Роль кинуренинов в регуляции поведения и процессов памяти у дрозофилы

Авторы

  • Александр Владимирович Журавлев Институт физиологии им. И. П. Павлова РАН
  • Екатерина Александровна Никитина Институт физиологии им. И. П. Павлова РАН; Российский государственный педагогический университет им. А. И. Герцена https://orcid.org/0000-0003-1897-8392
  • Елена Владимировна Савватеева-Попова Институт физиологии им. И. П. Павлова РАН

DOI:

https://doi.org/10.33910/2687-1270-2020-1-1-40-50

Ключевые слова:

кинуренины, дрозофила, 3-гидроксикинуренин, кинуреновая кислота, память

Аннотация

Метаболиты кинуренинового пути обмена триптофана (КПОТ), или кинуренины, обладают рядом нейроактивных свойств. Нарушения КПОТ наблюдаются при различных заболеваниях нервной системы, таких как болезни Хантингтона, Паркинсона и Альцгеймера, старческое слабоумие, шизофрения, депрессивные состояния и др. Известны два основных механизма воздействия кинуренинов на процессы в нервных клетках — модуляция активности клеточных рецепторов и модуляция окислительно-восстановительного потенциала. Так, кинуреновая кислота (KYNA) является неспецифическим антагонистом ионотропных рецепторов глутамата и ингибитором эксайтотоксических процессов. 3-гидроксикинуренин (3НОК) ингибирует перекисное окисление липидов, но в высокой концентрации вследствие окислительной аутодимеризации вызывает гиперпродукцию пероксида водорода, что приводит к гибели нервных клеток. Молекулярные механизмы нейроактивности кинуренинов удобно исследовать на простых модельных объектах, таких как пчела и дрозофила, мутации генов КПОТ у которых они специфически влияют на содержание кинуренинов. Удобство использования мутантов дрозофилы для изучения нейротропных свойств кинуренинов определяется рядом обстоятельств: 1) отсутствие пути синтеза NAD+ из 3HOK у насекомых и, следовательно, влияния дефектов КПОТ на энергетический метаболизм; 2) отсутствие у насекомых ряда метаболитов КПОТ, таких как хинолиновая кислота, потенциирующая нейротоксические свойства 3НОК; 3) высокий уровень 3НОК в организме в силу необходимости синтезировать в большом количестве пигмент ксантомматин; 4) методическая простота проведения генетических, физиологических и молекулярно-биологических исследований. Накопление 3НОК у мутанта cardinal (сd) дрозофилы вызывает нарушение брачной песни самца и развитие синаптической патологии на поздних сроках жизни имаго. Кроме того, у cd наблюдается возраст-зависимое нарушение среднесрочной памяти в парадигме условно-рефлекторного подавления ухаживания. Вышеуказанное позволяет рассматривать сd как модель сенильной деменции у человека. Напротив, у мутанта cinnabar (cn) с накоплением KYNA отмечено позитивное влияние данного нейропротектора на память и звукопродукцию. В целом продукты КПОТ оказывают активирующее действие на ЦНС и поведенческие процессы.

Библиографические ссылки

Aarsland, T. I., Landaas, E. T., Hegvik, T. A. et al. (2015) Serum concentrations of kynurenines in adult patients with attention-deficit hyperactivity disorder (ADHD): A case-control study. Behavioral and Brain Functions, vol. 11, article 36. DOI: 10.1186/s12993-015-0080-x (In English)

Ackerman, S. L., Siegle, R. W. (1986) Chemically reinforced conditioned courtship in Drosophila: responses of wild-type and dunce, amnesiac and don giovanni mutants. Journal of Neurogenetics, vol. 3, no. 2, pp. 111–123. PMID: 3083073. (In English)

Badawy, A. A. (2017) Kynurenine pathway of tryptophan metabolism: Regulatory and functional aspects. International Journal of Tryptophan Research, vol. 10, pp. 1–20. DOI: 10.1177/1178646917691938 (In English)

