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Kynurenines Impair Energy Metabolism in Rat Cerebral Cortex

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Growing evidence indicates that some metabolites derived from the kynurenine pathway, the major route of l-tryptophan catabolism, are involved in the neurotoxicity associated with several brain disorders, such as Huntington’s disease, Parkinson’s disease and Alzheimer’s disease, as well as in glutaryl-CoA dehydrogenase deficiency (GAI). Considering that the pathophysiology of the brain damage in these neurodegenerative disorders is not completely defined, in the present study, we investigated the in vitro effect of l-kynurenine (Kyn), kynurenic acid (KA), 3-hydroxykynurenine (3HK), 3-hydroxyanthranilic acid (3HA) and anthranilic acid (AA) on some parameters of energy metabolism, namely glucose uptake, 14CO2 production from [U-14C] glucose, [1-14C] acetate and [1,5-14C] citrate, as well as on the activities of the respiratory chain complexes I–IV and Na+,K+-ATPase activity in cerebral cortex from 30-day-old rats. We observed that all compounds tested, except l-kynurenine, significantly increased glucose uptake and inhibited 14CO2 production from [U-14C] glucose, [1-14C] acetate and [1,5-14C] citrate. In addition, the activities of complexes I, II and IV of the respiratory chain were significantly inhibited by 3HK, while 3HA inhibited complexes I and II activities and AA inhibited complexes I–III activities. Moreover, Na+,K+-ATPase activity was not modified by these kynurenines. Taken together, our present data provide evidence that various kynurenine intermediates provoke impairment of brain energy metabolism.

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REFERENCES

  • Anandatheerthavarada, H. K., Biswas, G., Robin, M. A., and Avadhani, N. G. (2003). Mitochondrial targeting and a novel transmembrane arrest of Alzheimer’s amyloid precursor protein impairs mitochondrial function in neuronal cells. J. Cell Biol. 161:41.

    Article  PubMed  CAS  Google Scholar 

  • Baran, H., Staniek, K., Kepplinger, B., Gille, L., Stolze, K., and Nohl, H. (2001). Kynurenic acid influences the respiratory parameters of rat heart mitochondria. Pharmacology 62:119–123.

    Article  PubMed  CAS  Google Scholar 

  • Baran, H., Staniek, K., Kepplinger, B., Stur, J., Draxler, M., and Nohl, H. (2003). Kynurenines and the respiratory parameters on rat heart mitochondria. Life Sci. 72:1103–1115.

    Article  PubMed  CAS  Google Scholar 

  • Beal, M. F. (2004). Mitochondrial dysfunction and oxidative damage in Alzheimer’s and Parkinson’s diseases and coenzyme Q10 as a potential treatment. J. Bioenerg. Biomembr. 36:381–386.

    Article  PubMed  CAS  Google Scholar 

  • Bender, D. A., and McCreanor, G. M. (1982). The preferred route of kynurenine metabolism in the rat. Biochem. Biophys. Acta 717:56–60.

    PubMed  CAS  Google Scholar 

  • Brown, R. R. (1971). Biochemistry and pathology of tryptophan metabolism and its regulation by amino acids, vitamin B6 and steroid hormone. Am. J. Clin. Nutr. 24:243–247.

    PubMed  CAS  Google Scholar 

  • Caspersen, C., Wang, N., Yao, J., Sosunov, A., Chen, X., Lustbader, J. W., Xu, H. W., Stern, D., McKhann, G., and Yan, S. D. (2005). Mitochondrial Abeta: A potential focal point for neuronal metabolic dysfunction in Alzheimer’s disease. FASEB J. 19:2040–2041.

    PubMed  CAS  Google Scholar 

  • Cassarino, D. S., and Bennett J. P., Jr. (1999). An evaluation of the role of mitochondria in neurodegenerative diseases: Mitochondrial mutations and oxidative pathology, protective nuclear responses, and cell death in neurodegeneration. Brain Res. Rev. 29:1–25.

