Cellular and Molecular Life Sciences

, Volume 71, Issue 10, pp 1839–1854 | Cite as

Glutamate transporters in the biology of malignant gliomas

Review

Abstract

Malignant gliomas are relentless tumors that offer a dismal clinical prognosis. They develop many biological advantages that allow them to grow and survive in the unique environment of the brain. The glutamate transporters system x c and excitatory amino acid transporters (EAAT) are emerging as key players in the biology and malignancy of these tumors. Gliomas manipulate glutamate transporter expression and function to alter glutamate homeostasis in the brain, which supports their own growth, invasion, and survival. As a consequence, malignant cells are able to quickly destroy and invade surrounding normal brain. Recent findings are painting a larger picture of these transporters in glioma biology, and as such are providing opportunities for clinical intervention for patients. This review will detail the current understanding of glutamate transporters in the biology of malignant gliomas and highlight some of the unique aspects of these tumors that make them so devastating and difficult to treat.

Keywords

Glioma Glutamate Glutamate transporter System xc (SXC) Excitatory amino acid transporter (EAAT) Glutamate receptors 

Notes

Acknowledgments

This work was supported by US National Institutes of Health grants R01NS052634, 2T32NS048039, and T32GM008361. The authors would also like to thank Dr. Sue Buckingham for her help in the editing of this manuscript.

