Skip to main content

Advertisement

Log in

The role of glutamate in neuronal ischemic injury: the role of spark in fire

  • Review Article
  • Published:
Neurological Sciences Aims and scope Submit manuscript

Abstract

Although being a physiologically important excitatory neurotransmitter, glutamate plays a pivotal role in various neurological disorders including ischemic neurological diseases. Its level is increased during cerebral ischemia with excessive neurological stimulation causing the glutamate-induced neuronal toxicity, excitotoxicity, and this is considered the triggering spark in the ischemic neuronal damage. The glutamatergic stimulation will lead to rise in the intracellular sodium and calcium, and the elevated intracellular calcium will lead to mitochondrial dysfunction, activation of proteases, accumulation of reactive oxygen species and release of nitric oxide. Interruption of the cascades of glutamate-induced cell death during ischemia may provide a way to prevent, or at least reduce, the ischemic damage. Various therapeutic options are suggested interrupting the glutamatergic pathways, e.g., inhibiting the glutamate synthesis or release, increasing its clearance, blocking of its receptors or preventing the rise in intracellular calcium. Development of these strategies may provide future treatment options in the management of ischemic stroke.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Wang Y, Qin ZH (2010) Molecular and cellular mechanisms of excitotoxic neuronal death. Apoptosis 15:1382–1402

    Article  PubMed  CAS  Google Scholar 

  2. Derouiche A (2004) The perisynaptic astrocyte process as a glial compartment immunolabeling for glutamine synthetase and other glial markers. In: Hertz L (ed) Non-neuronal cells of the nervous system. Function and dysfunction. Elsevier, Amsterdam, pp 147–163

    Google Scholar 

  3. Hertz L, Peng L, Dienel GA (2007) Energy metabolism in astrocytes, high rate of oxidative metabolism and spatiotemporal dependence on glycolysis/glycogenolysis. J Cereb Blood Flow Metab 27:219–249

    Article  PubMed  CAS  Google Scholar 

  4. Takeuchi H, Jin S, Wang J et al (2006) Tumor necrosis factor-alpha induces neurotoxicity via glutamate release from hemichannels of activated microglia in an autocrine manner. J Biol Chem 281:21362–21368

    Article  PubMed  CAS  Google Scholar 

  5. Reid CA, Bekkers JM, Clements JD (2003) Presynaptic Ca2+ channels: a functional patchwork. Trends Neurosci 26:683–687

    Article  PubMed  CAS  Google Scholar 

  6. Nicholls DG, Sihra TS, Sanchez-Prieto J (1987) Calcium-dependent and -independent release of glutamate from synaptosomes monitored by continuous fluorometry. J Neurochem 49:50–57

    Article  PubMed  CAS  Google Scholar 

  7. Shigeri Y, Seal RP, Shimamoto K (2004) Molecular pharmacology of glutamate transporters, EAATs and VGLUTs. Brain Res Rev 45:250–265

    Article  PubMed  CAS  Google Scholar 

  8. Danbolt NC (2001) Glutamate uptake. Prog Neurobiol 65:1–105

    Article  PubMed  CAS  Google Scholar 

  9. Köhr G (2006) NMDA receptor function: subunit composition versus spatial distribution. Cell Tissue Res 326:439–446

    Article  PubMed  CAS  Google Scholar 

  10. Sobczyk A, Scheuss V, Svoboda K (2005) NMDA receptor subunit dependent [Ca2+] signaling in individual hippocampal dendritic spines. J Neurosci 25:6037–6046

    Article  PubMed  CAS  Google Scholar 

  11. Kim MJ, Dunah AW, Wang YT, Sheng M (2005) Differential roles of NR2A- and NR2B-containing NMDA receptors in Ras-ERK signaling and AMPA receptor trafficking. Neuron 46:745–760

    Article  PubMed  CAS  Google Scholar 

  12. Nakanishi N, Tu S, Shin Y et al (2009) Neuroprotection by the NR3A subunit of the NMDA receptor. J Neurosci 29:5260–5265

    Article  PubMed  CAS  Google Scholar 

  13. Papadia S, Stevenson P, Hardingham NR, Bading H, Hardingham GE (2005) Nuclear Ca2+ and the cAMP response element-binding protein family mediate a late phase of activity-dependent neuroprotection. J Neurosci 25:4279–4287

    Article  PubMed  CAS  Google Scholar 

  14. Pokorska A, Vanhoutte P, Arnold FJ, Silvagno F, Hardingham GE, Bading H (2003) Synaptic activity induces signaling to CREB without increasing global levels of cAMP in hippocampal neurons. J Neurochem 84:447–452

    Article  PubMed  CAS  Google Scholar 

  15. Sheng M, Hoogenraad CC (2007) The postsynaptic architecture of excitatory synapses. Annu Rev Biochem 76:823–847

    Article  PubMed  CAS  Google Scholar 

  16. Forder JP, Tymianski M (2009) Postsynaptic mechanisms of excitotoxicity: involvement of postsynaptic density proteins, radicals, and oxidant molecules. Neuroscience 158:293–300

    Article  PubMed  CAS  Google Scholar 

  17. Cui H, Hayashi A, Sun HS et al (2007) PDZ protein interactions underlying NMDA receptor-mediated excitotoxicity and neuroprotection by PSD-95 inhibitors. J Neurosci 27:9901–9915

