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Kynurenic Acid Inhibits the Release of the Neurotrophic Fibroblast Growth Factor (FGF)-1 and Enhances Proliferation of Glia Cells, in vitro

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Summary

  1. 1.

    Kynurenic (KYNA) and quinolinic (QUIN) acids are neuroactive tryptophan metabolites formed along the kynurenine pathway: the first is considered a non-competitive antagonist and the second an agonist of glutamate receptors of NMDA type. The affinity of these compounds for glutamate receptors is, however, relatively low and does not explain KYNA neuroprotective actions in models of post-ischemic brain damage.

  2. 2.

    We evaluated KYNA effects on the release of fibroblast growth factor (FGF)-1, a potent neurotrophic cytokine. Because KYNA exhibits a neuroprotective profile in vitro and in vivo, we anticipated that it could function as an autocrine/paracrine inducer of FGF-1 release. Studies were performed in several models of FGF-1 secretion (FGF-1 transfected NIH 3T3 cells exposed to heat shock, A375 melanoma cells exposed to serum starvation, growth factor deprived human endothelial cells). To our surprise, KYNA, at low concentration, inhibited FGF-1 release in all cellular models. QUIN, a compound having opposite effects on glutamate receptors, also reduced this release, but its potency was significantly lower than that of KYNA.

  3. 3.

    KYNA and QUIN also displayed a major stimulatory effect on the proliferation rate of mouse microglia and human glioblastoma cells, in vitro.

  4. 4.

    Our data suggest that minor changes of local KYNA concentration may modulate FGF-1 release, cell proliferation, and ultimately tissue damage in different pathological conditions.

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Abbreviations

CL:

cell lysate

CM:

conditioned medium

DMEM:

Dulbecco's modified Eagle's medium

DTT:

dithiothreitol

FBS:

fetal bovine serum

FGF:

fibroblast growth factor

HS:

heat shock

HUVEC:

human umbilical vein endothelial cell

IDO:

indoleamine 2,3-dioxygenase

KP:

kynurenine pathway

KYN:

kynurenine

KYNA:

kynurenic acid

LDH:

lactate dehydrogenase

PAGE:

polyacrylamide gel electrophoresis

QUIN:

quinolinic acid

SDS:

sodium dodecyl sulfate

TEB:

Tris EDTA buffer

References

  • Basilico, C., and Moscatelli, D. (1992). The FGF family of growth factors and oncogenes. Adv. Cancer Res. 9:15–165.

    Google Scholar 

  • Bizon, J. L., Lauterborn, J. C., Isackson, P. J., and Gall, C. M. (1996). Acidic fibroblast growth factor mRNA is expressed by basal forebrain and striatal cholinergic neurons. J. Comp. Neurol. 366:379–389.

    Article  PubMed  CAS  Google Scholar 

  • Carpenedo, R., Chiarugi, A., Russi, P., Lombardi, G., Carlà, V., Pellicciari, R., Mattoli, L., and Moroni, F. (1994). Inhibitors of kynurenine hydroxylase and kynureninase increase cerebral formation of kynurenate and have sedative and anticonvulsant activities. Neuroscience 61:237–244.

    Article  PubMed  CAS  Google Scholar 

  • Carpenedo, R., Pittaluga, A., Cozzi, A., Attucci, S., Galli, A., Raiteri, M., and Moroni, F. (2001). Presynaptic kynurenate-sensitive receptors inhibit glutamate release. Eur. J. Neurosci. 13:2141–2147.

    Article  PubMed  CAS  Google Scholar 

  • Carpenedo, R., Meli, E., Peruginelli, F., Pellegrini-Giampietro, D. E., and Moroni, F. (2002). Kynurenine 3-mono-oxygenase inhibitors attenuate post-ischemic neuronal death in organotypic hippocampal slice cultures. J. Neurochem. 82:1465–1471.

    Article  PubMed  CAS  Google Scholar 

  • Chiarugi, A., Carpenedo, R., Molina, M. T., Mattoli, L., Pellicciari, R., and Moroni, F. (1995). Comparison of the neurochemical and behavioral effects resulting from the inhibition of kynurenine hydroxylase and/or kynureninase. J. Neurochem. 65:1176–1183.

    PubMed  CAS  Google Scholar 

  • Chiarugi, A., Dello Sbarba P., Paccagnini, A., Donnini, S., Filippi, S., and Moroni, F. (2000). Combined inhibition of indoleamine 2,3-dioxygenase and nitric oxide synthase modulates neurotoxin release by interferon-gamma-activated macrophages. J. Leukoc. Biol. 68:260–266.

    PubMed  CAS  Google Scholar 

  • Chiarugi, A., Cozzi, A., Ballerini, C., Massacesi, L., and Moroni, F. (2001). Kynurenine 3-mono-oxygenase activity and neurotoxic kynurenine metabolites increase in the spinal cord of rats with experimental allergic encephalomyelitis. Neuroscience 102:687–695.