References

  1. 1.
    Dolecek TA, Propp JM, Stroup NE, Kruchko C (2012) CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005–2009. Neuro-oncology 14(Suppl 5):v1–v49. doi: 10.1093/neuonc/nos218 PubMedCentralPubMedGoogle Scholar
  2. 2.
    Porter KR, McCarthy BJ, Freels S, Kim Y, Davis FG (2010) Prevalence estimates for primary brain tumors in the United States by age, gender, behavior, and histology. Neuro-oncology 12(6):520–527. doi: 10.1093/neuonc/nop066 PubMedCentralPubMedGoogle Scholar
  3. 3.
    Preusser M, de Ribaupierre S, Wohrer A, Erridge SC, Hegi M, Weller M, Stupp R (2011) Current concepts and management of glioblastoma. Ann Neurol 70(1):9–21. doi: 10.1002/ana.22425 PubMedGoogle Scholar
  4. 4.
    Adamson C, Kanu OO, Mehta AI, Di C, Lin N, Mattox AK, Bigner DD (2009) Glioblastoma multiforme: a review of where we have been and where we are going. Expert Opin Investig Drugs 18(8):1061–1083. doi: 10.1517/13543780903052764 PubMedGoogle Scholar
  5. 5.
    Chamberlain MC, Kormanik PA (1998) Practical guidelines for the treatment of malignant gliomas. West J Med 168(2):114–120PubMedCentralPubMedGoogle Scholar
  6. 6.
    Ruban A, Berkutzki T, Cooper I, Mohar B, Teichberg VI (2012) Blood glutamate scavengers prolong the survival of rats and mice with brain-implanted gliomas. Invest New Drugs. doi: 10.1007/s10637-012-9794-x PubMedCentralGoogle Scholar
  7. 7.
    Chung WJ, Sontheimer H (2009) Sulfasalazine inhibits the growth of primary brain tumors independent of nuclear factor-kappaB. J Neurochem 110(1):182–193. doi: 10.1111/j.1471-4159.2009.06129.x PubMedCentralPubMedGoogle Scholar
  8. 8.
    Chen RS, Song YM, Zhou ZY, Tong T, Li Y, Fu M, Guo XL, Dong LJ, He X, Qiao HX, Zhan QM, Li W (2009) Disruption of xCT inhibits cancer cell metastasis via the caveolin-1/beta-catenin pathway. Oncogene 28(4):599–609. doi: 10.1038/onc.2008.414 PubMedGoogle Scholar
  9. 9.
    Piao Y, Lu L, de Groot J (2009) AMPA receptors promote perivascular glioma invasion via beta1 integrin-dependent adhesion to the extracellular matrix. Neuro-oncology 11(3):260–273. doi: 10.1215/15228517-2008-094 PubMedCentralPubMedGoogle Scholar
  10. 10.
    Lyons SA, Chung WJ, Weaver AK, Ogunrinu T, Sontheimer H (2007) Autocrine glutamate signaling promotes glioma cell invasion. Cancer Res 67(19):9463–9471. doi: 10.1158/0008-5472.CAN-07-2034 PubMedCentralPubMedGoogle Scholar
  11. 11.
    Takeuchi S, Wada K, Toyooka T, Shinomiya N, Shimazaki H, Nakanishi K, Nagatani K, Otani N, Osada H, Uozumi Y, Matsuo H, Nawashiro H (2013) Increased xCT expression correlates with tumor invasion and outcome in patients with glioblastomas. Neurosurgery 72(1):33–41. doi: 10.1227/NEU.0b013e318276b2de (discussion 41)PubMedGoogle Scholar
  12. 12.
    Yuen TI, Morokoff AP, Bjorksten A, D’Abaco G, Paradiso L, Finch S, Wong D, Reid CA, Powell KL, Drummond KJ, Rosenthal MA, Kaye AH, O’Brien TJ (2012) Glutamate is associated with a higher risk of seizures in patients with gliomas. Neurology 79(9):883–889. doi: 10.1212/WNL.0b013e318266fa89 PubMedGoogle Scholar
  13. 13.
    Buckingham SC, Campbell SL, Haas BR, Montana V, Robel S, Ogunrinu T, Sontheimer H (2011) Glutamate release by primary brain tumors induces epileptic activity. Nat Med 17(10):1269–1274. doi: 10.1038/nm.2453 PubMedCentralPubMedGoogle Scholar
  14. 14.
    Chen J, McKay RM, Parada LF (2012) Malignant glioma: lessons from genomics, mouse models, and stem cells. Cell 149(1):36–47. doi: 10.1016/j.cell.2012.03.009 PubMedCentralPubMedGoogle Scholar
  15. 15.
    Westphal M, Lamszus K (2011) The neurobiology of gliomas: from cell biology to the development of therapeutic approaches. Nat Rev Neurosci 12(9):495–508. doi: 10.1038/nrn3060 PubMedGoogle Scholar
  16. 16.
    Ernest NJ, Sontheimer H (2009) Glioma. In: Editor-in-Chief: Larry RS (ed) Encyclopedia of neuroscience, vol 4. Academic, Oxford, pp 877–884. doi:http://dx.doi.org/10.1016/B978-008045046-9.09007-0
  17. 17.
    Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114(2):97–109. doi: 10.1007/s00401-007-0243-4 PubMedCentralPubMedGoogle Scholar
  18. 18.
    Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352(10):987–996. doi: 10.1056/NEJMoa043330 PubMedGoogle Scholar
  19. 19.
    Wen PY, Kesari S (2008) Malignant gliomas in adults. N Engl J Med 359(5):492–507. doi: 10.1056/NEJMra0708126 PubMedGoogle Scholar
  20. 20.
    Sudhof TC (1995) The synaptic vesicle cycle: a cascade of protein-protein interactions. Nature 375(6533):645–653. doi: 10.1038/375645a0 PubMedGoogle Scholar
  21. 21.
    Augustine GJ, Burns ME, DeBello WM, Pettit DL, Schweizer FE (1996) Exocytosis: proteins and perturbations. Annu Rev Pharmacol Toxicol 36:659–701. doi: 10.1146/annurev.pa.36.040196.003303 PubMedGoogle Scholar
  22. 22.
    Bergles DE, Roberts JD, Somogyi P, Jahr CE (2000) Glutamatergic synapses on oligodendrocyte precursor cells in the hippocampus. Nature 405(6783):187–191. doi: 10.1038/35012083 PubMedGoogle Scholar
  23. 23.
    Seifert G, Steinhauser C (2001) Ionotropic glutamate receptors in astrocytes. Prog Brain Res 132:287–299. doi: 10.1016/s0079-6123(01)32083-6 PubMedGoogle Scholar
  24. 24.
    Teichberg VI (1991) Glial glutamate receptors: likely actors in brain signaling. FASEB J 5(15):3086–3091PubMedGoogle Scholar
  25. 25.
    Steinhauser C, Gallo V (1996) News on glutamate receptors in glial cells. Trends Neurosci 19(8):339–345PubMedGoogle Scholar
  26. 26.
    Lee MC, Ting KK, Adams S, Brew BJ, Chung R, Guillemin GJ (2010) Characterisation of the expression of NMDA receptors in human astrocytes. PLoS ONE 5(11):e14123. doi: 10.1371/journal.pone.0014123 PubMedCentralPubMedGoogle Scholar
  27. 27.
    Murugan M, Ling EA, Kaur C (2013) Glutamate receptors in microglia. CNS Neurol Disord Drug Targets 12(6):773–784PubMedGoogle Scholar
  28. 28.
    Flores-Mendez MA, Martinez-Lozada Z, Monroy HC, Hernandez-Kelly LC, Barrera I, Ortega A (2013) Glutamate-dependent translational control in cultured Bergmann glia cells: eIF2alpha phosphorylation. Neurochem Res 38(7):1324–1332. doi: 10.1007/s11064-013-1024-1 PubMedGoogle Scholar