Bailey, C. H., Bartsch, D., Kandel, E. R. (1996) Toward a molecular definition of long-term memory storage. Proceedings of the National Academy of Sciences of the United States of America, vol. 93, no. 24, pp. 13445–13452. PMID: 8942955. DOI: 10.1073/pnas.93.24.13445 (In English)

Bryleva, E. Y., Brundin, L. (2016) Kynurenine pathway metabolites and suicidality. Neuropharmacology, vol. 112, pt. B, pp. 324–330. DOI: 10.1016/j.neuropharm.2016.01.034 (In English)

Campbell, B. M., Charych, E., Lee, A. W., Moller, T. (2014) Kynurenines in CNS disease: Regulation by inflammatory cytokines. Frontiers in Neuroscience, vol. 8, no. 12. DOI: 10.3389/fnins.2014.00012 (In English)

Ceresoli-Borroni, G., Guidetti, P., Amori, L. et al. (2007) Perinatal kynurenine 3-hydroxylase inhibition in rodents: Pathophysiological implications. Journal of Neuroscience Research, vol. 85, no. 4, pp. 845–854. PMID: 17279543. DOI: 10.1002/jnr.21183 (In English)

Christen, S., Peterhans, E., Stocker, R. (1990) Antioxidant activities of some tryptophan metabolites: Possible implication for inflammatory diseases. Proceedings of the National Academy of Sciences of the United States of America, vol. 87, no. 7, pp. 2506–2510. PMID: 2320571. (In English)

Colin-Gonzalez, A. L., Maya-Lopez, M., Pedraza-Chaverri, J. et al. (2014) The Janus faces of 3-hydroxykynurenine: Dual redox modulatory activity and lack of neurotoxicity in the rat striatum. Brain Research, vol. 1589, pp. 1–14. DOI: 10.1016/j.brainres.2014.09.034 (In English)

Danysz, W., Fadda, E., Wroblewski, J. T. et al. (1989) Kynurenate and 2-amino-5-phosphonovalerate interact with multiple binding sites of the N-methyl-D-aspartate-sensitive glutamate receptor domain. Neuroscience Letters, vol. 96, no. 3, pp. 340–344. (In English)

Davis, R. L., Kiger, J. A. (1981) dunce mutants of Drosophila melanogaster: Mutants defective in the cyclic AMP phosphodiesterase enzyme system. Journal of Cell Biology, vol. 90, no. 1, pp. 101–107. PMID: 6265472. DOI: 10.1083/jcb.90.1.101 (In English)

el-Defrawy, S. R., Boegman, R. J., Jhamandas, K., Beninger, R. J. (1986) The neurotoxic actions of quinolinic acid in the central nervous system. Canadian Journal of Physiology and Pharmacology, vol. 64, no. 3, pp. 369–375. PMID: 2939936. DOI: 10.1139/y86-060 (In English)

Fazio, F., Lionetto, L., Molinaro, G. et al. (2012) Cinnabarinic acid, an endogenous metabolite of the kynurenine pathway, activates type 4 metabotropic glutamate receptors. Molecular Pharmacology, vol. 81, no. 5, pp. 643–656. PMID: 22311707. DOI: 10.1124/mol.111.074765 (In English)

Ferre, J. (1983) Accumulation of kynurenic acid in the “cinnabar” mutant of Drosophila melanogaster as revealed by thin-layer chromatography. Insect Biochemistry, vol. 13, no. 3, pp. 289–294. DOI: 10.1016/0020-1790(83)90051-3 (In English)

Figon, F., Casas, J. (2019) Ommochromes in invertebrates: Biochemistry and cell biology. Biological Reviews, vol. 94, pp. 156–183. DOI: 10.1111/brv.12441 (In English)

Flieger, J., Święch-Zubilewicz, A., Śniegocki, T. et al. (2018) Determination of tryptophan and its major metabolites in fluid from the anterior chamber of the eye in diabetic patients with cataract by liquid chromotography mass spectrometry (LC-MS/MS). Molecules, vol. 23, no. 11, article E3012. DOI: 10.3390/molecules23113012 (In English)

