Kinureninski put katabolizma triptofana i shizofrenija

Miloš Marković

doi:10.5937/mp74-40330

Miloš Marković Medicinski fakultet, Beograd

DOI: https://doi.org/10.5937/mp74-40330

Ključne reči: kinureninski put, proinflamatorni citokini, shizofrenija

Sažetak

Razvoj novih terapija usmerenih ka oporavku pacijenata sa shizofrenijom najpre je uslovljen razumevanjem biološke osnove bolesti. Kinureninski put katabolizma triptofana u fokusu je psihijatrijskih istraživanja obzirom da njegovi kataboliti imaju neuroaktivno dejstvo, a jedno od značajnijih je efekat kinurenske kiseline kao jedinog endogenog NMDA receptorskog antagoniste. Prema kinureninskoj hipotezi kod pacijenata sa shizofrenijom dolazi do disbalansa ekscitatornih i neuroprotektivnih metabolita kinureninskog puta. Smatra se da povećana produkcija kinurenske kiseline dovodi do ekscesivne blokade NMDA glutamatnih i alfa-7 nikotinskih receptora, delujući kao okidač nastanka kako psihotičnih simptoma tako i kognitivnih deficita. Ovaj rad ima za cilj da analizira kinureninsku hipotezu shizofrenije, značajna istraživanja o promenama metabolita kinureninskog puta kod pacijenata sa shizofrenijom, kao i istraživanja mogućeg uticaja proinflamatornih citokina na kinureninski put.

Reference

1. Fleischhacker WW, Arango C, Arteel P, Barnes TRE, Carpenter W, Duckworth K, et al. Schizophrenia--time to commit to policy change. Schizophr Bull. 2014 Apr;40 Suppl 3:S165-194.

2. Murray CJ, Lopez AD. Global mortality, disability, and the contribution of risk factors: Global Burden of Disease Study. Lancet. 1997 May 17;349(9063):1436–42.

3. Marder SR, Cannon TD. Schizophrenia. N Engl J Med. 2019 Oct 31;381(18):1753–61.

4. Jablensky A, Sartorius N, Ernberg G, Anker M, Korten A, Cooper JE, et al. Schizophrenia: manifestations, incidence and course in different cultures. A World Health Organization ten-country study. Psychol Med Monogr Suppl. 1992;20:1–97.

5. Myint AM. Kynurenines: from the perspective of major psychiatric disorders. FEBS J. 2012 Apr;279(8):1375–85.

6. Freedman R. Schizophrenia. N Engl J Med. 2003 Oct 30;349(18):1738–49.

7. Horan WP, Harvey PO, Kern RS, Green MF, Neurocognition, Social Cognition and Functional Outcome in Schizophrenia. In: Gaebel W, editor. Schizophrenia: Current science and clinical practice. Oxford, UK: John Wiley & Sons, Ltd. 2011. p 67-107.

8. Heyes MP, Chen CY, Major EO, Saito K. Different kynurenine pathway enzymes limit quinolinic acid formation by various human cell types. Biochem J. 1997 Sep 1;326(Pt 2):351–6.

9. 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;12:768560.

10. Schwarcz R, Bruno JP, Muchowski PJ, Wu HQ. Kynurenines in the mammalian brain: when physiology meets pathology. Nat Rev Neurosci. 2012;13:465–77.

11. Plitman E, Iwata Y, Caravaggio F, Nakajima S, Chung JK, Gerretsen P, et al. Kynurenic Acid in Schizophrenia: A Systematic Review and Meta-analysis. Schizophr Bull. 2017 Jul 1;43(4):764–77.

12. Campbell BM, Charych E, Lee AW, Möller T. Kynurenines in CNS disease: regulation by inflammatory cytokines. Front Neurosci. 2014;8:12.

13. Urbanska EM, Chmiel-Perzyńska I, Perzyński A, Derkacz M, Owe- Larsson B, Endogenous kynurenic acid and neurotoxicity. In: Kostrzewa R, editor. Handbook of neurotoxicity, New Jork, USA: Springer, 2014 p 421–453

14. Szalardy L, Zadori D, Toldi J, Fulop F, Klivenyi P, Vecsei L. Manipulating kynurenic acid levels in the brain - on the edge between neuroprotection and cognitive dysfunction. Curr Top Med Chem. 2012;12(16):1797–806.

15. Perkins MN, Stone TW. An iontophoretic investigation of the actions of convulsant kynurenines and their interaction with the endogenous excitant quinolinic acid. Brain Res. 1982 Sep 9;247(1):184–7.

16. Guidetti P, Amori L, Sapko MT, Okuno E, Schwarcz R. Mitochondrial aspartate aminotransferase: a third kynurenate-producing enzyme in the mammalian brain. J Neurochem. 2007 Jul;102(1):103–11.

17. Javitt DC, Zukin SR, Heresco-Levy U, Umbricht D. Has an angel shown the way? Etiological and therapeutic implications of the PCP/NMDA model of schizophrenia. Schizophr Bull. 2012 Sep;38(5):958–66.