  29. 29.
    Jansson LC, Louhivuori L, Wigren HK, Nordstrom T, Louhivuori V, Castren ML, Akerman KE (2013) Effect of glutamate receptor antagonists on migrating neural progenitor cells. Eur J Neurosci 37(9):1369–1382. doi: 10.1111/ejn.12152 PubMedGoogle Scholar
  30. 30.
    Renzel R, Sadek AR, Chang CH, Gray WP, Seifert G, Steinhauser C (2013) Polarized distribution of AMPA, but not GABAA, receptors in radial glia-like cells of the adult dentate gyrus. Glia 61(7):1146–1154. doi: 10.1002/glia.22505 PubMedGoogle Scholar
  31. 31.
    Hollmann M, Heinemann S (1994) Cloned glutamate receptors. Annu Rev Neurosci 17:31–108. doi: 10.1146/annurev.ne.17.030194.000335 PubMedGoogle Scholar
  32. 32.
    Prickett TD, Samuels Y (2012) Molecular pathways: dysregulated glutamatergic signaling pathways in cancer. Clin Cancer Res 18(16):4240–4246. doi: 10.1158/1078-0432.CCR-11-1217 PubMedCentralPubMedGoogle Scholar
  33. 33.
    Danbolt NC (2001) Glutamate uptake. Prog Neurobiol 65(1):1–105PubMedGoogle Scholar
  34. 34.
    Nakanishi S (1994) Metabotropic glutamate receptors: synaptic transmission, modulation, and plasticity. Neuron 13(5):1031–1037PubMedGoogle Scholar
  35. 35.
    Tang CM, Dichter M, Morad M (1989) Quisqualate activates a rapidly inactivating high conductance ionic channel in hippocampal neurons. Science 243(4897):1474–1477PubMedGoogle Scholar
  36. 36.
    de Groot J, Sontheimer H (2011) Glutamate and the biology of gliomas. Glia 59(8):1181–1189. doi: 10.1002/glia.21113 PubMedCentralPubMedGoogle Scholar
  37. 37.
    Hardingham GE (2009) Coupling of the NMDA receptor to neuroprotective and neurodestructive events. Biochem Soc Trans 37(Pt 6):1147–1160. doi: 10.1042/BST0371147 PubMedCentralPubMedGoogle Scholar
  38. 38.
    Rojas A, Dingledine R (2013) Ionotropic glutamate receptors: regulation by G-protein-coupled receptors. Mol Pharmacol 83(4):746–752. doi: 10.1124/mol.112.083352 PubMedGoogle Scholar
  39. 39.
    Leonard AS, Lim IA, Hemsworth DE, Horne MC, Hell JW (1999) Calcium/calmodulin-dependent protein kinase II is associated with the N-methyl-d-aspartate receptor. Proc Natl Acad Sci USA 96(6):3239–3244PubMedCentralPubMedGoogle Scholar
  40. 40.
    Kim DY, Kim SH, Choi HB, Min C, Gwag BJ (2001) High abundance of GluR1 mRNA and reduced Q/R editing of GluR2 mRNA in individual NADPH-diaphorase neurons. Mol Cell Neurosci 17(6):1025–1033. doi: 10.1006/mcne.2001.0988 PubMedGoogle Scholar
  41. 41.
    Isaac JT, Ashby MC, McBain CJ (2007) The role of the GluR2 subunit in AMPA receptor function and synaptic plasticity. Neuron 54(6):859–871. doi: 10.1016/j.neuron.2007.06.001 PubMedGoogle Scholar
  42. 42.
    Pisani A, Gubellini P, Bonsi P, Conquet F, Picconi B, Centonze D, Bernardi G, Calabresi P (2001) Metabotropic glutamate receptor 5 mediates the potentiation of N-methyl-d-aspartate responses in medium spiny striatal neurons. Neuroscience 106(3):579–587PubMedGoogle Scholar
  43. 43.
    Gubellini P, Pisani A, Centonze D, Bernardi G, Calabresi P (2004) Metabotropic glutamate receptors and striatal synaptic plasticity: implications for neurological diseases. Prog Neurobiol 74(5):271–300. doi: 10.1016/j.pneurobio.2004.09.005 PubMedGoogle Scholar
  44. 44.
    Pisani A, Calabresi P, Centonze D, Bernardi G (1997) Enhancement of NMDA responses by group I metabotropic glutamate receptor activation in striatal neurones. Br J Pharmacol 120(6):1007–1014. doi: 10.1038/sj.bjp.0700999 PubMedCentralPubMedGoogle Scholar
  45. 45.
    Bonsi P, Cuomo D, De Persis C, Centonze D, Bernardi G, Calabresi P, Pisani A (2005) Modulatory action of metabotropic glutamate receptor (mGluR) 5 on mGluR1 function in striatal cholinergic interneurons. Neuropharmacology 49(Suppl 1):104–113. doi: 10.1016/j.neuropharm.2005.05.012 PubMedGoogle Scholar
  46. 46.
    Bergles DE, Jahr CE (1997) Synaptic activation of glutamate transporters in hippocampal astrocytes. Neuron 19(6):1297–1308PubMedGoogle Scholar
  47. 47.
    Berger T, Schnitzer J, Kettenmann H (1991) Developmental changes in the membrane current pattern, K+ buffer capacity, and morphology of glial cells in the corpus callosum slice. J Neurosci 11:3008–3024PubMedGoogle Scholar
  48. 48.
    Berger UV, DeSilva TM, Chen W, Rosenberg PA (2005) Cellular and subcellular mRNA localization of glutamate transporter isoforms GLT1a and GLT1b in rat brain by in situ hybridization. J Comp Neurol 492(1):78–89. doi: 10.1002/cne.20737 PubMedCentralPubMedGoogle Scholar
  49. 49.
    Chen W, Mahadomrongkul V, Berger UV, Bassan M, DeSilva T, Tanaka K, Irwin N, Aoki C, Rosenberg PA (2004) The glutamate transporter GLT1a is expressed in excitatory axon terminals of mature hippocampal neurons. J Neurosci 24(5):1136–1148. doi: 10.1523/jneurosci.1586-03.2004 PubMedCentralPubMedGoogle Scholar
  50. 50.
    Holmseth S, Dehnes Y, Huang YH, Follin-Arbelet VV, Grutle NJ, Mylonakou MN, Plachez C, Zhou Y, Furness DN, Bergles DE, Lehre KP, Danbolt NC (2012) The density of EAAC1 (EAAT3) glutamate transporters expressed by neurons in the mammalian CNS. J Neurosci 32(17):6000–6013. doi: 10.1523/jneurosci.5347-11.2012 PubMedGoogle Scholar
  51. 51.
    Dehnes Y, Chaudhry FA, Ullensvang K, Lehre KP, Storm-Mathisen J, Danbolt NC (1998) The glutamate transporter EAAT4 in rat cerebellar Purkinje cells: a glutamate-gated chloride channel concentrated near the synapse in parts of the dendritic membrane facing astroglia. J Neurosci 18(10):3606–3619PubMedGoogle Scholar
  52. 52.
    Massie A, Vandesande F, Arckens L (2001) Expression of the high-affinity glutamate transporter EAAT4 in mammalian cerebral cortex. Neuroreport 12(2):393–397PubMedGoogle Scholar
  53. 53.
    de Vivo L, Melone M, Bucci G, Rothstein JD, Conti F (2010) Quantitative analysis of EAAT4 promoter activity in neurons and astrocytes of mouse somatic sensory cortex. Neurosci Lett 474(1):42–45. doi: 10.1016/j.neulet.2010.03.003 PubMedGoogle Scholar