Foster, A. C., Vezzani, A., French, E. D., Schwarcz, R. (1984) Kynurenic acid blocks neurotoxicity and seizures induced in rats by the related brain metabolite quinolinic acid. Neuroscience Letters, vol. 48, no. 3, pp. 273–278. PMID: 6237279. DOI: 10.1016/0304-3940(84)90050-8 (In English)

Fuertig, R., Ceci, A., Camus, S. M. et al. (2016) LC–MS/MS-based quantification of kynurenine metabolites, tryptophan, monoamines and neopterin in plasma, cerebrospinal fluid and brain. Bioanalysis, vol. 8, no. 18, pp. 1903–1917. PMID: 27524289. DOI: 10.4155/bio-2016-0111 (In English)

Giorgini, F., Guidetti, P., Nguyen, Q. et al. (2005) A genomic screen in yeast implicates kynurenine 3-monooxygenase as a therapeutic target for Huntington disease. Nature Genetics, vol. 37, no. 5, pp. 526–531. PMID: 15806102. DOI: 10.1038/ng1542 (In English)

Green, E. W., Campesan, S., Breda, C. et al. (2012) Drosophila eye color mutants as therapeutic tools for Huntington disease. Fly (Austin), vol. 6, no. 2, pp. 117–120. PMID: 22634544. DOI: 10.4161/fly.19999 (In English)

Guidetti, P., Luthi-Carter, R. E., Augood, S. J., Schwarcz, R. (2004) Neostriatal and cortical quinolinate levels are increased in early grade Huntington’s disease. Neurobiology of Disease, vol. 17, no. 3, pp. 455–461. PMID: 15571981. DOI: 10.1016/j.nbd.2004.07.006 (In English)

Hilmas, C., Pereira, E. F., Alkondon, M. et al. (2001) The brain metabolite kynurenic acid inhibits alpha7 nicotinic receptor activity and increases non-alpha7 nicotinic receptor expression: Physiopathological implications. Journal of Neuroscience, vol. 21, no. 19, pp. 7463–7473. PMID: 11567036. DOI: 10.1523/JNEUROSCI.21-19-07463.2001 (In English)

Howells, A. J., Summers, K. M., Ryall, R. L. (1977) Developmental patterns of 3-hydroxykynurenine accumulation in white and various other color mutants of Drosophila melanogaster. Biochemical Genetics, vol. 15, no. 11–12, pp. 1049–1059. PMID: 414739. DOI: 10.1007/bf00484496 (In English)

Iwahashi, H., Ishii, T., Sugata, R., Kido, R. (1988) Superoxide dismutase enhances the formation of hydroxyl radicals in the reaction of 3-hydroxyanthranilic acid with molecular oxygen. Biochemical Journal, vol. 251, no. 3, pp. 893–899. DOI: 10.1042/bj2510893 (In English)

Kamyshev, N. G. (1980) Lifetime and its relationship to motor activity in Drosophila mutants of the tryptophanxanthommatin metabolic pathway. Doklady Akademii nauk SSSR, vol. 253, no. 6, pp. 355–357. (In English)

Keleman, K., Kruttner, S., Alenius, M., Dickson, B. J.. (2007) Function of the Drosophila CPEB protein Orb2 in long-term courtship memory. Nature Neuroscience, vol. 10, no. 12, pp. 1587–1593. PMID: 17965711. DOI: 10.1038/nn1996 (In English)

Kessler, M., Terramani, T., Lynch, G., Baudry, M. (1989) A glycine site associated with N-methyl-D-aspartic acid receptors: Characterization and identification of a new class of antagonists. Journal of Neurochemistry, vol. 52, no. 4, pp. 1319–1328. PMID: 2538568. DOI: 10.1111/j.1471-4159.1989.tb01881.x (In English)

Lapin, I. P. (1973) Kynurenines as probable participants of depression. Pharmakopsychiatrie — Neuro-Psychopharmacologie, vol. 6, no. 6, pp. 273–279. PMID: 4604664. DOI: 10.1055/s-0028-1094391 (In English)

Lapin, I. P. (2004) Stress. Trevogi. Alkogolism. Depressii [Stress. Alarms. Alcoholism. Depression]. Saint Petersburg: DEAN Publ., 224 p. (In Russian)

