The Role of Activation of the Tryptophan-Kynurenine Axis in the Pathogenesis of Acute Cerebrovascular Diseases: A Literature Review
Marina Grigolashvili 1,
Alina Seryogina 1,
Mira Beisembayeva 1,
Shynar Muratbekova 1,
Ivan Turkevich 2,
Yelena Shayakhmetova 1 * More Detail
1 Department of Neurology, Psychiatry and Rehabilitation, Karaganda Medical University, Karaganda, Kazakhstan
2 «Akzhan» Limited Liability Partnership, Karaganda, Kazakhstan
* Corresponding Author
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Author Contributions: Conceptualization, M. G.; methodology, Y. S. and S. M.; validation, Y. S., A. S. and M. B.; formal analysis, Y. S.; investigation, Y. S., A. S. and I. T.; writing – original draft preparation, Y. S., I. T. and S. M.; writing – review and editing, Y. S. and M. G.; visualization, Y. S.; supervision, M. G.; project administration, M. G. All authors have read and agreed to the published version of the manuscript.
ABSTRACT
Introduction: Acute cerebrovascular disorders are a major contributor to adult disability. The underlying processes that contribute to their development include inflammation, excitotoxicity, oxidative stress, and dysregulation of the tryptophan–kynurenine pathway, which is essential for neuronal survival. However, the precise mechanisms and significance of these processes are not fully comprehended, and their influence on the efficacy of therapeutic approaches remains uncertain.
The aim of this study is to investigate the role of the tryptophan-kynurenine metabolic pathway in the development of stroke and its potential as a biomarker and therapeutic target.
Results and Conclusions: Tryptophan metabolism primarily occurs through the kynurenine pathway. Among its metabolites, kynurenine, kynurenic and choline acids are the most significant. Them have both neuroprotective and neurotoxic effects. Activation of the kynurenine pathway is linked to chronic inflammation, increasing the risk of cardiovascular and neurodegenerative conditions. Kynurenic and choline acids regulate N-methyl-D-aspartate receptor activity and oxidative stress. The increased production of choline and 3-hydroxyanthranilic acid due to oxidative stress is a major mechanism of neuronal damage under ischemic. The regulation of the balance between the neuroprotective and neurotoxic properties of metabolites produced by the kynurenine pathway is essential for normal brain function.
CITATION
Grigolashvili M, Seryogina A, Beisembayeva M, Muratbekova S, Turkevich I, Shayakhmetova Y. The Role of Activation of the Tryptophan-Kynurenine Axis in the Pathogenesis of Acute Cerebrovascular Diseases: A Literature Review. J Clin Med Kaz. 2025.
https://doi.org/10.23950/jcmk/15943
REFERENCES
- Cuartero MI, de la Parra J, García-Culebras A, Ballesteros I, Lizasoain I, Moro M. The Kynurenine Pathway in the Acute and Chronic Phases of Cerebral Ischemia. Curr Pharm Des. 2016; 22(8): 1060–1073. https://doi.org/10.2174/1381612822666151214125950.
- Yang Y, Liu X, Xie C, Shi J. The role of the kynurenine pathway in cardiovascular disease. Front Cardiovasc Med. 2024; 11: 1–13. https://doi.org/10.3389/fcvm.2024.1406856.
- Gáspár R, Halmi D, Demján V, Berkecz R, Pipicz M, Csont T. Kynurenine Pathway Metabolites as Potential Clinical Biomarkers in Coronary Artery Disease. Front Immunol. 2021; 12: 1–20. https://doi.org/10.3389/fimmu.2021.768560.
- Hajsl M, Hlavackova A, Broulikova K, Sramek M, Maly M, Dyr JE, Suttnar J. Tryptophan Metabolism, Inflammation, and Oxidative Stress in Patients with Neurovascular Disease. Metabolites. 2020; 10(5): 1–19. http://dx.doi.org/10.3390/metabo10050208.