  54. 54.
    Lee A, Anderson AR, Barnett NL, Stevens MG, Pow DV (2012) Alternate splicing and expression of the glutamate transporter EAAT5 in the rat retina. Gene 506(2):283–288. doi: 10.1016/j.gene.2012.07.010 PubMedGoogle Scholar
  55. 55.
    Arriza JL, Eliasof S, Kavanaugh MP, Amara SG (1997) Excitatory amino acid transporter 5, a retinal glutamate transporter coupled to a chloride conductance. Proc Natl Acad Sci USA 94(8):4155–4160PubMedCentralPubMedGoogle Scholar
  56. 56.
    Lee A, Anderson AR, Stevens M, Beasley S, Barnett NL, Pow DV (2013) Excitatory amino acid transporter 5 is widely expressed in peripheral tissues. Eur J Histochem 57(1):e11. doi: 10.4081/ejh.2013.e11 PubMedCentralPubMedGoogle Scholar
  57. 57.
    Lehre KP, Levy LM, Ottersen OP, Storm-Mathisen J, Danbolt NC (1995) Differential expression of two glial glutamate transporters in the rat brain: quantitative and immunocytochemical observations. J Neurosci 15(3 Pt 1):1835–1853PubMedGoogle Scholar
  58. 58.
    Danbolt NC, Storm-Mathisen J, Kanner BI (1992) An [Na+ + K+] coupled l-glutamate transporter purified from rat brain is located in glial cell processes. Neuroscience 51(2):295–310PubMedGoogle Scholar
  59. 59.
    Levy LM, Lehre KP, Rolstad B, Danbolt NC (1993) A monoclonal antibody raised against an [Na(+) + K+]coupled l-glutamate transporter purified from rat brain confirms glial cell localization. FEBS Lett 317(1–2):79–84PubMedGoogle Scholar
  60. 60.
    Furness DN, Dehnes Y, Akhtar AQ, Rossi DJ, Hamann M, Grutle NJ, Gundersen V, Holmseth S, Lehre KP, Ullensvang K, Wojewodzic M, Zhou Y, Attwell D, Danbolt NC (2008) A quantitative assessment of glutamate uptake into hippocampal synaptic terminals and astrocytes: new insights into a neuronal role for excitatory amino acid transporter 2 (EAAT2). Neuroscience 157(1):80–94. doi: 10.1016/j.neuroscience.2008.08.043 PubMedCentralPubMedGoogle Scholar
  61. 61.
    Aoyama K, Suh SW, Hamby AM, Liu J, Chan WY, Chen Y, Swanson RA (2006) Neuronal glutathione deficiency and age-dependent neurodegeneration in the EAAC1 deficient mouse. Nat Neurosci 9(1):119–126. doi: 10.1038/nn1609 PubMedGoogle Scholar
  62. 62.
    Danbolt NC, Pines G, Kanner BI (1990) Purification and reconstitution of the sodium- and potassium-coupled glutamate transport glycoprotein from rat brain. Biochemistry 29(28):6734–6740PubMedGoogle Scholar
  63. 63.
    Haugeto O, Ullensvang K, Levy LM, Chaudhry FA, Honore T, Nielsen M, Lehre KP, Danbolt NC (1996) Brain glutamate transporter proteins form homomultimers. J Biol Chem 271(44):27715–27722PubMedGoogle Scholar
  64. 64.
    Tanaka K, Watase K, Manabe T, Yamada K, Watanabe M, Takahashi K, Iwama H, Nishikawa T, Ichihara N, Kikuchi T, Okuyama S, Kawashima N, Hori S, Takimoto M, Wada K (1997) Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1. Science 276(5319):1699–1702PubMedGoogle Scholar
  65. 65.
    Gochenauer GE, Robinson MB (2001) Dibutyryl-cAMP (dbcAMP) up-regulates astrocytic chloride-dependent l-[3H]glutamate transport and expression of both system xc(-) subunits. J Neurochem 78(2):276–286PubMedGoogle Scholar
  66. 66.
    Burdo J, Dargusch R, Schubert D (2006) Distribution of the cystine/glutamate antiporter system xc- in the brain, kidney, and duodenum. J Histochem Cytochem 54(5):549–557. doi: 10.1369/jhc.5A6840.2006 PubMedGoogle Scholar
  67. 67.
    Piani D, Fontana A (1994) Involvement of the cystine transport system xc- in the macrophage-induced glutamate-dependent cytotoxicity to neurons. J Immunol (Baltim Md: 1950) 152(7):3578–3585Google Scholar
  68. 68.
    Murphy TH, Schnaar RL, Coyle JT (1990) Immature cortical neurons are uniquely sensitive to glutamate toxicity by inhibition of cystine uptake. FASEB J 4(6):1624–1633PubMedGoogle Scholar
  69. 69.
    Massie A, Schallier A, Mertens B, Vermoesen K, Bannai S, Sato H, Smolders I, Michotte Y (2008) Time-dependent changes in striatal xCT protein expression in hemi-Parkinson rats. Neuroreport 19(16):1589–1592. doi: 10.1097/WNR.0b013e328312181c PubMedGoogle Scholar
  70. 70.
    Pow DV (2001) Visualising the activity of the cystine–glutamate antiporter in glial cells using antibodies to aminoadipic acid, a selectively transported substrate. Glia 34(1):27–38PubMedGoogle Scholar
  71. 71.
    Lewerenz J, Hewett SJ, Huang Y, Lambros M, Gout PW, Kalivas PW, Massie A, Smolders I, Methner A, Pergande M, Smith SB, Ganapathy V, Maher P (2013) The cystine/glutamate antiporter system x(c)(-) in health and disease: from molecular mechanisms to novel therapeutic opportunities. Antioxid Redox Signal 18(5):522–555. doi: 10.1089/ars.2011.4391 PubMedCentralPubMedGoogle Scholar
  72. 72.
    Bannai S (1986) Exchange of cystine and glutamate across plasma membrane of human fibroblasts. J Biol Chem 261(5):2256–2263PubMedGoogle Scholar
  73. 73.
    Sato H, Tamba M, Ishii T, Bannai S (1999) Cloning and expression of a plasma membrane cystine/glutamate exchange transporter composed of two distinct proteins. J Biol Chem 274(17):11455–11458PubMedGoogle Scholar
  74. 74.
    Sagara JI, Miura K, Bannai S (1993) Maintenance of neuronal glutathione by glial cells. J Neurochem 61(5):1672–1676PubMedGoogle Scholar
  75. 75.
    Watanabe H, Bannai S (1987) Induction of cystine transport activity in mouse peritoneal macrophages. J Exp Med 165(3):628–640PubMedGoogle Scholar
  76. 76.
    Deneke SM, Fanburg BL (1989) Regulation of cellular glutathione. Am J Physiol 257(4 Pt 1):L163–L173PubMedGoogle Scholar
  77. 77.
    Lo M, Wang YZ, Gout PW (2008) The x(c)- cystine/glutamate antiporter: a potential target for therapy of cancer and other diseases. J Cell Physiol 215(3):593–602. doi: 10.1002/jcp.21366 PubMedGoogle Scholar
  78. 78.
    Shih AY, Erb H, Sun X, Toda S, Kalivas PW, Murphy TH (2006) Cystine/glutamate exchange modulates glutathione supply for neuroprotection from oxidative stress and cell proliferation. J Neurosci 26(41):10514–10523. doi: 10.1523/jneurosci.3178-06.2006 PubMedGoogle Scholar