    Article  PubMed  CAS  Google Scholar 

  • Cassina, A., and Radi, R. (1996). Differential inhibitory action of nitric oxide and peroxynitrite on mitochondrial electron transport. Arch. Biochem. Biophys. 328:309–316.

    Article  PubMed  CAS  Google Scholar 

  • Chan, K. M., Delfert, D., and Junger, K. D. (1986). A direct colorimetric assay for Ca2+-stimulated ATPase activity. Anal. Biochem. 157:375–380.

    Article  PubMed  CAS  Google Scholar 

  • Christen, S., Peterhans, E., and Stocker, R. (1990). Antioxidant activities of some tryptophan metabolites: Possible implication for inflammatory diseases. Proc. Natl. Acad. Sci. USA 87:2506–2510.

    Google Scholar 

  • Coyle, J. T., and Puttfarcken, P. (1993). Oxidative stress, glutamate, and neurodegenerative disorders. Science 363:689–695.

    Article  Google Scholar 

  • da Silva, C. G., Ribeiro, C. A., Leipnitz, G., Dutra-Filho, C. S., Wyse, A. T., Wannmacher, C. M., Sarkis, J. J., Jakobs, C., and Wajner, M. (2002). Inhibition of cytochrome c oxidase activity in rat cerebral cortex and human skeletal muscle by D-2-hydroxyglutaric acid in vitro. Biochim. Biophys. Acta 1586:81–91.

    PubMed  CAS  Google Scholar 

  • Di Donato, S. (2000). Disorders related to mitochondrial membranes: Pathology of the respiratory chain and neurodegeneration. J. Inherit. Metab. Dis. 23:247–263.

    Article  PubMed  CAS  Google Scholar 

  • Dutra, J. C., Wajner, M., Wannmacher, C. F., Dutra-Filho, C. S., and Wannmacher, C. M. D. (1991). Effects of methylmalonate and propionate on glucose and ketone bodies uptake in vitro by brain of developing rats. Biochem. Med. Metab. Res. 45:56–64.

    Article  CAS  Google Scholar 

  • Dykens, J. A., Sullivan, S. G., and Stern, A. (1987). Oxidative reactivity of the tryptophan metabolites 3-hydroxyanthranilate, cinnabarinate, quinolinate and picolinate. Biochem. Pharmacol. 36:211–217.

    Article  PubMed  CAS  Google Scholar 

  • Dykens, J. A., Sullivan, S. G., and Stern, A. (1989). Glucose metabolism and hemoglobin reactivity in human red blood cells exposed to the tryptophan metabolites 3-hydroxyanthranilate, quinolinate and picolinate. Biochem. Pharmacol. 38:1555–1562.

    Article  PubMed  CAS  Google Scholar 

  • Eastman, C. L., and Guilarte, T. R. (1990). The role of hydrogen peroxide in the in vitro cytotoxicity of 3-hydroxykynurenine. Neurochem. Res. 15:1101–1107.

    Article  PubMed  CAS  Google Scholar 

  • Eastman, C. L., Guilarte, T. R., and Lever, J. R. (1992). Uptake of 3-hydroxykynurenine measured in rat brain slices and in a neuronal cell line. Brain Res. 584:110–116.

    Article  PubMed  CAS  Google Scholar 

  • Fischer, J. C., Ruitenbeek, W., Berden, J. A., Trijbels, J. M., Veerkamp, J. H., Stadhouders, M., Sengers, R. C., and Janssen, A. J. (1985). Differential investigation of the capacity of succinate oxidation in human skeletal muscle. Clin. Chim. Acta 153:23–36.

    Article  PubMed  CAS  Google Scholar 

  • Foster, A. C., Vezzani. A., French, E. D., and Schwarcz, R. (1984). Kynurenic acid blocks neurotoxicity and seizures induced in rats by the related brain metabolite quinolinic acid. Neurosci. Lett. 48:273–278.

    Article  PubMed  CAS  Google Scholar 

  • Germano, I. M., Pitts, L. H., Meldrum, B. S., Bartkowski, H. M., and Simon, R. P. (1987). Kynurenate inhibition of cell excitation decreases stroke size and deficits. Ann. Neurol. 22:730–734.