- Mor A, Tankiewicz-Kwedlo A, Ciwun M, Lewkowicz J, Pawlak D. Kynurenines as a Novel Target for the Treatment of Inflammatory Disorders. Cells. 2024; 13(15): 1–29. https://doi.org/10.3390/cells13151259.
- Roth W, Zadeh K, Vekariya R, Ge Y, Mohamadzadeh M. Tryptophan Metabolism and Gut-Brain Homeostasis. Int J Mol Sci. 2021; 22(6): 1–23. https://doi.org/10.3390/ijms22062973.
- Cervenka I, Agudelo LZ, Ruas JL. Kynurenines: Tryptophan's metabolites in exercise, inflammation, and mental health. Science. 2017; 357(6349): 1–8. https://doi.org/10.1126/science.aaf9794.
- Li D, Yu S, Long Y, Shi A, Deng J, Ma Y, Wen J, Li X, Liu S, Zhang Y, Wan J, Li N, Ao R. Tryptophan metabolism: Mechanism-oriented therapy for neurological and psychiatric disorders. Front Immunol. 2022; 13: 1–18. https://doi.org/10.3389/fimmu.2022.985378.
- Lim CK, Fernández-Gomez FJ, Braidy N, Estrada C, Costa C, Costa S, Bessede A, Fernandez-Villalba E, Zinger A, Herrero MT, Guillemin GJ. Involvement of the kynurenine pathway in the pathogenesis of Parkinson's disease. Prog Neurobiol. 2017; 155: 76–95. https://doi.org/10.1016/j.pneurobio.2015.12.009.
- Colpo GD, Venna VR, McCullough LD, Teixeira AL. Systematic Review on the Involvement of the Kynurenine Pathway in Stroke: Pre-clinical and Clinical Evidence. Front Neurol. 2019; 10: 1–14. https://doi.org/10.3389/fneur.2019.00778.
- Genestet C, Le Gouellec A, Chaker H, Polack B, Guery B, Toussaint B, Stasia M. Scavenging of reactive oxygen species by tryptophan metabolites helps Pseudomonas aeruginosa escape neutrophil killing. Free Radic Biol Med. 2014; 73: 400–410. https://doi.org/10.1016/j.freeradbiomed.2014.06.003.
- Mor A, Tankiewicz-Kwedlo A, Krupa A, Pawlak D. Role of Kynurenine Pathway in Oxidative Stress during Neurodegenerative Disorders. Cells. 2021; 10(7); 1–30. https://doi.org/10.3390/cells10071603.
- Mithaiwala MN, Santana-Coelho D, Porter GA, O'Connor JC. Neuroinflammation and the Kynurenine Pathway in CNS Disease: Molecular Mechanisms and Therapeutic Implications. Cells. 2021; 10(6); 1–42. https://doi.org/10.3390/cells10061548.
- Baumgartner R, Forteza MJ, Ketelhuth DFJ. The interplay between cytokines and the Kynurenine pathway in inflammation and atherosclerosis. Cytokine. 2019; 122: 1–9. https://doi.org/10.1016/j.cyto.2017.09.004.
- Salminen A. Role of indoleamine 2,3-dioxygenase 1 (IDO1) and kynurenine pathway in the regulation of the aging process. Ageing Res Rev. 2022; 75: 1–13. https://doi.org/10.1016/j.arr.2022.101573.
- Brouns R, Verkerk R, Aerts T, De Surgeloose D, Wauters A, Scharpé S, De Deyn PP. The role of tryptophan catabolism along the kynurenine pathway in acute ischemic stroke. Neurochem Res. 2010; 35(9): 1315–1322. https://doi.org/10.1007/s11064-010-0187-2.
- Bansal Y, Singh R, Parhar I, Kuhad A, Soga T. Quinolinic Acid and Nuclear Factor Erythroid 2-Related Factor 2 in Depression: Role in Neuroprogression. Front Pharmacol. 2019; 10: 1–11. http://dx.doi.org/10.3389/fphar.2019.00452.
