Effect of Kynurenic Acid on Pupae Viability of Drosophila melanogaster cinnabar and cardinal Eye Color Mutants with Altered Tryptophan-Kynurenine Metabolism

  • Valeriya Navrotskaya
  • Artur Wnorowski
  • Waldemar Turski
  • Gregory Oxenkrug
ORIGINAL ARTICLE

Abstract

Kynurenic acid (KYNA) is one of the metabolites of evolutionary conserved tryptophan (Trp)/kynurenine (Kyn) metabolic pathway. Elevation of KYNA contributes to development of psychosis in schizophrenia but attenuates neurodegeneration in Drosophila model of Huntington’s disease. We have reported that KYNA increased lethality of pupae of wild-type flies, but not of vermilion (v) mutants with impaired formation of Kyn from Trp, suggesting that KYNA toxicity depends on its interaction with downstream Kyn metabolites [i.e., 3-hydroxykynurenine (3-HK) and/or xanthurenic acid (XA)]. The present study aimed to further explore the mechanisms of KYNA-induced lethality by the assessment of KYNA effect on pupae of two Drosophila mutants: cinnabar (cn), characterized by higher KYNA and lower 3-HK production, and cardinal (cd), characterized by higher 3-HK and XA levels compared to wild-type flies. Our microarray datamining revealed that the gene expression pattern of enzymes forming Trp/Kyn pathway stands in line with previously reported developmental changes in KYNA, 3-HK, and XA concentrations in wild-type and mutant flies. Administration of KYNA increased pupae lethality in cd, but not in cn mutants. Present data suggest that toxic effect of exogenous KYNA depends on the presence of 3-HK and/or XA. This is further supported by our finding that early stages of Drosophila development are associated with a positive expression pattern of genes encoding sulfotransferases, enzymes that are inhibited by KYNA and are involved in detoxification of XA. Alternatively, the toxic effect of KYNA might depend on anti-proliferative effects of KYNA.

Keywords

Kynurenine Kynurenine-3-monooxygenase Kynurenic acid 3-Hydroxykynurenine Drosophila melanogaster vermilion cinnabar cardinal, pupae 

Notes

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

All applicable international, national, and institutional guidelines for the care and use of animals were followed. All procedures performed in the study involving animals were in accordance with the ethical standards of the institution at which the studies were conducted.

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Genetics and CytologyV.N. Karazin Kharkiv National UniversityKharkivUkraine
  2. 2.Department of BiopharmacyMedical University of LublinLublinPoland
  3. 3.Department of Experimental and Clinical PharmacologyMedical University of LublinLublinPoland
  4. 4.Psychiatry and Inflammation Program, Department of PsychiatryTufts University School of Medicine and Tufts Medical CenterBostonUSA

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