  79. 79.
    Sato H, Shiiya A, Kimata M, Maebara K, Tamba M, Sakakura Y, Makino N, Sugiyama F, Yagami K, Moriguchi T, Takahashi S, Bannai S (2005) Redox imbalance in cystine/glutamate transporter-deficient mice. J Biol Chem 280(45):37423–37429. doi: 10.1074/jbc.M506439200 PubMedGoogle Scholar
  80. 80.
    Ogunrinu TA, Sontheimer H (2010) Hypoxia increases the dependence of glioma cells on glutathione. J Biol Chem 285(48):37716–37724. doi: 10.1074/jbc.M110.161190 PubMedCentralPubMedGoogle Scholar
  81. 81.
    Meister A (1988) Glutathione metabolism and its selective modification. J Biol Chem 263(33):17205–17208PubMedGoogle Scholar
  82. 82.
    Singh S, Khan AR, Gupta AK (2012) Role of glutathione in cancer pathophysiology and therapeutic interventions. J Exp Ther Oncol 9(4):303–316PubMedGoogle Scholar
  83. 83.
    Benjamin AM, Quastel JH (1975) Metabolism of amino acids and ammonia in rat brain cortex slices in vitro: a possible role of ammonia in brain function. J Neurochem 25(3):197–206PubMedGoogle Scholar
  84. 84.
    Martinez-Hernandez A, Bell KP, Norenberg MD (1977) Glutamine synthetase: glial localization in brain. Science 195(4284):1356–1358PubMedGoogle Scholar
  85. 85.
    Chaudhry FA, Reimer RJ, Edwards RH (2002) The glutamine commute: take the N line and transfer to the A. J Cell Biol 157(3):349–355. doi: 10.1083/jcb.200201070 PubMedCentralPubMedGoogle Scholar
  86. 86.
    Jenstad M, Quazi AZ, Zilberter M, Haglerod C, Berghuis P, Saddique N, Goiny M, Buntup D, Davanger S, S Haug FM , Barnes CA, McNaughton BL, Ottersen OP, Storm-Mathisen J, Harkany T, Chaudhry FA (2009) System A transporter SAT2 mediates replenishment of dendritic glutamate pools controlling retrograde signaling by glutamate. Cereb Cortex 19(5):1092–1106. doi: 10.1093/cercor/bhn151 PubMedGoogle Scholar
  87. 87.
    Kvamme E, Torgner IA, Roberg B (2001) Kinetics and localization of brain phosphate activated glutaminase. J Neurosci Res 66(5):951–958PubMedGoogle Scholar
  88. 88.
    Svenneby G (1970) Pig brain glutaminase: purification and identification of different enzyme forms. J Neurochem 17(11):1591–1599PubMedGoogle Scholar
  89. 89.
    Bellocchio EE, Hu H, Pohorille A, Chan J, Pickel VM, Edwards RH (1998) The localization of the brain-specific inorganic phosphate transporter suggests a specific presynaptic role in glutamatergic transmission. J Neurosci 18(21):8648–8659PubMedGoogle Scholar
  90. 90.
    Fremeau RT Jr, Troyer MD, Pahner I, Nygaard GO, Tran CH, Reimer RJ, Bellocchio EE, Fortin D, Storm-Mathisen J, Edwards RH (2001) The expression of vesicular glutamate transporters defines two classes of excitatory synapse. Neuron 31(2):247–260PubMedGoogle Scholar
  91. 91.
    Nakanishi T, Sugawara M, Huang W, Martindale RG, Leibach FH, Ganapathy ME, Prasad PD, Ganapathy V (2001) Structure, function, and tissue expression pattern of human SN2, a subtype of the amino acid transport system N. Biochem Biophys Res Commun 281(5):1343–1348. doi: 10.1006/bbrc.2001.4504 PubMedGoogle Scholar
  92. 92.
    Cubelos B, Gonzalez-Gonzalez IM, Gimenez C, Zafra F (2005) Amino acid transporter SNAT5 localizes to glial cells in the rat brain. Glia 49(2):230–244. doi: 10.1002/glia.20106 PubMedGoogle Scholar
  93. 93.
    Chaudhry FA, Reimer RJ, Krizaj D, Barber D, Storm-Mathisen J, Copenhagen DR, Edwards RH (1999) Molecular analysis of system N suggests novel physiological roles in nitrogen metabolism and synaptic transmission. Cell 99(7):769–780PubMedGoogle Scholar
  94. 94.
    Boulland JL, Osen KK, Levy LM, Danbolt NC, Edwards RH, Storm-Mathisen J, Chaudhry FA (2002) Cell-specific expression of the glutamine transporter SN1 suggests differences in dependence on the glutamine cycle. Eur J Neurosci 15(10):1615–1631PubMedGoogle Scholar
  95. 95.
    Boulland JL, Rafiki A, Levy LM, Storm-Mathisen J, Chaudhry FA (2003) Highly differential expression of SN1, a bidirectional glutamine transporter, in astroglia and endothelium in the developing rat brain. Glia 41(3):260–275. doi: 10.1002/glia.10188 PubMedGoogle Scholar
  96. 96.
    Martinez-Lozada Z, Guillem AM, Flores-Mendez M, Hernandez-Kelly LC, Vela C, Meza E, Zepeda RC, Caba M, Rodriguez A, Ortega A (2013) GLAST/EAAT1-induced glutamine release via SNAT3 in Bergmann glial cells: evidence of a functional and physical coupling. J Neurochem 125(4):545–554. doi: 10.1111/jnc.12211 PubMedGoogle Scholar
  97. 97.
    Nissen-Meyer LS, Popescu MC, el Hamdani H, Chaudhry FA (2011) Protein kinase C-mediated phosphorylation of a single serine residue on the rat glial glutamine transporter SN1 governs its membrane trafficking. J Neurosci 31(17):6565–6575. doi: 10.1523/jneurosci.3694-10.2011 PubMedGoogle Scholar
  98. 98.
    Nissen-Meyer LS, Chaudhry FA (2013) Protein kinase C phosphorylates the system N glutamine transporter SN1 (Slc38a3) and regulates its membrane trafficking and degradation. Front Endocrinol 4:138. doi: 10.3389/fendo.2013.00138 Google Scholar
  99. 99.
    Broer A, Deitmer JW, Broer S (2004) Astroglial glutamine transport by system N is upregulated by glutamate. Glia 48(4):298–310. doi: 10.1002/glia.20081 PubMedGoogle Scholar
  100. 100.
    Coulter DA, Eid T (2012) Astrocytic regulation of glutamate homeostasis in epilepsy. Glia 60(8):1215–1226. doi: 10.1002/glia.22341 PubMedCentralPubMedGoogle Scholar
  101. 101.
    Albrecht J, Sidoryk-Wegrzynowicz M, Zielinska M, Aschner M (2010) Roles of glutamine in neurotransmission. Neuron Glia Biol 6(4):263–276. doi: 10.1017/s1740925x11000093 PubMedGoogle Scholar
  102. 102.
    Choi DW (1988) Glutamate neurotoxicity and diseases of the nervous system. Neuron 1(8):623–634PubMedGoogle Scholar
  103. 103.
    Nicholls D, Attwell D (1990) The release and uptake of excitatory amino acids. Trends Pharmacol Sci 11(11):462–468PubMedGoogle Scholar
  104. 104.
    Herman MA, Jahr CE (2007) Extracellular glutamate concentration in hippocampal slice. J Neurosci 27(36):9736–9741. doi: 10.1523/jneurosci.3009-07.2007 PubMedCentralPubMedGoogle Scholar