    Article  PubMed  CAS  Google Scholar 

  18. Santos SD, Carvalho AL, Caildeira MV, Duarte CB (2009) Regulation of AMPA receptors and synaptic plasticity. Neuroscience 158:105–125

    Article  PubMed  CAS  Google Scholar 

  19. Jane DE, Lodge D, Collingridge GL (2009) Kainate receptors: pharmacology, function and therapeutic potential. Neuropharmacology 56:90–113

    Article  PubMed  CAS  Google Scholar 

  20. Lerma J (2003) Roles and rules of kainate receptors in synaptic transmission. Nat Rev Neurosci 4:481–495

    Article  PubMed  CAS  Google Scholar 

  21. Benarroch EE (2008) Metabotropic glutamate receptors: synaptic modulators and therapeutic targets for neurologic disease. Neurology 70:964–968

    Article  PubMed  Google Scholar 

  22. Pacheco R, Ciruela F, Casadó V et al (2004) Group I metabotropic glutamate receptors mediate a dual role of glutamate in T cell activation. J Biol Chem 279:33352–33358

    Article  PubMed  CAS  Google Scholar 

  23. Conn PJ, Pin JP (1997) Pharmacology and functions of metabotropic glutamate receptors. Annu Rev Pharmacol Toxicol 37:205–237

    Article  PubMed  CAS  Google Scholar 

  24. Knöpfel T, Lukic S, Leonard T, Flor PJ, Kuhn R, Gasparini F (1995) Pharmacological characterization of MCCG and MAP4 at the mGluR1b, mGluR2 and mGluR4a human metabotropic glutamate receptor subtypes. Neuropharmacology 34:1099–1102

    Article  PubMed  Google Scholar 

  25. Toms NJ, Jane DE, Kemp MC, Bedingfield JS, Roberts PJ (1996) The effects of (RS)-alpha-cyclopropyl-4-phosphonophenylglycine ((RS)-CPPG), a potent and selective metabotropic glutamate receptor antagonist. Br J Pharmacol 119:851–854

    PubMed  CAS  Google Scholar 

  26. Siesjö BK, Bengtsson F, Grampp W, Theander S (1989) Calcium, excitotoxins, and neuronal death in brain. Ann NY Acad Sci 568:234–251

    Article  PubMed  Google Scholar 

  27. Nishizawa Y (2001) Glutamate release and neuronal damage in ischemia. Life Sci 69:369–381

    Article  PubMed  CAS  Google Scholar 

  28. McCulloch J (1994) Glutamate receptor antagonists in cerebral ischaemia. J Neural Transm Suppl 43:71–79

    PubMed  CAS  Google Scholar 

  29. Brouns R, De Deyn PP (2009) The complexity of neurobiological processes in acute ischemic stroke. Clin Neurol Neurosurg 111:483–495

    Article  PubMed  CAS  Google Scholar 

  30. Obrenovitch TP, Richards DA (1995) Extracellular neurotransmitter changes in cerebral ischaemia. Cerebvasc Brain Metab Rev 7:1–54

    CAS  Google Scholar 

  31. Shimada N, Graf R, Rosner G, Wakayama A, George CP, Heiss WD (1989) Ischemic flow threshold for extracellular glutamate increase in cat cortex. J Cereb Blood Flow Metab 9:603–606

    Article  PubMed  CAS  Google Scholar 

  32. Jones TH, Morawetz RB, Crowell RM, Marcoux FW, FitzGibbon SJ, DeGirolami U, Ojemann RG (1981) Thresholds of focal cerebral ischemia in awake monkeys. J Neurosurg 54:773–782

    Article  PubMed  CAS  Google Scholar 

  33. Huang R, Hertz L (1994) Effect on anoxia on glutamate formation from glutamine in cultured neurons, dependence on neuronal subtype. Brain Res 660:129–137

    Article  PubMed  CAS  Google Scholar 

  34. Hansen AJ (1985) Effect of anoxia on ion distribution in the brain. Physiol Rev 65:101–148

    PubMed  CAS  Google Scholar 

  35. Kimelberg HK, Mongin AA (1998) Swelling-activated release of excitatory amino acids in the brain, relevance for pathophysiology. Contrib Nephrol 123:240–257

    Article  PubMed  CAS  Google Scholar 

  36. Coffey ET, Sihra TS, Nicholls DG, Pocock JM (1994) Phosphorylation of synapsin I and MARCKS in nerve terminals is mediated by Ca2+ entry via an Aga-GI sensitive Ca2+ channel which is coupled to glutamate exocytosis. FEBS Lett 353:264–268

    Article  PubMed  CAS  Google Scholar 

  37. Mena FV, Baab PJ, Zielke CL, Zielke HR (2000) In vivo glutamine hydrolysis in the formation of extracellular glutamate in the injured rat brain. J Neurosci Res 60:632–641

    Article  PubMed  CAS  Google Scholar 

  38. Rossi DJ, Oshima T, Attwell D (2000) Glutamate release in severe brain ischaemia is mainly by reversed uptake. Nature 403:316–321

    Article  PubMed  CAS  Google Scholar 

  39. Sheldon AL, Robinson MB (2007) The role of glutamate transporters in neurodegenerative diseases and potential opportunities for intervention. Neurochem Int 51:333–355

    Article  PubMed  CAS  Google Scholar 

  40. Ketheeswaranathan P, Turner NA, Spary EJ, Batten TF, McColl BW, Saha S (2011) Changes in glutamate transporter expression in mouse forebrain areas following focal ischemia. Brain Res 1418C:93–103