    Article  PubMed  CAS  Google Scholar 

  • Gill, R., and Woodruf, G. N. (1990). The neuroprotective actions of kynurenic acid and MK-801 in gerbils are synergistic and not related to hypothermia. Eur. J. Pharmacol. 176:143–149.

    Article  PubMed  CAS  Google Scholar 

  • Guidetti, P., Bates, G. P., Graham, R. K., Hayden, M. R., Leavitt, B. R., MacDonald, M. E., Slow, E. J., Wheeler, V. C., Woodman, B., and Schwarcz, R. (2006). Elevated brain 3-hydroxykynurenine and quinolinate levels in Huntington disease mice. Neurobiol. Dis. 23:190–197.

    Google Scholar 

  • Guillemin, G. J., and Brew, B. J. (2002). Implications of the kynurenine pathway and quinolinic acid in Alzheimer’s disease. Redox Rep. 7:199–206.

    Article  PubMed  CAS  Google Scholar 

  • Hartai, H., Klivenyi, P., Janaky, T., Penke, B., Dux, L., and Vecsei, L. (2005). Kynurenine metabolism in plasma and in red blood cells in Parkinson’s disease. J. Neurol. Sci. 239:31–35.

    Article  PubMed  CAS  Google Scholar 

  • Heyes, M. P. (1987). Hypothesis: A role for quinolinic acid in the neuropathology of glutaric aciduria type I. Can. J. Neurol. Sci. 14:441–443.

    PubMed  CAS  Google Scholar 

  • Heyes, M. P., Saito, K., Crowley, J. S., Davis, L. E., Demitrack, M. A., Der, M., Dilling, L. A., Elia, J., Kruesi, M. J., Lackner, A., Larsen, S. A., Lee, K., Leonard, H. L., Markey, S. P., Martin, A., Milstein, S., Mouradian, M. M., Pranzatelli, M. R., Quearry, B. J., Salazar, A., Smith, M., Strauss, S. E., Sunderland, T., Swedo, S. W., and Tourtellotte, W. W. (1992). Quinolinic acid and kynurenine pathway metabolism in inflammatory and non-inflammatory neurological disease. Brain 115:1249–1273.

    Article  PubMed  Google Scholar 

  • Jones, D. H., and Matus, A. I. (1974). Isolation of synaptic plasma membrane from brain by combined flotation-sedimentation density gradient centrifugation. Biochim. Biophys. Acta 356:276–287.

    Article  PubMed  CAS  Google Scholar 

  • Keeney, P. M., Xie, J., Capaldi, R. A., and Bennett, Jr. J. P. (2006). Parkinson’s disease brain mitochondrial complex I has oxidatively damaged subunits and is functionally impaired and misassembled. J. Neurosci. 26:5256–5264.

    Article  PubMed  CAS  Google Scholar 

  • Lowry, O. H., Rosebrough, N. J., Farr, A. L., and Randall, R. J. (1951). Protein measurement with the Folin phenol reagent. J. Biol. Chem. 193:265–275.

    PubMed  CAS  Google Scholar 

  • Morita, T., Saito, K., Takemura, M., Maekawa, N., Fujigaki, S., Fujii, H., Wada, H., Takeuchi, S., Noma, A., and Seishima, M. (1999). l-Tryptophan-kynurenine pathway metabolite 3-hydroxyanthranilic acid induces apoptosis in macrophage-derived cells under pathophysiological conditions. Adv. Exp. Med. Biol. 467:559–563.

    PubMed  CAS  Google Scholar 

  • Ogawa, T., Matson, W. R., Beal, M. F., Myers, R. H., Bird, E. D., Milbury, P., and Saso, S. (1992). Kynurenine pathway abnormalities in Parkinson’s disease. Neurology 42:1702–1706.

    PubMed  CAS  Google Scholar 

  • Okamoto, H. (1971). Influence of l-thyroxine on kynurenine 3-hydroxylase, monoamine oxidase, and rotenone-insensitive NADH-cytochrome c reductase in mitochondrial outer membrane. Biochem. Biophys. Res. Commun. 43:827–833.

