and nicotinamide (NAA) in human cerebrospinal fluid (CSF) and plasma. In addition, our new method clearly separates the peaks of the isomers, PIC and NA. Moreover, metabolites of the kynurenine pathway have been linked to the pathophysiology of bipolar disorder and suicide. In this thesis, we thus analyzed the concentrations of kynurenine pathway metabolites in the CSF of suicide attempters and patients with bipolar disorder. All patients were stratified into groups according to their history of suicide behavior. As previously reported, we found a reduced CSF PIC/QUIN ratio in suicide attempters. Furthermore, patients with bipolar disorder and a history of suicide behavior had lower CSF PIC concentrations than those without, giving further support for the hypothesis that low CSF PIC is a predictor of suicidality vulnerability. A negative correlation between an ACMSD genetic variant and the CSF PIC/QUIN ratio in patients with bipolar disorder with a history of suicide behavior was discovered, suggesting that polymorphism in ACMSD is linked to excess QUIN formation at the expense of PIC. In patients with bipolar disorder, we also found elevated CSF kynurenine/tryptophan ratio, KYNA, and PIC concentrations clearly demonstrating induction of the kynurenine pathway in these patients.

In the process of developing biomarkers, it is also important to understand if and how daily activity, such as physical exercise affects their concentration. The majority of exercise studies investigating kynurenines published so far have focused on a few kynurenine metabolites, and most often not taken into consideration the exercise habit of the participants that might affect the results. In the last part of this thesis, we thus investigated how different types of exercise influence central and peripheral levels of kynurenine pathway metabolites. Specifically, we investigated how one bout of sprint interval exercise (SIE) affects plasma kynurenine pathway metabolites of healthy subjects belonging to different age groups. In detail, the SIE session consisted of 6 repetitions of 30-seconds all-out cycling with 4-minutes passive recovery periods in between. Moreover, in another cohort of healthy subjects with a background of different exercise habits, we investigated how aerobic exercise affected kynurenine pathway metabolites and immune markers in plasma and CSF. In this study, participants were divided into two groups based on their existing level of physical activity habits. One group performed an acute intense exercise program for four days (two days of 30 minutes high-intensity interval training, and two days of running for at least 60 minutes) and the second training group performed 30 minutes of running, three times weekly, for 4 weeks.

The results clearly show that both types of exercise tested (aerobic and anaerobic) influence kynurenine pathway metabolites. We found that plasma levels of kynurenine increased 1 hour after the SIE session in healthy elderly subjects, while levels of KYNA increased after 24 hours. We further found that acute exercise intervention, increased the CSF levels of KYNA, 3HK, and PIC, while tryptophan and kynurenine remained unchanged. Furthermore, in the training group, the CSF kynurenine/tryptophan ratio increased. Tryptophan and kynurenine, on the other hand, decreased significantly after acute exercise, while KYNA, 3-HK, QUIN, and PIC in the plasma did not change in any of the groups. Some immune markers showed a tendency towards an increase in both plasma and CSF but were not statistically significant. In plasma, kynurenine and PIC levels were correlated with aberrant immune markers profile. While in CSF, kynurenine and QUIN levels, and also the ratio of kynurenine/tryptophan were associated with immune protein marker profiles. One important finding was the positive correlation between PIC levels in plasma and CSF.

In the present thesis, we have developed a novel method for the simultaneous quantification of kynurenine pathway metabolites. We also confirm that the brain kynurenine pathway in patients with bipolar disorder is activated as well as we show data supporting that low PIC might indicate vulnerability for suicidal behavior. Furthermore, we confirm that both central and peripheral kynurenine pathway metabolites are affected by physical exercise.

List of scientific papers

I. Lilly Schwieler, Ada Trepci, Stanislaw Krzyzanowski, Sigurd Hermansson, Mathias Granqvist, Fredrik Piehl, Tomas Venckunas, Marius Brazaitis, Sigitas Kamandulis, Daniel Lindqvist, A. Daniel Jones, Sophie Erhardt, Lena Brundin. A novel, robust method for quantification of multiple kynurenines pathway metabolites in the cerebrospinal fluid. Bioanalysis. 12(6):379-392, 2020.
https://doi.org/10.4155/bio-2019-0303

II. Ada Trepci, Carl M. Sellgren, Erik Pålsson, Lena Brundin, Neda Khanlarkhani, Lilly Schwieler, Mikael Landén, Sophie Erhardt. Central levels of tryptophan metabolites in subjects with bipolar disorder. European Neuropsychopharmacology. 43:52-62, 2021.
https://doi.org/10.1016/j.euroneuro.2020.11.018

III. Ada Trepci, Sophie Imbeault, Victoria L. Wyckelsma, Håkan Westerblad, Sigurd Hermansson, Daniel C. Andersson, Fredrik Piehl, Tomas Venckunas, Marius Brazaitis, Sigitas Kamandulis, Lena Brundin, Sophie Erhardt, Lilly Schwieler. Quantification of plasma kynurenine metabolites following one bout of sprint interval exercise. International Journal of Tryptophan Research. 13:1178646920978241, 2020.
https://doi.org/10.1177/1178646920978241

IV. Josef Isung, Mathias Granqvist, Ada Trepci, Jesse Huang, Lilly Schwieler, Marie Kierkegaard, Sophie Erhardt, Jussi Jokinen, Fredrik Piehl. Differential effects on blood and cerebrospinal fluid immune protein markers and kynurenine pathway metabolites from aerobic physical exercise in healthy subjects. Scientific Reports. 11(1):1669, 2021.
https://doi.org/10.1038/s41598-021-81306-4