    Article  CAS  Google Scholar 

  41. Globus MY, Busto R, Dietrich WD, Martinez E, Valdes I, Ginsberg MD (1988) Effect of ischemia on the in vivo release of striatal dopamine, glutamate, and g-aminobutyric acid studied by intracerebral microdialysis. J Neurochem 51:1455–1464

    Article  PubMed  CAS  Google Scholar 

  42. Lucas DR, Newhouse JP (1957) The toxic effect of sodium l-glutamate on the inner layers of the retina. AMA Arch Ophthalmol 58:193–201

    Article  PubMed  CAS  Google Scholar 

  43. Choi DW, Maulucci-Gedde M, Kriegstein AR (1987) Glutamate neurotoxicity in cortical cell culture. J Neurosci 7:357–368

    PubMed  CAS  Google Scholar 

  44. 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 43:1369–1374

    Article  PubMed  CAS  Google Scholar 

  45. Novelli A, Reilly JA, Lysko PG, Henneberry RC (1988) Glutamate becomes neurotoxic via the N-methyl-d-aspartate receptor when intracellular energy levels are reduced. Brain Res 451:205–212

    Article  PubMed  CAS  Google Scholar 

  46. Meldrum B, Evans M, Griffiths T, Simon R (1985) Ischaemic brain damage: the role of excitatory activity and of calcium entry. Br J Anaesth 57:44–46

    Article  PubMed  CAS  Google Scholar 

  47. Hugon J, Vallat JM, Dumas M (1996) Role of glutamate and excitotoxicity in neurologic diseases. Rev Neurol 152:239–248

    PubMed  CAS  Google Scholar 

  48. Furukawa K, Fu W, Li Y, Witke W, Kwiatkowski DJ, Mattson MP (1997) The actin-severing protein gelsolin modulates calcium channel and NMDA receptor activities and vulnerability to excitotoxicity in hippocampal neurons. J Neurosci 17:8178–8186

    PubMed  CAS  Google Scholar 

  49. Dobrek L, Thor P (2011) Glutamate NMDA receptors in pathophysiology and pharmacotherapy of selected nervous system diseases. Postepy Hig Med Dosw 65:338–346

    Google Scholar 

  50. Simeone TA, Sanchez RM, Rho JM (2004) Molecular biology and ontogeny of glutamate receptors in the mammalian central nervous system. J Child Neurol 19:343–360

    Article  PubMed  Google Scholar 

  51. Szydlowska K, Tymianski M (2010) Calcium, ischemia and excitotoxicity. Cell Calcium 47:122–129

    Article  PubMed  CAS  Google Scholar 

  52. Lazarawicz JW (1996) Calcium transients in brain ischemia: role in neuronal injury. Acta Neurobiol Exp 56:299–311

    Google Scholar 

  53. Cano-Abad MF, Villarroya M, García AG, Gabilan NH, López MG (2001) Calcium entry through L-type calcium channels causes mitochondrial disruption and chromaffin cell death. J Biol Chem 276:39695–39704

    Article  PubMed  CAS  Google Scholar 

  54. Yagami T, Ueda K, Sakaeda T et al (2004) Protective effects of a selective L-type voltage -sensitive calcium channel blocker, S-312-d, on neuronal cell death. Biochem Pharmacol 67:1153–1165

    Article  PubMed  CAS  Google Scholar 

  55. Rothman SM, Olney JW (1995) Excitotoxicity and the NMDA receptor—still lethal after eight years. Trends Neurosci 18:57–58

    Article  PubMed  CAS  Google Scholar 

  56. Mizuno F, Barabas P, Krizaj D, Akopian A (2010) Glutamate-induced internalization of Ca(v)13 L-type Ca(2+) channels protects retinal neurons against excitotoxicity. J Physiol 588:953–966

    Article  PubMed  CAS  Google Scholar 

  57. Nash MS, Saunders R, Young KW, Challiss RA, Nahorski SR (2001) Reassessment of the Ca2+ sensing property of a type I metabotropic glutamate receptor by simultaneous measurement of inositol 1,4,5-trisphosphate and Ca2+ in single cells. J Biol Chem 276:19286–19293

    Article  PubMed  CAS  Google Scholar 

  58. Trudeau LE, Parpura V, Haydon PG (1999) Activation of neurotransmitter release in hippocampal nerve terminals during recovery from intracellular acidification. J Neurophysiol 81:2627–2635

    PubMed  CAS  Google Scholar 

  59. Grinstein S, Woodside M, Sardet C, Pouyssegur J, Rotin D (1992) Activation of the Na+/H+ antiporter during cell volume regulation. J Biol Chem 267:23823–23828

    PubMed  CAS  Google Scholar 

  60. Lee BK, Lee DH, Parka S et al (2009) Effects of KR 33028, a novel Na+/H+ exchanger-1 inhibitor, on glutamate-induced neuronal cell death and ischemia induced cerebral infarct. Brain Res 1248:22–30

    Article  PubMed  CAS  Google Scholar 

  61. Favero TG, Zable AC, Abramson JJ (1995) Hydrogen peroxide stimulates the Ca2+ release channel from skeletal muscle sarcoplasmic reticulum. J Biol Chem 270:25557–25563

    Article  PubMed  CAS  Google Scholar 

  62. Celsi F, Pizzo P, Brini M et al (2009) Mitochondria, calcium and cell death: a deadly triad in neurodegeneration. Biochim Biophys Acta 1787:335–344