Linzen, B. (1974) The tryptophan to ommochrome pathway in insects. Advances in Insect Physiology, vol. 10, pp. 117–246. (In English)

Lopatina, N. G., Chesnokova, E. G., Smirnov, V. B. et al. (2004) Kinureninoviy put’ obmena triptofana i ego znachenie v nejrofiziologii nasekomykh [Kynurenine pathway of tryptophan metabolism and its significance in neurophysiology of insects]. Entomologicheskoe obozrenie — Entomological Review, vol. 83, no. 1, pp. 3–22. (In Russian)

Lopatina, N. G., Zachepilo, T. G., Chesnokova, E. G., Savvateeva-Popova, E. V. (2011) Behavioral and molecular consequences of deficiency of endogenous kynurenines in honeybees (Apis mellifera L.). Neuroscience and Behavioral Physiology, vol. 41, no. 6, pp. 626–631. DOI: 10.1007/s11055-011-9465-y (In English)

Mangge, H., Becker, K., Fuchs, D., Gostner, J. M. (2014) Antioxidants, inflammation and cardiovascular disease. World Journal of Cardiology, vol. 6, no. 6, pp. 462–477. PMID: 24976919. DOI: 10.4330/wjc.v6.i6.462 (In English)

Miller, A. H., Haroon, E., Raison, C. L., Felger, J. C. (2013) Cytokine targets in the brain: Impact on neurotransmitters and neurocircuits. Depress Anxiety, vol. 30, no. 4, pp. 297–306. PMID: 23468190. DOI: 10.1002/da.22084 (In English)

Moroni, F., Russi, P., Lombardi, G. et al. (1988) Presence of kynurenic acid in the mammalian brain. Journal of Neurochemistry, vol. 51, no. 1, pp. 177–180. PMID: 3379401. DOI: 10.1111/j.1471-4159.1988.tb04852.x (In English)

Nikitina, E. A., Chernikova, D. A., Vasilieva, O. V. et al. (2018) Effekt vozdejstviya antioksidantov na formirovanie srednesrochnoj pamyati u mutanta cardinal Drosophila melanogaster [Effect of antioxidants on medium-term memory formation in Drosophila melanogaster cardinal mutant]. Biotekhnologiya — Biotechnology, vol. 34, no. 3, pp. 67–77. (In Russian)

Okuda, S., Nishiyama, N., Saito, H., Katsuki, H. (1996) Hydrogen peroxide-mediated neuronal cell death induced by an endogenous neurotoxin, 3-hydroxykynurenine. Proceedings of the National Academy of Sciences of the United States of America, vol. 93, no. 22, pp. 12553–12558. DOI: 10.1073/pnas.93.22.12553 (In English)

Okuda, S., Nishiyama, N., Saito, H., Katsuki, H. (1998) 3-hydroxykynurenine, an endogenous oxidative stress generator, causes neuronal cell death with apoptotic features and region selectivity. Journal of Neurochemistry, vol. 70, no. 1, pp. 299–307. PMID: 9422375. DOI: 10.1046/j.1471-4159.1998.70010299.x (In English)

Oxenkrug, G. F. (2015) Increased plasma levels of xanthurenic and kynurenic acids in type 2 diabetes. Molecular Neurobiology, vol. 52, no. 2, pp. 805–810. PMID: 26055228. DOI: 10.1007/s12035-015-9232-0 (In English)

Oxenkrug, G., van der Hart, M., Summergrad, P. (2015) Elevated anthranilic acid plasma concentrations in type 1 but not type 2 diabetes mellitus. Integrative Molecular Medicine, vol. 2, no. 5, pp. 365–368. PMID: 26523229. DOI: 10.15761/IMM.1000169 (In English)

Parrott, J. M., O’Connor, J. C. (2015) Kynurenine 3-monooxygenase: An influential mediator of neuropathology. Frontiers in Psychiatry, vol. 6, article 116. PMID: 26347662. DOI: 10.3389/fpsyt.2015.00116 (In English)