  105. 105.
    Jabaudon D, Shimamoto K, Yasuda-Kamatani Y, Scanziani M, Gahwiler BH, Gerber U (1999) Inhibition of uptake unmasks rapid extracellular turnover of glutamate of nonvesicular origin. Proc Natl Acad Sci USA 96(15):8733–8738PubMedCentralPubMedGoogle Scholar
  106. 106.
    Choi DW (1992) Excitotoxic cell death. J Neurobiol 23(9):1261–1276. doi: 10.1002/neu.480230915 PubMedGoogle Scholar
  107. 107.
    Fujikawa DG (2005) Prolonged seizures and cellular injury: understanding the connection. Epilepsy behav 7(Suppl 3):S3–S11. doi: 10.1016/j.yebeh.2005.08.003 PubMedGoogle Scholar
  108. 108.
    Mattson MP (2008) Glutamate and neurotrophic factors in neuronal plasticity and disease. Ann NY Acad Sci 1144:97–112. doi: 10.1196/annals.1418.005 PubMedCentralPubMedGoogle Scholar
  109. 109.
    Torp R, Arvin B, Le Peillet E, Chapman AG, Ottersen OP, Meldrum BS (1993) Effect of ischaemia and reperfusion on the extra- and intracellular distribution of glutamate, glutamine, aspartate and GABA in the rat hippocampus, with a note on the effect of the sodium channel blocker BW1003C87. Exp Brain Res 96(3):365–376PubMedGoogle Scholar
  110. 110.
    Lipton P (1999) Ischemic cell death in brain neurons. Physiol Rev 79(4):1431–1568PubMedGoogle Scholar
  111. 111.
    Benveniste H, Drejer J, Schousboe A, Diemer NH (1984) Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis. J Neurochem 43(5):1369–1374PubMedGoogle Scholar
  112. 112.
    Rossi DJ, Oshima T, Attwell D (2000) Glutamate release in severe brain ischaemia is mainly by reversed uptake. Nature 403(6767):316–321. doi: 10.1038/35002090 PubMedGoogle Scholar
  113. 113.
    Kim K, Lee SG, Kegelman TP, Su ZZ, Das SK, Dash R, Dasgupta S, Barral PM, Hedvat M, Diaz P, Reed JC, Stebbins JL, Pellecchia M, Sarkar D, Fisher PB (2011) Role of excitatory amino acid transporter-2 (EAAT2) and glutamate in neurodegeneration: opportunities for developing novel therapeutics. J Cell Physiol 226(10):2484–2493. doi: 10.1002/jcp.22609 PubMedCentralPubMedGoogle Scholar
  114. 114.
    Watkins S, Sontheimer H (2012) Unique biology of gliomas: challenges and opportunities. Trends Neurosci 35(9):546–556. doi: 10.1016/j.tins.2012.05.001 PubMedCentralPubMedGoogle Scholar
  115. 115.
    Chung WJ, Lyons SA, Nelson GM, Hamza H, Gladson CL, Gillespie GY, Sontheimer H (2005) Inhibition of cystine uptake disrupts the growth of primary brain tumors. J Neurosci 25(31):7101–7110. doi: 10.1523/JNEUROSCI.5258-04.2005 PubMedCentralPubMedGoogle Scholar
  116. 116.
    de Groot JF, Liu TJ, Fuller G, Yung WK (2005) The excitatory amino acid transporter-2 induces apoptosis and decreases glioma growth in vitro and in vivo. Cancer Res 65(5):1934–1940. doi: 10.1158/0008-5472.CAN-04-3626 PubMedGoogle Scholar
  117. 117.
    Ye ZC, Sontheimer H (1999) Glioma cells release excitotoxic concentrations of glutamate. Cancer Res 59(17):4383–4391PubMedGoogle Scholar
  118. 118.
    Dunlop J, Lou Z, McIlvain HB (1999) Properties of excitatory amino acid transport in the human U373 astrocytoma cell line. Brain Res 839(2):235–242PubMedGoogle Scholar
  119. 119.
    Ye ZC, Rothstein JD, Sontheimer H (1999) Compromised glutamate transport in human glioma cells: reduction-mislocalization of sodium-dependent glutamate transporters and enhanced activity of cystine–glutamate exchange. J Neurosci 19(24):10767–10777PubMedGoogle Scholar
  120. 120.
    Jimenez AL, Chou AH, Khadadadi O, Palos TP, Howard BD (2003) Wnt-1 has multiple effects on the expression of glutamate transporters. Neurochem Int 42(4):345–351PubMedGoogle Scholar
  121. 121.
    Guo H (2002) Human glioma cells and undifferentiated primary astrocytes that express aberrant EAAT2 mRNA inhibit normal EAAT2 protein expression and prevent cell death. Mol Cell Neurosci 21(4):546–560. doi: 10.1006/mcne.2002.1198 PubMedGoogle Scholar
  122. 122.
    Zschocke J, Allritz C, Engele J, Rein T (2007) DNA methylation dependent silencing of the human glutamate transporter EAAT2 gene in glial cells. Glia 55(7):663–674. doi: 10.1002/glia.20497 PubMedGoogle Scholar
  123. 123.
    Palos TP, Ramachandran B, Boado R, Howard BD (1996) Rat C6 and human astrocytic tumor cells express a neuronal type of glutamate transporter. Brain Res Mol Brain Res 37(1–2):297–303PubMedGoogle Scholar
  124. 124.
    Marcus HJ, Carpenter KL, Price SJ, Hutchinson PJ (2010) In vivo assessment of high-grade glioma biochemistry using microdialysis: a study of energy-related molecules, growth factors and cytokines. J Neurooncol 97(1):11–23. doi: 10.1007/s11060-009-9990-5 PubMedGoogle Scholar
  125. 125.
    Savaskan NE, Seufert S, Hauke J, Trankle C, Eyupoglu IY, Hahnen E (2011) Dissection of mitogenic and neurodegenerative actions of cystine and glutamate in malignant gliomas. Oncogene 30(1):43–53. doi: 10.1038/onc.2010.391 PubMedGoogle Scholar
  126. 126.
    Takaki J, Fujimori K, Miura M, Suzuki T, Sekino Y, Sato K (2012) l-glutamate released from activated microglia downregulates astrocytic l-glutamate transporter expression in neuroinflammation: the ‘collusion’ hypothesis for increased extracellular l-glutamate concentration in neuroinflammation. J Neuroinflamm 9:275. doi: 10.1186/1742-2094-9-275 Google Scholar
  127. 127.
    Medina MA, Sanchez-Jimenez F, Marquez J, Rodriguez Quesada A, Nunez de Castro I (1992) Relevance of glutamine metabolism to tumor cell growth. Mol Cell Biochem 113(1):1–15PubMedGoogle Scholar
  128. 128.
    Portais JC, Martin M, Canioni P, Merle M (1993) Glutathione, but not glutamine, is detected in 13C-NMR spectra of perchloric acid extracts from C6 glioma cells. FEBS Lett 327(3):301–306PubMedGoogle Scholar
  129. 129.
    Sidoryk M, Matyja E, Dybel A, Zielinska M, Bogucki J, Jaskolski DJ, Liberski PP, Kowalczyk P, Albrecht J (2004) Increased expression of a glutamine transporter SNAT3 is a marker of malignant gliomas. Neuroreport 15(4):575–578PubMedGoogle Scholar
  130. 130.