    Article  PubMed  CAS  Google Scholar 

  63. Mattson MP (2007) Calcium and neurodegeneration. Aging Cell 6:337–350

    Article  PubMed  CAS  Google Scholar 

  64. Kaneko S, Kawakami S, Hara Y et al (2006) A critical role of TRPM2 in neuronal cell death by hydrogen peroxide. J Pharmacol Sci 101:66–76

    Article  PubMed  CAS  Google Scholar 

  65. Naziroğlu M (2007) New molecular mechanisms on the activation of TRPM2 channels by oxidative stress and ADP-ribose. Neurochem Res 32:1990–2001

    Article  PubMed  CAS  Google Scholar 

  66. Du J, Xie J, Yue L (2009) Intracellular calcium activates TRPM2 and its alternative spliced isoforms. Proc Natl Acad Sci USA 106:7239–7244

    Article  PubMed  CAS  Google Scholar 

  67. Bae CY, Sun HS (2011) TRPM7 in cerebral ischemia and potential target for drug development in stroke. Acta Pharmacol Sin 32:725–733

    Article  PubMed  CAS  Google Scholar 

  68. Duchen MR (2000) Mitochondria and calcium: from cell signaling to cell death. J Physiol 1:57–68

    Article  Google Scholar 

  69. Nicholls DG, Johnson-Cadwell L, Vesce S, Jekabsons M, Yadava N (2007) Bioenergetics of mitochondria in cultured neurons and their role in glutamate excitotoxicity. J Neurosci Res 85:3206–3212

    Article  PubMed  CAS  Google Scholar 

  70. Zaidan E, Sims NR (1994) The calcium content of mitochondria from brain subregions following short-term forebrain ischemia and recirculation in the rat. J Neurochem 63:1812–1819

    Article  PubMed  CAS  Google Scholar 

  71. Schild L, Huppelsberg J, Kahlert S, Keilhoff G, Reiser G (2003) Brain mitochondria are primed by moderate Ca2+ rise upon hypoxia/reoxygenation for functional breakdown and morphological disintegration. J Biol Chem 278:25454–25460

    Article  PubMed  CAS  Google Scholar 

  72. Li CY, Chin TY, Chueh SH (2004) Rat cerebellar granule cells are protected from glutamate-induced excitotoxicity by S-nitrosoglutathione but not glutathione. Am J Physiol Cell Physiol 286:893–904

    Article  Google Scholar 

  73. Bernardi P, Scorrano L, Colonna R, Petronilli V, Di Lisa F (1999) Mitochondria and cell death. Mechanistic aspects and methodological issues. Eur J Biochem 264:687–701

    Article  PubMed  CAS  Google Scholar 

  74. Robertson CL, Bucci CJ, Fiskum G (2004) Mitochondrial response to calcium in the developing brain. Brain Res Dev Brain Res 151:141–148

    Article  PubMed  CAS  Google Scholar 

  75. Hansson MJ, Mattiasson G, Månsson R et al (2004) The nonimmunosuppressive cyclosporin analogs NIM811 and UNIL025 display nanomolar potencies on permeability transition in brain-derived mitochondria. J Bioenerg Biomembr 36:407–413

    Article  PubMed  CAS  Google Scholar 

  76. Schinzel AC, Takeuchi O, Huang Z et al (2005) Cyclophilin D is a component of mitochondrial permeability transition and mediates neuronal cell death after focal cerebral ischemia. Proc Natl Acad Sci USA 102:12005–12010

    Article  PubMed  CAS  Google Scholar 

  77. Robertson CL, Scafidi S, McKenna MC, Fiskum G (2009) Mitochondrial mechanisms of cell death and neuroprotection in pediatric ischemic and traumatic brain injury. Exp Neurol 218:371–380

    Article  PubMed  CAS  Google Scholar 

  78. Love S (2003) Apoptosis and brain ischaemia. Prog Neuro-psychopharmacol Biol Psychiatry 27:267–282

    Article  CAS  Google Scholar 

  79. Li SY, Jia YH, Sun WG et al (2010) Stabilization of mitochondrial function by tetramethylpyrazine protects against kainate-induced oxidative lesions in the rat hippocampus. Free Radic Biol Med 48:597–608

    Article  PubMed  CAS  Google Scholar 

  80. Le DA, Wu Y, Huang Z et al (2002) Caspase activation and neuroprotection in caspase-3-deficient mice after in vivo cerebral ischemia and in vitro oxygen glucose deprivation. Proc Natl Acad Sci USA 99:15188–15193

    Article  PubMed  CAS  Google Scholar 

  81. Ma J, Endres M, Moskowitz MA (1998) Synergistic effects of caspase inhibitors and MK-801 in brain injury after transient focal cerebral ischaemia in mice. Br J Pharmacol 124:756–762

    Article  PubMed  CAS  Google Scholar 

  82. Kerr LE, McGregor AL, Amet LE et al (2004) Mice overexpressing human caspase 3 appear phenotypically normal but exhibit increased apoptosis and larger lesion volumes in response to transient focal cerebral ischaemia. Cell Death Differ 11:1102–1111

    Article  PubMed  CAS  Google Scholar 

  83. Rosell A, Cuadrado E, Alvarez-Sabin J et al (2008) Caspase-3 is related to infarct growth after human ischemic stroke. Neurosci Lett 430:1–6