- Yan EB, Frugier T, Lim CK, Heng B, Sundaram G, Tan M, Rosenfeld JV, Walker DW, Guillemin GJ, Morganti-Kossmann MC. Activation of the kynurenine pathway and increased production of the excitotoxin quinolinic acid following traumatic brain injury in humans. J Neuroinflammation. 2015; 12: 1–17. https://doi.org/10.1186/s12974-015-0328-2.
- Wu Y, Mai N, Zhong X, Wen Y, Zhou Y, Li H, Shang D, Hu L, Chen X, Chen B, Zhang M, Ning Y. Kynurenine pathway changes in late-life depression with memory deficit. Psychiatry Res. 2018; 269: 45–49. https://doi.org/10.1016/j.psychres.2018.08.041.
- Fujikawa M, Ueda M, Maruyama K. Role of Kynurenine and Its Derivatives in the Neuroimmune System. Int J Mol Sci. 2024; 25(13); 1–19. https://doi.org/10.3390/ijms25137144.
- Ramírez-Ortega D, Ramiro-Salazar A, González-Esquivel D, Ríos C, Pineda B, Pérez de la Cruz V. 3-Hydroxykynurenine and 3-Hydroxyanthranilic Acid Enhance the Toxicity Induced by Copper in Rat Astrocyte Culture. Oxid Med Cell Longev. 2017; 2017: 1–12. https://doi.org/10.1155/2017/2371895.
- Behl T, Kaur I, Sehgal A, Singh S, Bhatia S, Al-Harrasi A, Zengin G, Bumbu AG, Cioara F, Nechifor AC, Gitea D, Bungau AF, Toma MM, Bungau SG. The Footprint of Kynurenine Pathway in Neurodegeneration: Janus-Faced Role in Parkinson's Disorder and Therapeutic Implications. Int J Mol Sci. 2021; 22(13); 1–29. https://doi.org/10.3390/ijms22136737.
- Brown SJ, Huang XF, Newell KA. The kynurenine pathway in major depression: What we know and where to next. Neurosci Biobehav Rev. 2021; 127: 917–927. https://doi.org/10.1016/j.neubiorev.2021.05.018.
- Zuo H, Ueland PM, Ulvik A, Eussen SJ, Vollset SE, Nygård O, Midttun Ø, Theofylaktopoulou D, Meyer K, Tell GS. Plasma Biomarkers of Inflammation, the Kynurenine Pathway, and Risks of All-Cause, Cancer, and Cardiovascular Disease Mortality: The Hordaland Health Study. Am J Epidemiol. 2016; 183(4): 249–258. https://doi.org/10.1093/aje/kwv242.
- Wang F, Liu M, Ma D, Cai Z, Liu L, Wang J, Zhang W, Zhao L, Zhai C, Xu Y. Dendritic cell-expressed IDO alleviates atherosclerosis by expanding CD4. Int Immunopharmacol. 2023; 116: 109758. https://doi.org/10.1016/j.intimp.2023.109758.
- Li M, Kwok MK, Fong SSM, Schooling CM. Effects of tryptophan, serotonin, and kynurenine on ischemic heart diseases and its risk factors: a Mendelian Randomization study. Eur J Clin Nutr. 2020; 74(4): 613–621. https://doi.org/10.1038/s41430-020-0588-5
- Lovelace MD, Varney B, Sundaram G, Lennon MJ, Lim CK, Jacobs K, Guillemin GJ, Brew BJ. Recent evidence for an expanded role of the kynurenine pathway of tryptophan metabolism in neurological diseases. Neuropharmacology. 2017; 112(Pt B): 373–388. https://doi.org/10.1016/j.neuropharm.2016.03.024.
- Schwarcz R, Stone TW. The kynurenine pathway and the brain: Challenges, controversies and promises. Neuropharmacology. 2017; 112(Pt B): 237–247. https://doi.org/10.1016/j.neuropharm.2016.08.003.
- Pires AS, Sundaram G, Heng B, Krishnamurthy S, Brew BJ, Guillemin GJ. Recent advances in clinical trials targeting the kynurenine pathway. Pharmacol Ther. 2022; 236: 108055. https://doi.org/10.1016/j.pharmthera.2021.108055.