    Dranoff G, Elion GB, Friedman HS, Campbell GL, Bigner DD (1985) Influence of glutamine on the growth of human glioma and medulloblastoma in culture. Cancer Res 45(9):4077–4081PubMedGoogle Scholar
  131. 131.
    Seltzer MJ, Bennett BD, Joshi AD, Gao P, Thomas AG, Ferraris DV, Tsukamoto T, Rojas CJ, Slusher BS, Rabinowitz JD, Dang CV, Riggins GJ (2010) Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1. Cancer Res 70(22):8981–8987. doi: 10.1158/0008-5472.can-10-1666 PubMedCentralPubMedGoogle Scholar
  132. 132.
    Rzeski W, Turski L, Ikonomidou C (2001) Glutamate antagonists limit tumor growth. Proc Natl Acad Sci USA 98(11):6372–6377. doi: 10.1073/pnas.091113598 PubMedCentralPubMedGoogle Scholar
  133. 133.
    D’Onofrio M, Arcella A, Bruno V, Ngomba RT, Battaglia G, Lombari V, Ragona G, Calogero A, Nicoletti F (2003) Pharmacological blockade of mGlu2/3 metabotropic glutamate receptors reduces cell proliferation in cultured human glioma cells. J Neurochem 84(6):1288–1295PubMedGoogle Scholar
  134. 134.
    Ishiuchi S, Tsuzuki K, Yoshida Y, Yamada N, Hagimura N, Okado H, Miwa A, Kurihara H, Nakazato Y, Tamura M, Sasaki T, Ozawa S (2002) Blockage of Ca(2+)-permeable AMPA receptors suppresses migration and induces apoptosis in human glioblastoma cells. Nat Med 8(9):971–978. doi: 10.1038/nm746 PubMedGoogle Scholar
  135. 135.
    Matute C, Arellano RO, Conde-Guerri B, Miledi R (1992) mRNA coding for neurotransmitter receptors in a human astrocytoma. Proc Natl Acad Sci USA 89(8):3399–3403PubMedCentralPubMedGoogle Scholar
  136. 136.
    Patt S, Labrakakis C, Bernstein M, Weydt P, Cervos-Navarro J, Nisch G, Kettenmann H (1996) Neuron-like physiological properties of cells from human oligodendroglial tumors. Neuroscience 71(2):601–611PubMedGoogle Scholar
  137. 137.
    Labrakakis C, Patt S, Weydt P, Cervos-Navarro J, Meyer R, Kettenmann H (1997) Action potential-generating cells in human glioblastomas. J Neuropathol Exp Neurol 56(3):243–254PubMedGoogle Scholar
  138. 138.
    Labrakakis C, Patt S, Hartmann J, Kettenmann H (1998) Glutamate receptor activation can trigger electrical activity in human glioma cells. Eur J Neurosci 10(6):2153–2162PubMedGoogle Scholar
  139. 139.
    Frithz G, Ronquist G, Hugosson R (1982) Perspectives of adenylate kinase activity and glutathione concentration in cerebrospinal fluid of patients with ischemic and neoplastic brain lesions. Eur Neurol 21(1):41–47PubMedGoogle Scholar
  140. 140.
    Boveris A, Oshino N, Chance B (1972) The cellular production of hydrogen peroxide. Biochem J 128(3):617–630PubMedCentralPubMedGoogle Scholar
  141. 141.
    Estrela JM, Ortega A, Obrador E (2006) Glutathione in cancer biology and therapy. Crit Rev Clin Lab Sci 43(2):143–181. doi: 10.1080/10408360500523878 PubMedGoogle Scholar
  142. 142.
    Feun LG, Savaraj N, Landy HJ (1994) Drug resistance in brain tumors. J Neurooncol 20(2):165–176PubMedGoogle Scholar
  143. 143.
    Bump EA, Brown JM (1990) Role of glutathione in the radiation response of mammalian cells in vitro and in vivo. Pharmacol Ther 47(1):117–136PubMedGoogle Scholar
  144. 144.
    Brouazin-Jousseaume V, Guitton N, Legue F, Chenal C (2002) GSH level and IL-6 production increased in sertoli cells and astrocytes after gamma irradiation. Anticancer Res 22(1A):257–262PubMedGoogle Scholar
  145. 145.
    Kim JY, Kanai Y, Chairoungdua A, Cha SH, Matsuo H, Kim DK, Inatomi J, Sawa H, Ida Y, Endou H (2001) Human cystine/glutamate transporter: cDNA cloning and upregulation by oxidative stress in glioma cells. Biochim Biophys Acta 1512(2):335–344PubMedGoogle Scholar
  146. 146.
    Oh MC, Kim JM, Safaee M, Kaur G, Sun MZ, Kaur R, Celli A, Mauro TM, Parsa AT (2012) Overexpression of calcium-permeable glutamate receptors in glioblastoma derived brain tumor initiating cells. PLoS ONE 7(10):e47846. doi: 10.1371/journal.pone.0047846 PubMedCentralPubMedGoogle Scholar
  147. 147.
    Maas S, Patt S, Schrey M, Rich A (2001) Underediting of glutamate receptor GluR-B mRNA in malignant gliomas. Proc Natl Acad Sci USA 98(25):14687–14692. doi: 10.1073/pnas.251531398 PubMedCentralPubMedGoogle Scholar
  148. 148.
    Millan A, Arias-Montano JA, Mendez JA, Hernandez-Kelly LC, Ortega A (2004) Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors signaling complexes in Bergmann glia. J Neurosci Res 78(1):56–63. doi: 10.1002/jnr.20237 PubMedGoogle Scholar
  149. 149.
    Millan A, Aguilar P, Mendez JA, Arias-Montano JA, Ortega A (2001) Glutamate activates PP125(FAK) through AMPA/kainate receptors in Bergmann glia. J Neurosci Res 66(4):723–729PubMedGoogle Scholar
  150. 150.
    Golubovskaya VM, Huang G, Ho B, Yemma M, Morrison CD, Lee J, Eliceiri BP, Cance WG (2013) Pharmacologic blockade of FAK autophosphorylation decreases human glioblastoma tumor growth and synergizes with temozolomide. Mol Cancer Ther 12(2):162–172. doi: 10.1158/1535-7163.mct-12-0701 PubMedCentralPubMedGoogle Scholar
  151. 151.
    Hecker TP, Grammer JR, Gillespie GY, Stewart J Jr, Gladson CL (2002) Focal adhesion kinase enhances signaling through the Shc/extracellular signal-regulated kinase pathway in anaplastic astrocytoma tumor biopsy samples. Cancer Res 62(9):2699–2707PubMedGoogle Scholar
  152. 152.
    Lindemann C, Hackmann O, Delic S, Schmidt N, Reifenberger G, Riemenschneider MJ (2011) SOCS3 promoter methylation is mutually exclusive to EGFR amplification in gliomas and promotes glioma cell invasion through STAT3 and FAK activation. Acta Neuropathol 122(2):241–251. doi: 10.1007/s00401-011-0832-0 PubMedGoogle Scholar
  153. 153.
    Yoshida Y, Tsuzuki K, Ishiuchi S, Ozawa S (2006) Serum-dependence of AMPA receptor-mediated proliferation in glioma cells. Pathol Int 56(5):262–271. doi: 10.1111/j.1440-1827.2006.01954.x PubMedGoogle Scholar
  154. 154.
    de Groot JF, Piao Y, Lu L, Fuller GN, Yung WK (2008) Knockdown of GluR1 expression by RNA interference inhibits glioma proliferation. J Neurooncol 88(2):121–133. doi: 10.1007/s11060-008-9552-2 PubMedGoogle Scholar
  155. 155.