    Article  PubMed  CAS  Google Scholar 

  • Cozzi, A., Carpenedo, R., and Moroni, F. (1999). Kynurenine hydroxylase inhibitors reduce ischemic brain damage: Studies with (m-nitrobenzoyl)-alanine (mNBA) and 3,4-dimethoxy-[-N-4-(nitrophenyl)thiazol-2yl]-benzenesulfonamide (Ro 61-8048) in models of focal or global brain ischemia. J. Cereb. Blood Flow Metab. 19:771–777.

    PubMed  CAS  Google Scholar 

  • Friesel, R., and Maciag, T. (1999). Fibroblast growth factor prototype release and fibroblast growth factor receptor signaling. Thromb. Haemost. 82:748–754.

    PubMed  CAS  Google Scholar 

  • Guillemin, G. J., Kerr, S. J., Smythe, G. A., Smith, D. G., Kapoor, V., Armati, P. J., Croitoru, J., and Brew, B. J. (2001). Kynurenine pathway metabolism in human astrocytes: A paradox for neuronal protection. J. Neurochem. 78:842–853.

    Article  PubMed  CAS  Google Scholar 

  • Hilmas, C., Pereira, E. F. R., Alkondon, M., Rassoulpour, A., Schwarcz, R., and Albuquerque, E. X. (2001). The brain metabolite kynurenic acid inhibits alpha7 nicotinic receptor activity and increases non-alpha7 nicotinic receptor expression: Physiopathological implications. J. Neurosci. 21:7463–7473.

    PubMed  CAS  Google Scholar 

  • Holmes, E. W. (1988). Determination of serum kynurenine and hepatic tryptophan dioxygenase activity by high-performance liquid chromatography. Anal. Biochem. 172:518–525.

    Article  PubMed  CAS  Google Scholar 

  • Hossain, M. A., Russell, J. C., Gomez, R., Laterra, J., and Gomes, R. (2002). Neuroprotection by scatter factor/hepatocyte growth factor and FGF-1 in cerebellar granule neurons is phosphatidylinositol 3-kinase/akt-dependent and MAPK/CREB-independent. J. Neurochem. 81:365–378.

    PubMed  CAS  Google Scholar 

  • Jackson, A., Friedman, S., Zhan, X., Engleka, K. A., Forough, R., and Maciag, T. (1992). Heat shock induces the release of fibroblast growth factor 1 from NIH 3T3 cells. Proc. Natl. Acad. Sci. U.S.A. 89:10691–10695.

    PubMed  CAS  Google Scholar 

  • Kessler, M., Terramani, T., Lynch, G., and Baudry, M. (1989). A glycine site associated with N-methyl-d-aspartic acid receptors: Characterization and identification of a new class of antagonists. J. Neurochem. 52:1319–1328.

    PubMed  CAS  Google Scholar 

  • Le, R., and Esquenazi, S. (2002). Astrocytes mediate cerebral cortical neuronal axon and dendrite growth, in part, by release of fibroblast growth factor. Neurol. Res. 24:81–92.

    PubMed  Google Scholar 

  • Mocchetti, I., and Wrathall, J. R. (1995). Neurotrophic factors in central nervous system trauma. J. Neurotrauma 12:853–870.

    Article  PubMed  CAS  Google Scholar 

  • Moroni, F., Russi, P., Lombardi, G., Beni, M., and Carlà, V. (1988). Presence of kynurenic acid in the mammalian brain. J. Neurochem. 51:177–181.

    PubMed  CAS  Google Scholar 

  • Moroni, F., Pellegrini-Giampietro, D. E., Alesiani, M., Cherici, G., Mori, F., and Galli, A. (1989). Glycine and kynurenate modulate the glutamate receptors in the myenteric plexus and in cortical membranes. Eur. J. Pharmacol. 163:123–126.

    Article  PubMed  CAS  Google Scholar 

  • Moroni, F., Russi, P., Gallo-Mezo, M. A., Moneti, G., and Pellicciari, R. (1991). Modulation of quinolinic and kynurenic acid content in the rat brain: Effects of endotoxins and nicotinylalanine. J. Neurochem. 57:1630–1635.

    PubMed  CAS  Google Scholar 

  • Moroni, F. (1999). Tryptophan metabolism and brain function: Focus on kynurenine and other indole metabolites. Eur. J. Pharmacol. 375:87–100.

    Article  PubMed  CAS  Google Scholar 

  • Rassoulpour, A., Wu, H. Q., Ferre, S., and Schwarcz, R. (2005). Nanomolar concentrations of kynurenic acid reduce extracellular dopamine levels in the striatum. J. Neurochem. 93:762–765.

    Article  PubMed  CAS  Google Scholar 

  • Russi, P., Alesiani, M., Lombardi, G., Davolio, P., Pellicciari, R., and Moroni, F. (1992). Nicotinylalanine increases the formation of kynurenic acid in the brain and antagonizes convulsions. J. Neurochem. 59:2076–2080.

    PubMed  CAS  Google Scholar 

  • Sassano, M., Granucci, F., Seveso, M., Marconi, G., Foti, M., and Ricciardi-Castagnoli, P. (1994). Molecular cloning of a recombinant retrovirus carrying a mutated envAKR-mycMH2 fusion gene immortalizing cells of the monocytic-macrophage lineage. Oncogene 9:1473–1477.