    Article  PubMed  CAS  Google Scholar 

  84. Zhang Y, Bhavnani BR (2005) Glutamate-induced apoptosis in primary cortical neurons is inhibited by equine estrogens via down-regulation of caspase-3 and prevention of mitochondrial cytochrome c release. BMC Neurosci 24:6–13

    Google Scholar 

  85. Czogalla A, Sikorski AF (2005) Spectrin and calpain: a ‘target’ and a ‘sniper’ in the pathology of neuronal cells. Cell Mol Life Sci 62:1913–1924

    Article  PubMed  CAS  Google Scholar 

  86. Jiang SX, Zheng RY, Zeng JQ, Li XL, Han Z, Hou ST (2010) Reversible inhibition of intracellular calcium influx through NMDA receptors by imidazoline I(2) receptor antagonists. Eur J Pharmacol 629:12–19

    Article  PubMed  CAS  Google Scholar 

  87. Bhatt A, Kaverina I, Otey C, Huttenlocher A (2002) Regulation of focal complex composition and disassembly by the calcium-dependent protease calpain. J Cell Sci 115:3415–3425

    PubMed  CAS  Google Scholar 

  88. Gores GJ, Miyoshi H, Botla R, Aguilar HI, Bronk SF (1998) Induction of the mitochondrial permeability transition as a mechanism of liver injury during cholestasis: a potential role for mitochondrial proteases. Biochim Biophys Acta 1366:167–175

    Article  PubMed  CAS  Google Scholar 

  89. Ray SK, Wilford GG, Crosby CV, Hogan EL, Banik NL (1999) Diverse stimuli induce calpain overexpression and apoptosis in C6 glioma cells. Brain Res 829:18–27

    Article  PubMed  CAS  Google Scholar 

  90. Hara MR, Snyder SH (2007) Cell signaling and neuronal death. Annu Rev Pharmacol Toxicol 47:117–141

    Article  PubMed  CAS  Google Scholar 

  91. Xu W, Wong TP, Chery N, Gaertner T, Wang YT, Baudry M (2007) Calpain-mediated mGluR1alpha truncation: a key step in excitotoxicity. Neuron 53:399–412

    Article  PubMed  CAS  Google Scholar 

  92. Bano D, Munarriz E, Chen HL et al (2007) The plasma membrane Na+/Ca2+ exchanger is cleaved by distinct protease families in neuronal cell death. Ann NY Acad Sci 1099:451–455

    Article  PubMed  CAS  Google Scholar 

  93. Gerencser AA, Mark KA, Hubbard AE et al (2009) Real-time visualization of cytoplasmic calpain activation and calcium deregulation in acute glutamate excitotoxicity. J Neurochem 110:990–1004

    Article  PubMed  CAS  Google Scholar 

  94. Small DL, Morley P, Buchan MA (1999) Biology of ischemic cerebral cell death. Prog Cardiovasc Dis 42:185–207

    Article  PubMed  CAS  Google Scholar 

  95. Wu HY, Tomizawa K, Oda Y et al (2004) Critical role of calpain-mediated cleavage of calcineurin in excitotoxic neurodegeneration. J Biol Chem 279:4929–4940

    Article  PubMed  CAS  Google Scholar 

  96. Kim MJ, Jo DG, Hong GS et al (2002) Calpain-dependent cleavage of cain/cabin1 activates calcineurin to mediate calcium-triggered cell death. Proc Natl Acad Sci USA 99:9870–9875

    Article  PubMed  CAS  Google Scholar 

  97. Wood DE, Thomas A, Devi LA et al (1998) Bax cleavage is mediated by calpain during drug-induced apoptosis. Oncogene 17:1069–1078

    Article  PubMed  CAS  Google Scholar 

  98. Chan SL, Mattson MP (1999) Caspase and calpain substrates: roles in synaptic plasticity and cell death. J Neurosci Res 58:167–190

    Article  PubMed  CAS  Google Scholar 

  99. Neumar RW, Xu YA, Gada H, Guttmann RP, Siman R (2003) Cross-talk between calpain and caspase proteolytic systems during neuronal apoptosis. J Biol Chem 278:14162–14167

    Article  PubMed  CAS  Google Scholar 

  100. Blomgren K, Zhu C, Wang X et al (2001) Synergistic activation of caspase-3 by m-calpain after neonatal hypoxia–ischemia: a mechanism of “pathological apoptosis”? J Biol Chem 276:10191–10198

    Article  PubMed  CAS  Google Scholar 

  101. Wang KK, Posmantur R, Nath R et al (1998) Simultaneous degradation of αII- and βII-spectrin by caspase 3 (CPP32) in apoptotic cells. J Biol Chem 273:22490–22497

    Article  PubMed  CAS  Google Scholar 

  102. McCord JM, Roy RS, Schaffer SW (1985) Free radicals and myocardial ischemia. The role of xanthine oxidase. Adv Myocardiol 5:183–189

    PubMed  CAS  Google Scholar 

  103. Won SJ, Kim DY, Gwag BJ (2002) Cellular and molecular pathways of ischemic neuronal death. J Biochem Mol Biol 35:67–86

    Article  PubMed  CAS  Google Scholar 

  104. Frederickson CJ, Moncrieff DW (1994) Zinc-containing neurons. Biol Signals 3:127–139

    Article  PubMed  CAS  Google Scholar 

  105. Suh SW, Chen JW, Motamedi M et al (2000) Evidence that synoptically-released zinc contributes to neuronal injury after traumatic brain injury. Brain Res 852:268–273