18. Kozak R, Campbell BM, Strick CA, Horner W, Hoffmann WE, Kiss T, et al. Reduction of Brain Kynurenic Acid Improves Cognitive Function. J Neurosci. 2014 Aug 6;34(32):10592–602.

19. Wonodi I, Schwarcz R. Cortical Kynurenine Pathway Metabolism: A Novel Target for Cognitive Enhancement in Schizophrenia. Schizophr Bull. 2010 Mar;36(2):211–8.

20. Moghaddam B, Krystal JH. Capturing the angel in “angel dust”: twenty years of translational neuroscience studies of NMDA receptor antagonists in animals and humans. Schizophr Bull. 2012 Sep;38(5):942–9.

21. Erhardt S, Blennow K, Nordin C, Skogh E, Lindström LH, Engberg G. Kynurenic acid levels are elevated in the cerebrospinal fluid of patients with schizophrenia. Neurosci Lett. 2001 Nov 2;313(1–2):96–8.

22. Linderholm KR, Skogh E, Olsson SK, Dahl ML, Holtze M, Engberg G, et al. Increased levels of kynurenine and kynurenic acid in the CSF of patients with schizophrenia. Schizophr Bull. 2012 May;38(3):426–32.

23. Schwarcz R, Rassoulpour A, Wu HQ, Medoff D, Tamminga CA, Roberts RC. Increased cortical kynurenate content in schizophrenia. Biol Psychiatry. 2001 Oct 1;50(7):521–30.

24. Szymona K, Zdzisińska B, Karakuła-Juchnowicz H, Kocki T, Kandefer-Szerszeń M, Flis M, et al. Correlations of Kynurenic Acid, 3-Hydroxykynurenine, sIL-2R, IFN-α, and IL-4 with Clinical Symptoms During Acute Relapse of Schizophrenia. Neurotox Res. 2017 Jul;32(1):17–26.

25. Chiappelli J, Notarangelo FM, Pocivavsek A, Thomas MAR, Rowland LM, Schwarcz R, et al. Influence of plasma cytokines on kynurenine and kynurenic acid in schizophrenia. Neuropsychopharmacology. 2018 Jul;43(8):1675–80.

26. De Picker L, Fransen E, Coppens V, Timmers M, de Boer P, Oberacher H, et al. Immune and Neuroendocrine Trait and State Markers in Psychotic Illness: Decreased Kynurenines Marking Psychotic Exacerbations. Front Immunol. 2019;10:2971.

27. Cao B, Chen Y, Ren Z, Pan Z, McIntyre RS, Wang D. Dysregulation of kynurenine pathway and potential dynamic changes of kynurenine in schizophrenia: A systematic review and meta-analysis. Neurosci Biobehav Rev. 2021 Apr;123:203–14.

28. Kindler J, Lim CK, Weickert CS, Boerrigter D, Galletly C, Liu D, et al. Dysregulation of kynurenine metabolism is related to proinflammatory cytokines, attention, and prefrontal cortex volume in schizophrenia. Mol Psychiatry. 2020 Nov;25(11):2860–72.

29. Dunjic Kostic B, Pantovic M, Ivković M, Damjanovic A, Lačković M, Jasovic Gasic M, Shizofrenija i citikini. Engrami 2015;37:55-61 (Serbian)

30. Lestage J, Verrier D, Palin K, Dantzer R. The enzyme indoleamine 2,3-dioxygenase is induced in the mouse brain in response to peripheral administration of lipopolysaccharide and superantigen. Brain Behav Immun. 2002 Oct;16(5):596–601.

31. O’Connor JC, André C, Wang Y, Lawson MA, Szegedi SS, Lestage J, et al. Interferon-gamma and tumor necrosis factor-alpha mediate the upregulation of indoleamine 2,3-dioxygenase and the induction of depressive-like behavior in mice in response to bacillus Calmette-Guerin. J Neurosci. 2009 Apr 1;29(13):4200–9

32. Reale M, Costantini E, Greig NH. Cytokine Imbalance in Schizophrenia. From Research to Clinic: Potential Implications for Treatment. Front Psychiatry. 2021;12:536257.

33. Miller BJ, Buckley P, Seabolt W, Mellor A, Kirkpatrick B. Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry. 2011 Oct 1;70(7):663–71.

34. Upthegrove R, Manzanares-Teson N, Barnes NM. Cytokine function in medication-naive first episode psychosis: a systematic review and meta-analysis. Schizophr Res. 2014 May;155(1–3):101–8.

35. Frydecka D, Krzystek-Korpacka M, Lubeiro A, Stramecki F, Stańczykiewicz B, Beszłej JA, et al. Profiling inflammatory signatures of schizophrenia: A cross-sectional and meta-analysis study. Brain Behav Immun. 2018 Jul;71:28–36.

36. Najjar S, Pearlman DM. Neuroinflammation and white matter pathology in schizophrenia: systematic review. Schizophr Res. 2015 Jan;161(1):102–12.

37. Pedraz-Petrozzi B, Elyamany O, Rummel C, Mulert C. Effects of inflammation on the kynurenine pathway in schizophrenia - a systematic review. J Neuroinflammation. 2020 Feb 15;17(1):56.