Pearson, S. J., Meldrum, A., Reynolds, G. P. (1995) An investigation of the activities of 3-hydroxykynureninase and kynurenine aminotransferase in the brain in Huntington’s disease. Journal of Neural Transmission: General Section, vol. 102, no. 1, pp. 67–73. DOI: 10.1007/BF01276566 (In English)

Quinn, W. G., Harris, W. A., Benzer, S. (1974) Conditioned behavior in Drosophila melanogaster. Proceedings of the National Academy of Sciences of the United States of America, vol. 71, no. 3, pp. 708–712. PMID: 4207071. DOI: 10.1073/pnas.71.3.708 (In English)

Raison, C. L., Dantzer, R., Kelley, K. W. et al. (2010) CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-alpha: Relationship to CNS immune responses and depression. Molecular Psychiatry, vol. 15, no. 4, pp. 393–403. PMID: 19918244. DOI: 10.1038/mp.2009.116 (In English)

Ryall, R. L., Howells, A J. (1974) Ommochrome biosynthetic pathway of Drosophila melanogaster: Variations in levels of enzyme activities and intermediates during adult development. Insect Biochemistry, vol. 4, no. 1, pp. 47–61. DOI: 10.1016/0020-1790(74)90041-9 (In English)

Sakai, T., Tamura, T., Kitamoto, T., Kidokoro, Y. (2004) A clock gene, period, plays a key role in long-term memory formation in Drosophila. Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 45, pp. 16058–16063. PMID: 15522971. DOI: 10.1073/pnas.0401472101 (In English)

Savvateeva, E. (1991) Kynurenines in the regulation of behavior in insects. Advances in Experimental Medicine and Biology, vol. 294, pp. 319–328. DOI: 10.1007/978-1-4684-5952-4_29 (In English)

Savvateeva, E., Popov, A., Kamyshev, N. et al. (2000) Age-dependent memory loss, synaptic pathology and altered brain plasticity in the Drosophila mutant cardinal accumulating 3-hydroxykynurenine. Journal of Neural Transmission, vol. 107, no. 5, pp. 581–601. PMID: 11072753. DOI: 10.1007/s007020070080 (In English)

Savvateeva-Popova, E. V., Popov, A. V., Heinemann, T., Riederer, P. (2003) Drosophila mutants of the kynurenine pathway as a model for ageing studies. Advances in Experimental Medicine and Biology, vol. 527, pp. 713–722. DOI: 10.1007/978-1-4615-0135-0_84 (In English)

Savvateeva-Popova, Е. V., Nikitina, E. A., Medvedeva, А. V. (2015) Neurogenetics and neuroepigenetics. Russian Journal of Genetics, vol. 51, no. 5, pp. 518–528. DOI: 10.1134/S1022795415050075 (In English)

Schwarcz, R., Bruno, J. P., Muchowski, P. J., Wu, H. Q. (2012) Kynurenines in the mammalian brain: When physiology meets pathology. Nature Review Neuroscience, vol. 13, no. 7, pp. 465–477. PMID: 22678511. DOI: 10.1038/nrn3257 (In English)

Siegel, R. W., Hall, J. C. (1979) Conditioned responses in courtship behavior of normal and mutant Drosophila. Proceedings of the National Academy of Sciences of the United States of America, vol. 76, no. 7, pp. 3430–3434. PMID: 16592682. DOI: 10.1073/pnas.76.7.3430 (In English)

Stone, T. W. (1991) Kynurenine and glycine enhance neuronal sensitivity to N-methyl-D-aspartate. Life Science, vol. 48, no. 8, pp. 765–772. PMID: 1994184. DOI: 10.1016/0024-3205(91)90091-o (In English)

Summers, K. M., Howells, A J., Pyliotis, N. A. (1982) Biology of eye pigmentation in insects. Advances in Insect Physiology, vol. 16, pp. 119–166. DOI: 10.1016/S0065-2806(08)60153-8 (In English)

Turski, W. A., Nakamura, M., Todd, W. P. et al. (1988) Identification and quantification of kynurenic acid in human brain tissue. Brain Research, vol. 454, no. 1–2, pp. 164–169. PMID: 3409000. DOI: 10.1016/0006-8993(88)90815-3 (In English)