    Article  PubMed  CAS  Google Scholar 

  106. Colvin RA, Davis N, Nipper RW, Carter PA (2000) Zinc transport in the brain: routes of zinc influx and efflux in neurons. J Nutr 130:1484–1487

    Google Scholar 

  107. Shuttleworth CW, Weiss JH (2011) Zinc: new clues to diverse roles in brain ischemia. Trends Pharmacol Sci 32:480–486

    Article  PubMed  CAS  Google Scholar 

  108. Rothman SM, Yamada KA, Lancaster N (1993) Nordihydroguaiaretic acid attenuates NMDA neurotoxicity—action beyond the receptor. Neuropharmacology 32:1279–1288

    Article  PubMed  CAS  Google Scholar 

  109. Miettinen S, Fusco FR, Yrjänheikki J et al (1997) Spreading depression and focal brain ischemia induce cyclooxygenase-2 in cortical neurons through N-methyl-d-aspartic acid-receptors and phospholipase A2. Proc Natl Acad Sci USA 94:6500–6505

    Article  PubMed  CAS  Google Scholar 

  110. Ikeda-Matsuo Y, Hirayama Y, Ota A, Uematsu S, Akira S, Sasaki Y (2010) Microsomal prostaglandin E synthase-1 and cyclooxygenase-2 are both required for ischaemic excitotoxicity. Br J Pharmacol 159:1174–1186

    Article  PubMed  CAS  Google Scholar 

  111. Iadecola C, Niwa K, Nogawa S et al (2001) Reduced susceptibility to ischemic brain injury and N-methyl-d-aspartate-mediated neurotoxicity in cyclooxygenase-2-deficient mice. Proc Natl Acad Sci USA 98:1294–1299

    Article  PubMed  CAS  Google Scholar 

  112. Christopherson KS, Hillier BJ, Lim WA, Bredt DS (1999) PSD-95 assembles a ternary complex with the N-methyl-d-aspartic acid receptor and a bivalent neuronal NO synthase PDZ domain. J Biol Chem 274:27467–27473

    Article  PubMed  CAS  Google Scholar 

  113. Dawson VL, Dawson TM, London ED, Bredt DS, Snyder SH (1991) Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures. Proc Natl Acad Sci USA 88:6368–6371

    Article  PubMed  CAS  Google Scholar 

  114. Bredt DS (1996) NO NMDA receptor activity. Nat Biotechnol 14:944

    Article  PubMed  CAS  Google Scholar 

  115. Guix FX, Uribesalgo I, Coma M, Muňoz FJ (2005) The physiology and pathophysiology of nitric oxide in the brain. Prog Neurobiol 76:126–152

    Article  PubMed  CAS  Google Scholar 

  116. Haynes V, Elfering SL, Squires RJ et al (2003) Mitochondrial nitric-oxide synthase: role in pathophysiology. IUBMB Life 55:599–603

    Article  PubMed  CAS  Google Scholar 

  117. Llansola M, Felipo V (2010) Metabotropic glutamate receptor 5, but not 1, modulates NMDA receptor-mediated activation of neuronal nitric oxide synthase. Neurochem Int 56:535–545

    Article  PubMed  CAS  Google Scholar 

  118. Gutiérrez-Martín Y, Martín-Romero FJ, Henao F, Gutiérrez-Merino C (2005) Alteration of cytosolic free calcium homeostasis by SIN-1: high sensitivity of L-type Ca2+ channels to extracellular oxidative/nitrosative stress in cerebellar granule cells. J Neurochem 92:973–989

    Article  PubMed  CAS  Google Scholar 

  119. Lovs S (1999) Oxidative stress in brain ischemia. Brain Pathol 9:119–131

    Google Scholar 

  120. Gepdiremen A, Hacimuftuoglu A, Buyukokuroglu ME, Suleyman H (2002) Nitric oxide donor sodium nitroprusside induces neurotoxicity in cerebellar granular cell culture in rats by an independent mechanism from L-type or dantrolene-sensitive calcium channels. Biol Pharm Bull 25:1295–1297

    Article  PubMed  CAS  Google Scholar 

  121. Frandsen A, Andersen CF, Schousboe A (1992) Possible role of cGMP in excitatory amino acid induced cytotoxicity in cultured cerebral cortical neurons. Neurochem Res 17:35–43

    Article  PubMed  CAS  Google Scholar 

  122. Montoliu C, Llansola M, Kosenko E, Corbalán R, Felipo V (1999) Role of cyclic GMP in glutamate neurotoxicity in primary cultures of cerebellar neurons. Neuropharmacology 38:1883–1891

    Article  PubMed  CAS  Google Scholar 

  123. Itoh T, Itoh A, Horiuchi K, Pleasure D (1998) AMPA receptor-mediated excitotoxicity in human NT2-N neurons results from loss of intracellular Ca2+ homeostasis following marked elevation of intracellular Na+. J Neurochem 71:112–124

    Article  PubMed  CAS  Google Scholar 

  124. Lin CH, Chen PS, Gean PW (2008) Glutamate preconditioning prevents neuronal death induced by combined oxygen–glucose deprivation in cultured cortical neurons. Eur J Pharmacol 589:85–93

    Article  PubMed  CAS  Google Scholar 

  125. Bae JH, Mun KC, Park WK et al (2002) EGCG attenuates AMPA-induced intracellular calcium increase in hippocampal neurons. Biochem Biophys Res Commun 290:1506–1512