    Article  PubMed  CAS  Google Scholar 

  • Okuda, S., Nishiyama, N., Saito, H., and Katsuki, H. (1996). Hydrogen peroxide-mediated neuronal cell death induced by an endogenous neurotoxin, 3-hydroxykynurenine. Proc. Natl. Acad. Sci. U.S.A. 93:12553–12558.

    Article  PubMed  CAS  Google Scholar 

  • Okuda, S., Nishiyama, N., Saito, H., and Katsuki, H. (1998). 3-Hydroxykynurenine, an endogenous oxidative stress generator, causes neuronal cell death with apoptotic features and region selectivity. J. Neurochem. 70:299–307.

    Article  PubMed  CAS  Google Scholar 

  • Pearson, S. J., and Reynolds, G. P. (1991). Determination of 3-hydroxykynurenine in human brain and plasma by high-performance liquid chromatography with electrochemical detection. Increased concentrations in hepatic encephalopathy. J. Chromatogr. 565:436–440.

    Article  PubMed  CAS  Google Scholar 

  • Pearson, S. J., and Reynolds, G. P. (1992). Increased brain concentrations of a neurotoxin, 3-hydroxykynurenine, in Huntington’s disease. Neurosci. Lett. 144:199–201.

    Article  PubMed  CAS  Google Scholar 

  • Powell, C. S., and Jackson, R. M. (2003). Mitochondrial complex I, aconitase, and succinate dehydrogenase during hypoxia-reoxygenation: Modulation of enzyme activities by MnSOD. Am. J. Physiol. Lung. Cell. Mol. Physiol. 285:189–198.

    Google Scholar 

  • Reis de Assis, D., Maria, R. de C., Borba Rosa, R., Schuck, P. F., Ribeiro, C. A., da Costa Ferreira, G., Dutra-Filho, C. S., Terezinha de Souza Wyse, A., Duval Wannmacher, C. M., Santos Perry, M. L., and Wajner, M. (2004). Inhibition of energy metabolism in cerebral cortex of young rats by the medium-chain fatty acids accumulating in MCAD deficiency. Brain Res. 1030:141–151.

    Article  PubMed  CAS  Google Scholar 

  • Reynolds, G. P., and Pearson, S. J. (1989). Increased brain 3-hydroxykynurenine in Huntington’s disease. Lancet 2:979–980.

    Article  PubMed  CAS  Google Scholar 

  • Rustin, P., Chretien, D., Bourgeron, T., Gérard, B., Rötig, A., Saudubray, J. M., and Munnich, A. (1994). Biochemical and molecular investigations in respiratory chain deficiencies. Clin. Chim. Acta 228:35–51.

    Article  PubMed  CAS  Google Scholar 

  • Saft, C., Zange, J., Andrich, J., Muller, K., Lindenberg, K., Landwehrmeyer, B., Vorgerd, M., Kraus, P. H., Przuntek, H., and Schols, L. (2005). Mitochondrial impairment in patients and asymptomatic mutation carriers of Huntington’s disease. Mov. Disord. 20:674–679.

    Article  PubMed  Google Scholar 

  • Sardar, A. M., Bell, J. E., and Reynolds, G. P. (1995). Increased concentrations of the neurotoxin 3-hydroxykynurenine in the frontal cortex of HIV-1-positive patients. J. Neurochem. 64:932–935.

    Article  PubMed  CAS  Google Scholar 

  • Schapira, A. H., Mann, V. M., Cooper, J. M., Dexter, D., Daniel, S. E., Jenner, P., Clark, J. B., and Marsden, C. D. (1990). Anatomic and disease specificity of NADH CoQ1 reductase (complex I) deficiency in Parkinson’s disease. J. Neurochem. 55:2142–2145.

    Article  PubMed  CAS  Google Scholar 

  • Schwarcz, R., and Pellicciari, R. (2002). Manipulation of brain kynurenines: Glial targets, neuronal effects, and clinical opportunities. J. Pharmacol. Exp. Ther. 303:1–10.