Valko, M., Leibfritz, D., Moncol, J. et al. (2007) Free radicals and antioxidants in normal physiological functions and human disease. International Journal of Biochemistry & Cell Biology, vol. 39, no. 1, pp. 44–84. PMID: 16978905. DOI: 10.1016/j.biocel.2006.07.001 (In English)

Wang, J., Simonavicius, N., Wu, X. et al. (2006) Kynurenic acid as a ligand for orphan G protein-coupled receptor GPR35. Journal of Biological Chemisty, vol. 281, no. 31, pp. 22021–22028. PMID: 16754668. DOI: 10.1074/jbc.M603503200 (In English)

Widner, B., Leblhuber, F., Walli, J. et al. (2000) Tryptophan degradation and immune activation in Alzheimer’s disease. Journal of Neural Transmission, vol. 107, no. 3, pp. 343–353. PMID: 10821443. DOI: 10.1007/s007020050029 (In English)

Widner, B., Leblhuber, F., Fuchs, D. (2002) Increased neopterin production and tryptophan degradation in advanced Parkinson’s disease. Journal of Neural Transmission, vol. 109, no. 2, pp. 181–189. PMID: 12075858. DOI: 10.1007/s007020200014 (In English)

Wiley, K., Forrest, H. S. (1981) Terminal synthesis of xanthommatin in Drosophila melanogaster. IV. Enzymatic and nonenzymatic catalysis. Biochemical Genetics, vol. 19, no. 11–12, pp. 1211–1221. PMID: 6802132. DOI: 10.1007/bf00484574 (In English)

Winbush, A., Reed, D., Chang, P. L. et al. (2012) Identification of gene expression changes associated with long-term memory of courtship rejection in Drosophila males. G3 (Bethesda), vol. 2, no. 11, pp. 1437–1445. PMID: 23173095. DOI: 10.1534/g3.112.004119 (In English)

Wonodi, I., Schwarcz, R. (2010) Cortical kynurenine pathway metabolism: A novel target for cognitive enhancement in schizophrenia. Schizophrenia Bulletin, vol. 36, no. 2, pp. 211–218. PMID: 20147364. DOI: 10.1093/schbul/sbq002 (In English)

Zakharov, G. A., Zhuravlev, A. V., Payalina, T. L. et al. (2012) The effect of mutations of the kynurenine pathway of tryptophan metabolism on locomotor behavior and gene expression in glutamatergic and cholinergic systems of D. melanogaster. Russian Journal of Genetics: Applied Research, vol. 2, no. 2, pp. 197–204. DOI: 10.1134/S2079059712020141 (In English)

Zhuravlev, A. V., Zakharov, G A., Shchegolev, B. F., Savvateeva-Popova, E. V. (2012) Stacking interaction and its role in kynurenic acid binding to glutamate ionotropic receptors. Journal of Molecular Modelling, vol. 18, no. 5, pp. 1755–1766. PMID: 21833825. DOI: 10.1007/s00894-011-1206-1 (In English)

Zhuravlev, A. V., Nikitina, E. A., Savvateeva-Popova, E. V. (2015) Obuchenie i pamyat’ u drozofily: fiziologo-geneticheskie osnovy [Education and memory in Drosophila: Physiological and genetic bases]. Uspekhi fiziologicheskikh nauk, vol. 46, no. 1, pp. 76–92. (In Russian)

Zhuravlev, A. V., Zakharov, G. A., Shchegolev, B. F., Savvateeva-Popova, E. V. (2016) Antioxidant properties of kynurenines: Density functional theory calculations. PLOS Computational Biology, vol. 12, no. 11, article e1005213. DOI: 10.1371/journal.pcbi.1005213 (In English)

Zhuravlev, A. V., Vetrovoy, O. V., Savvateeva-Popova, E. V. (2018) Enzymatic and non-enzymatic pathways of kynurenines’ dimerization: The molecular factors for oxidative stress development. PLOS Computational Biology, vol. 14, no. 12, article e1006672. DOI: 10.1371/journal.pcbi.1006672 (In English)

Опубликован

02.03.2020

Выпуск

Раздел

Обзоры