    Article  PubMed  CAS  Google Scholar 

  126. Endres M, Dirnagl U (2003) Ischemia and stroke. In: Alzheimer C (ed) Molecular and cellular biology of neuroprotection in the CNS. Advances in experimental medicine and biology. Kluwer, New York, pp 455–473

    Google Scholar 

  127. Tang Y, Lu A, Aronow BJ, Wagner KR, Sharp FR (2002) Genomic responses of the brain to ischemic stroke, intracerebral hemorrhage, kainate seizures, hypoglycaemia, and hypoxia. Eur J Neurosci 15:1937–1952

    Article  PubMed  Google Scholar 

  128. Mohammadi S, Pavlik A, Krajci D, Al-Sarraf H (2009) NMDA preconditioning and neuroprotection in vivo: delayed onset of kainic acid-induced neurodegeneration and c-Fos attenuation in CA3a neurons. Brain Res 1256:162–172

    Article  PubMed  CAS  Google Scholar 

  129. Blanco M, Lizasoain I, Sobrino T, Vivancos J, Castillo J (2006) Ischemic preconditioning: a novel target for neuroprotective therapy. Cerebrovasc Dis 21:38–47

    Article  PubMed  CAS  Google Scholar 

  130. Andrade AL, Rossi DJ (2010) Simulated ischaemia induces Ca2+-independent glutamatergic vesicle release through actin filament depolymerization in area CA1 of the hippocampus. J Physiol 588:1499–1514

    Article  PubMed  CAS  Google Scholar 

  131. Liu AJ, Hu YY, Li WB, Xu J, Zhang M (2011) Cerebral ischemic pre-conditioning enhances the binding characteristics and glutamate uptake of glial glutamate transporter-1 in hippocampal CA1 subfield of rats. J Neurochem 119:202–209

    Article  PubMed  CAS  Google Scholar 

  132. Zhang M, Li WB, Geng JX et al (2007) The upregulation of glial glutamate transporter-1 participates in the induction of brain ischemic tolerance in rats. J Cereb Blood Flow Metab 27:1352–1368

    Article  PubMed  CAS  Google Scholar 

  133. Beurrier C, Faideau M, Bennouar KE et al (2010) Ciliary neurotrophic factor protects striatal neurons against excitotoxicity by enhancing glial glutamate uptake. PLoS One 5:8550

    Article  CAS  Google Scholar 

  134. Chen M, Lu T, Chen X et al (2008) Differential roles of NMDA receptor subtypes in ischemic neuronal cell death and ischemic tolerance. Stroke 39:3042–3048

    Article  PubMed  CAS  Google Scholar 

  135. Barone FC, White RF, Spera PA et al (1998) Ischemic preconditioning and brain tolerance: temporal histological and functional outcomes, protein synthesis requirement, and interleukin-1 receptor antagonist and early gene expression. Stroke 29:1937–1950

    Article  PubMed  CAS  Google Scholar 

  136. Mabuchi T, Kitagawa K, Kuwabara K (2001) Phosphorylation of cAMP response element-binding protein in hippocampal neurons as a protective response after exposure to glutamate in vitro and ischemia in vivo. J Neurosci 21:9204–9213

    PubMed  CAS  Google Scholar 

  137. Fujino T, Lee WC, Nedivi E (2003) Regulation of CPG15 by signaling pathways that mediate synaptic plasticity. Mol Cell Neurosci 24:538–554

    Article  PubMed  CAS  Google Scholar 

  138. Putz U, Harwell C, Nedivi E (2005) Soluble CPG15 expressed during early development rescues cortical progenitors from apoptosis. Nat Neurosci 8:322–331

    Article  PubMed  CAS  Google Scholar 

  139. Zausinger S, Schöller K, Plesnila N, Schmid-Elsaesser R (2003) Combination drug therapy and mild hypothermia after transient focal cerebral ischemia in rats. Stroke 34:2246–2251

    Article  PubMed  CAS  Google Scholar 

  140. Takeuchi H, Jin S, Suzuki H et al (2008) Blockade of microglial glutamate release protects against ischemic brain injury. Exp Neurol 214:144–146

    Article  PubMed  CAS  Google Scholar 

  141. Ghoddoussi F, Galloway MP, Jambekar A, Bame M, Needleman R, Brusilow WS (2010) Methionine sulfoximine, an inhibitor of glutamine synthetase, lowers brain glutamine and glutamate in a mouse model of ALS. J Neurol Sci 290:41–47

    Article  PubMed  CAS  Google Scholar 

  142. Huang R, Hertz L (1995) Neuroprotective effect of phenylsuccinate, an inhibitor of cytosolic glutamate formation from glutamine, under anoxic conditions but not during exposure to exogenous glutamate. Neurosci Lett 183:22–26

    Article  PubMed  CAS  Google Scholar 

  143. Lin TY, Lu CW, Wang SJ (2009) Inhibitory effect of glutamate release from rat cerebrocortical synaptosomes by dextromethorphan and its metabolite 3-hydroxymorphinan. Neurochem Int 54:526–534

    Article  PubMed  CAS  Google Scholar 

  144. Lai PC, Huang YT, Wu CC, Lai CJ, Wang PJ, Chiu TH (2011) Ceftriaxone attenuates hypoxic-ischemic brain injury in neonatal rats. J Biomed Sci 18:69

    Article  PubMed  CAS  Google Scholar 

  145. Guan T, Qian Y, Tang X et al (2011) Maslinic acid, a natural inhibitor of glycogen phosphorylase, reduces cerebral ischemic injury in hyperglycemic rats by GLT-1 up-regulation. J Neurosci Res 89:1829–1839