    PubMed  CAS  Google Scholar 

  • Schwarcz, R., Whetsell, W. O., and Mangano, R. M. (1983). Quinolinic acid: An endogenous metabolite that produces axon-sparing lesions in rat brain. Science 219:316–318.

    PubMed  CAS  Google Scholar 

  • Stone, T. W., and Perkins, M. N. (1981). Quinolinic acid: A potent endogenous excitant at amino acid receptors in CNS. Eur. J. Pharmacol. 72:411–412.

    Article  PubMed  CAS  Google Scholar 

  • Stone, T. W., and Connick, J. (1985). Quinolinic acid and other kynurenines in the central nervous system. Neuroscience 15:507–617.

    Article  Google Scholar 

  • Stone, T. W. (1993). Neuropharmacology of quinolinic and kynurenic acids. Pharmacol. Rev. 45:309–379.

    PubMed  CAS  Google Scholar 

  • Stone, T. W. (2000). Development and therapeutic potential of kynurenic acid and kynurenine derivatives for neuroprotection. Trends Pharmacol. Sci. 21:149–154.

    Article  PubMed  CAS  Google Scholar 

  • Swartz, K. J., Matson, W. R., MacGarvey, U., Ryan, E. A., and Beal, M. F. (1990). Measurement of kynurenic acid in mammalian brain extracts and cerebrospinal fluid by high-performance liquid chromatography with fluorometric and coulometric electrode array detection. Anal. Biochem. 185:363–376.

    Article  PubMed  CAS  Google Scholar 

  • Tarantini, F., LaVallee, T., Jackson, A., Gamble, S., Mouta Carreira, C., Garfinkel, S., Burgess, W. H., and Maciag, T. (1998). The extravesicular domain of synaptotagmin-1 is released with the latent fibroblast growth factor-1 homodimer in response to heat shock. J. Biol. Chem. 273:22209–22216.

    Article  PubMed  CAS  Google Scholar 

  • Tarantini, F., Micucci, I., Bellum, S., Landriscina, M., Garfinkel, S., Prudovsky, I., and Maciag, T. (2001). The precursor but not the mature form of IL1α blocks the release of FGF1 in response to heat shock. J. Biol. Chem. 276:5147–5151.

    Article  PubMed  CAS  Google Scholar 

  • Turski, W. A., Nakamura, M., Todd, W. P., Carpenter, B. K., Whetsell, W. O., and Schwarcz, R. (1988). Identification and quantification of kynurenic acid in human brain tissue. Brain Res. 454:164–169.

    Article  PubMed  CAS  Google Scholar 

  • Wu, H. Q., Ungerstedt, U., and Schwarcz, R. (1992). Regulation of kynurenic acid synthesis studied by microdialysis in the dorsal hippocampus of unanesthetized rats. Eur. J. Pharmacol. 213:375–380.

    Article  PubMed  CAS  Google Scholar 

  • Wu, H. Q., Guidetti, P., Goodman, J. H., Varasi, M., Ceresoli-Borroni, G., Speciale, C., Scharfman, H. E., and Schwarcz, R. (2000). Kynurenergic manipulations influence excitatory synaptic function and excitotoxic vulnerability in the rat hippocampus in vivo. Neuroscience 97:243–251.

    Article  PubMed  CAS  Google Scholar 

  • Xie, D., Yin, D., Tong, X., O'Kelly, J., Mori, A., Miller, C., Black, K., Gui, D., Said, J. W., and Koeffler, H. P. (2004). Cyr61 is overexpressed in gliomas and involved in integrin-linked kinase-mediated Akt and beta-catenin-TCF/Lef signaling pathways. Cancer Res. 64:1987–1996.

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Critical Care Medicine and Surgery, Geriatric Medicine Unit, University of Florence, School of Medicine, Centro Polivalente per la Didattica e la Ricerca (Cubo Alto), Viale Pieraccini n. 6, Florence, 50139, Italy

    Claudia Di Serio, Ilaria Angeli, Laura Doria, Isabella Micucci, Silvia Pellerito, Patrizia Mirone, Giulio Masotti & Francesca Tarantini

  2. Department of Pharmacology, University of Florence, Florence, Italy

    Andrea Cozzi & Flavio Moroni

Authors
  1. Claudia Di Serio
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  2. Andrea Cozzi
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  3. Ilaria Angeli
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  4. Laura Doria
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  5. Isabella Micucci
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  6. Silvia Pellerito
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  7. Patrizia Mirone
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  8. Giulio Masotti
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  9. Flavio Moroni
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  10. Francesca Tarantini
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Correspondence to Francesca Tarantini.

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Serio, C.D., Cozzi, A., Angeli, I. et al. Kynurenic Acid Inhibits the Release of the Neurotrophic Fibroblast Growth Factor (FGF)-1 and Enhances Proliferation of Glia Cells, in vitro . Cell Mol Neurobiol 25, 981–993 (2005). https://doi.org/10.1007/s10571-005-8469-y

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  • DOI: https://doi.org/10.1007/s10571-005-8469-y

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