    Ciccarelli R, Sureda FX, Casabona G, Di Iorio P, Caruso A, Spinella F, Condorelli DF, Nicoletti F, Caciagli F (1997) Opposite influence of the metabotropic glutamate receptor subtypes mGlu3 and -5 on astrocyte proliferation in culture. Glia 21(4):390–398PubMedGoogle Scholar
  156. 156.
    Lee SG, Kim K, Kegelman TP, Dash R, Das SK, Choi JK, Emdad L, Howlett EL, Jeon HY, Su ZZ, Yoo BK, Sarkar D, Kim SH, Kang DC, Fisher PB (2011) Oncogene AEG-1 promotes glioma-induced neurodegeneration by increasing glutamate excitotoxicity. Cancer Res 71(20):6514–6523. doi: 10.1158/0008-5472.CAN-11-0782 PubMedCentralPubMedGoogle Scholar
  157. 157.
    Gegelashvili G, Dehnes Y, Danbolt NC, Schousboe A (2000) The high-affinity glutamate transporters GLT1, GLAST, and EAAT4 are regulated via different signalling mechanisms. Neurochem Int 37(2–3):163–170PubMedGoogle Scholar
  158. 158.
    Sontheimer H (2008) A role for glutamate in growth and invasion of primary brain tumors. J Neurochem 105(2):287–295. doi: 10.1111/j.1471-4159.2008.05301.x PubMedCentralPubMedGoogle Scholar
  159. 159.
    Behrens PF, Langemann H, Strohschein R, Draeger J, Hennig J (2000) Extracellular glutamate and other metabolites in and around RG2 rat glioma: an intracerebral microdialysis study. J Neurooncol 47(1):11–22PubMedGoogle Scholar
  160. 160.
    Takano T, Lin JH, Arcuino G, Gao Q, Yang J, Nedergaard M (2001) Glutamate release promotes growth of malignant gliomas. Nat Med 7(9):1010–1015. doi: 10.1038/nm0901-1010 PubMedGoogle Scholar
  161. 161.
    van Breemen MS, Rijsman RM, Taphoorn MJ, Walchenbach R, Zwinkels H, Vecht CJ (2009) Efficacy of anti-epileptic drugs in patients with gliomas and seizures. J Neurol 256(9):1519–1526. doi: 10.1007/s00415-009-5156-9 PubMedGoogle Scholar
  162. 162.
    Matthew E, Sherwin AL, Welner SA, Odusote K, Stratford JG (1980) Seizures following intracranial surgery: incidence in the first post-operative week. Can J Neurol Sci 7(4):285–290PubMedGoogle Scholar
  163. 163.
    Beaumont A, Whittle IR (2000) The pathogenesis of tumour associated epilepsy. Acta Neurochir 142(1):1–15PubMedGoogle Scholar
  164. 164.
    During MJ, Spencer DD (1993) Extracellular hippocampal glutamate and spontaneous seizure in the conscious human brain. Lancet 341(8861):1607–1610PubMedGoogle Scholar
  165. 165.
    Fan G, Sun B, Wu Z, Guo Q, Guo Y (2004) In vivo single-voxel proton MR spectroscopy in the differentiation of high-grade gliomas and solitary metastases. Clin Radiol 59(1):77–85. doi: 10.1016/j.crad.2003.08.006 PubMedGoogle Scholar
  166. 166.
    Senner V, Kohling R, Puttmann-Cyrus S, Straub H, Paulus W, Speckmann EJ (2004) A new neurophysiological/neuropathological ex vivo model localizes the origin of glioma-associated epileptogenesis in the invasion area. Acta Neuropathol 107(1):1–7. doi: 10.1007/s00401-003-0771-5 PubMedGoogle Scholar
  167. 167.
    Campbell SL, Buckingham SC, Sontheimer H (2012) Human glioma cells induce hyperexcitability in cortical networks. Epilepsia 53(8):1360–1370. doi: 10.1111/j.1528-1167.2012.03557.x PubMedCentralPubMedGoogle Scholar
  168. 168.
    Bianchi MG, Franchi-Gazzola R, Reia L, Allegri M, Uggeri J, Chiu M, Sala R, Bussolati O (2012) Valproic acid induces the glutamate transporter excitatory amino acid transporter-3 in human oligodendroglioma cells. Neuroscience 227:260–270. doi: 10.1016/j.neuroscience.2012.09.055 PubMedGoogle Scholar
  169. 169.
    Aguirre G, Rosas S, Lopez-Bayghen E, Ortega A (2008) Valproate-dependent transcriptional regulation of GLAST/EAAT1 expression: involvement of Ying-Yang 1. Neurochem Int 52(7):1322–1331. doi: 10.1016/j.neuint.2008.01.015 PubMedGoogle Scholar
  170. 170.
    Rothstein JD, Patel S, Regan MR, Haenggeli C, Huang YH, Bergles DE, Jin L, Dykes Hoberg M, Vidensky S, Chung DS, Toan SV, Bruijn LI, Su ZZ, Gupta P, Fisher PB (2005) Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature 433(7021):73–77. doi: 10.1038/nature03180 PubMedGoogle Scholar
  171. 171.
    Jacobs VL, De Leo JA (2013) Increased glutamate uptake in astrocytes via propentofylline results in increased tumor cell apoptosis using the CNS-1 glioma model. J Neurooncol 114(1):33–42. doi: 10.1007/s11060-013-1158-7 PubMedGoogle Scholar
  172. 172.
    Sattler R, Tyler B, Hoover B, Coddington LT, Recinos V, Hwang L, Brem H, Rothstein JD (2013) Increased expression of glutamate transporter GLT-1 in peritumoral tissue associated with prolonged survival and decreases in tumor growth in a rat model of experimental malignant glioma. J Neurosurg 119(4):878–886. doi: 10.3171/2013.6.jns122319 PubMedGoogle Scholar
  173. 173.
    Vanhoutte N, Abarca-Quinones J, Jordan BF, Gallez B, Maloteaux JM, Hermans E (2009) Enhanced expression of the high affinity glutamate transporter GLT-1 in C6 glioma cells delays tumour progression in rat. Exp Neurol 218(1):56–63. doi: 10.1016/j.expneurol.2009.04.004 PubMedGoogle Scholar
  174. 174.
    Vanhoutte N, Hermans E (2008) Glutamate-induced glioma cell proliferation is prevented by functional expression of the glutamate transporter GLT-1. FEBS Lett 582(13):1847–1852. doi: 10.1016/j.febslet.2008.04.053 PubMedGoogle Scholar
  175. 175.
    Iwamoto FM, Kreisl TN, Kim L, Duic JP, Butman JA, Albert PS, Fine HA (2010) Phase 2 trial of talampanel, a glutamate receptor inhibitor, for adults with recurrent malignant gliomas. Cancer 116(7):1776–1782. doi: 10.1002/cncr.24957 PubMedCentralPubMedGoogle Scholar
  176. 176.
    Grossman SA, Ye X, Chamberlain M, Mikkelsen T, Batchelor T, Desideri S, Piantadosi S, Fisher J, Fine HA (2009) Talampanel with standard radiation and temozolomide in patients with newly diagnosed glioblastoma: a multicenter phase II trial. J Clin Oncol 27(25):4155–4161. doi: 10.1200/jco.2008.21.6895 PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Basel 2013

Authors and Affiliations

  1. 1.Department of Neurobiology, Center for Glial Biology in MedicineUniversity of Alabama at BirminghamBirminghamUSA

Personalised recommendations