    Article  PubMed  CAS  Google Scholar 

  • Shoffner, J. M. (1997). Oxidative phosphorylation defects and Alzheimer’s disease. Neurogenetics 1:193–197.

    Article  Google Scholar 

  • Stone, T. W., Mackay, G. M., Forrest, C. M., Clark, C. J., and Darlington, L. G. (2003). Tryptophan metabolites and brain disorders. Clin. Chem. Lab. Med. 41:852–859.

    Article  PubMed  CAS  Google Scholar 

  • Tretter, L., and Adam-Vizi, V. (2005). Alpha-ketoglutarate dehydrogenase: A target and generator of oxidative stress. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 360:2335–2345.

    Article  PubMed  CAS  Google Scholar 

  • Tretter, L., Sipos, I., and Adam-Vizi, V. (2004). Initiation of neuronal damage by complex I deficiency and oxidative stress in Parkinson’s disease. Neurochem. Res. 29:569–577.

    Article  PubMed  CAS  Google Scholar 

  • Trinder, P. A. (1969). Determination of blood glucose using on oxidase system with a non-carcinogenic chromogen. J. Clin. Pathol. 22:158–161.

    Article  PubMed  CAS  Google Scholar 

  • Tsakiris, S., and Deliconstantinos, G. (1984). Influence of phosphatidylserine on (Na+,K+)-stimulated ATPase and acetylcholinesterase activities of dog brain synaptosomal plasma membranes. Biochem. J. 220:301–307.

    PubMed  CAS  Google Scholar 

  • Varadkar, S., and Surtees, R. (2004). Glutaric aciduria type I and kynurenine pathway metabolites: A modified hypothesis. J. Inherit. Metab. Dis. 27:835–842.

    Article  PubMed  CAS  Google Scholar 

  • Vásquez-Vivar, J., Kalyanaraman, B., and Kennedy, M. C. (2000). Mitochondrial aconitase is a source of hydroxyl radical. J. Biol. Biochem. 275:14064–14069.

    Article  Google Scholar 

  • Vazquez, S., Garner, B., Sheil, M. M., and Truscott, R. J. (2000). Characterization of the major autoxidation products of 3-hydroxykynurenine under physiological conditions. Free Radic. Res. 32:11–23.

    Article  PubMed  CAS  Google Scholar 

  • Wen, J. J., and Garg, N. (2004). Oxidative modification of mitochondrial respiratory complexes in response to the stress of Trypanosoma cruzi infection. Free Radic. Biol. Med. 37:2072–2081.

    Article  PubMed  CAS  Google Scholar 

  • Wolfensberger, M., Amsler, U., Cuenod, M., Foster, A. C., Whetsell, W. O., Jr., and Schwarcz, R. (1983). Identification of quinolinic acid in rat and human brain tissue. Neurosci. Lett. 41:247–252.

    Article  PubMed  CAS  Google Scholar 

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ACKNOWLEDGMENTS

This work was supported by grants from CNPq, PRONEX II, FAPERGS and PROPESQ/UFRGS.

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  1. Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600- Anexo, CEP 90035-003, Porto Alegre, RS, Brazil

    Patrícia Fernanda Schuck, Anelise Tonin, Gustavo da Costa Ferreira, Carolina Maso Viegas, Alexandra Latini, Clovis Milton Duval Wannmacher, Angela Terezinha de Souza Wyse, Carlos Severo Dutra-Filho & Moacir Wajner

  2. Serviço de Genética Médica do Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil

    Alexandra Latini & Moacir Wajner

  3. Universidade Luterana do Brasil, Canoas, RS, Brazil

    Moacir Wajner

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  1. Patrícia Fernanda Schuck
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  2. Anelise Tonin
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  3. Gustavo da Costa Ferreira
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Schuck, P.F., Tonin, A., da Costa Ferreira, G. et al. Kynurenines Impair Energy Metabolism in Rat Cerebral Cortex. Cell Mol Neurobiol 27, 147–160 (2007). https://doi.org/10.1007/s10571-006-9124-y

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