    Article  PubMed  CAS  Google Scholar 

  146. Verma R, Mishra V, Gupta K, Sasmal D, Raghubir R (2011) Neuroprotection by rosiglitazone in transient focal cerebral ischemia might not be mediated by glutamate transporter-1. J Neurosci Res 89:1849–1858

    Article  PubMed  CAS  Google Scholar 

  147. Petty MA, Neumann-Haefelin C, Kalisch J, Sarhan S, Wettstein JG, Juretschke HP (2003) In vivo neuroprotective effects of ACEA 1021 confirmed by magnetic resonance imaging in ischemic stroke. Eur J Pharmacol 474:53–62

    Article  PubMed  CAS  Google Scholar 

  148. Fang JH, Wang XH, Xu ZR, Jiang FG (2010) Neuroprotective effects of bis(7)-tacrine against glutamate-induced retinal ganglion cells damage. BMC Neurosci 11:31

    Article  PubMed  CAS  Google Scholar 

  149. Muir KW, Grosset DG, Gamzu E, Lees KR (1994) Pharmacological effects of the non-competitive NMDA antagonist CNS 1102 in normal volunteers. Br J Clin Pharmacol 38:33–38

    PubMed  CAS  Google Scholar 

  150. Keller M, Griesmaier E, Auer M et al (2008) Dextromethorphan is protective against sensitized N-methyl-d-aspartate receptor-mediated excitotoxic brain damage in the developing mouse brain. Eur J Neurosci 27:874–883

    Article  PubMed  Google Scholar 

  151. Olney JW (1994) Neurotoxicity of NMDA receptor antagonists: an overview. Psychopharmacol Bull 30:533–540

    PubMed  CAS  Google Scholar 

  152. Warach S, Kaufman D, Chiu D et al (2006) Effect of the glycine antagonist gavestinel on cerebral infarcts in acute stroke patients, a randomized placebo-controlled trial: The GAIN MRI Substudy. Cerebrovasc Dis 21:106–111

    Article  PubMed  CAS  Google Scholar 

  153. Shibuta S, Varathan S, Mashimo T (2006) Ketamine and thiopental sodium: individual and combined neuroprotective effects on cortical cultures exposed to NMDA or nitric oxide. Br J Anaesth 97:517–524

    Article  PubMed  CAS  Google Scholar 

  154. Ovbiagele B, Kidwell CS, Starkman S, Saver JL (2003) Neuroprotective agents for the treatment of acute ischemic stroke. Curr Neurol Neurosci Rep 3:9–20

    Article  PubMed  Google Scholar 

  155. Babu CS, Ramanathan M (2009) Pre-ischemic treatment with memantine reversed the neurochemical and behavioural parameters but not energy metabolites in middle cerebral artery occluded rats. Pharmacol Biochem Behav 92:424–432

    Article  PubMed  CAS  Google Scholar 

  156. Park CK, Nehls DG, Graham DI, Teasdale GM, McCulloch J (1988) Focal cerebral ischaemia in the cat: treatment with the glutamate antagonist MK-801 after induction of ischaemia. J Cereb Blood Flow Metab 8:757–762

    Article  PubMed  CAS  Google Scholar 

  157. Bannan PE, Graham DI, Lees KR, McCulloch J (1994) Neuroprotective effect of remacemide hydrochloride in focal cerebral ischemia in the cat. Brain Res 664:271–275

    Article  PubMed  CAS  Google Scholar 

  158. Yurkewicz L, Weaver J, Bullock MR, Marshall LF (2005) The effect of the selective NMDA receptor antagonist traxoprodil in the treatment of traumatic brain injury. J Neurotrauma 22:1428–1443

    Article  PubMed  Google Scholar 

  159. Gill R, Nordholm L, Lodge D (1992) The neuroprotective actions of 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX) in a rat focal ischaemia model. Brain Res 580:35–43

    Article  PubMed  CAS  Google Scholar 

  160. Montero M, Nielsen M, Rønn LC, Møller A, Noraberg J, Zimmer J (2007) Neuroprotective effects of the AMPA antagonist PNQX in oxygen–glucose deprivation in mouse hippocampal slice cultures and global cerebral ischemia in gerbils. Brain Res 1177:124–135

    Article  PubMed  CAS  Google Scholar 

  161. O’Neill MJ, Bogaert L, Hicks CA et al (2000) LY377770, a novel iGlu5 kainate receptor antagonist with neuroprotective effects in global and focal cerebral ischaemia. Neuropharmacology 39:1575–1588

    Article  PubMed  Google Scholar 

  162. Koh JY, Palmer E, Cotman CW (1991) Activation of the metabotropic glutamate receptor attenuates N-methyl-d-aspartate neurotoxicity in cortical cultures. Proc Natl Acad Sci USA 88:9431–9435

    Article  PubMed  CAS  Google Scholar 

  163. Bao WL, Williams AJ, Faden AI, Tortella FC (2001) Selective mGluR5 receptor antagonist or agonist provides neuroprotection in a rat model of focal cerebral ischemia. Brain Res 922:173–179

    Article  PubMed  CAS  Google Scholar 

  164. Bond A, Ragumoorthy N, Monn JA et al (1999) LY379268, a potent and selective group II metabotropic glutamate receptor agonist, is neuroprotective in gerbil global, but not focal, cerebral ischaemia. Neurosci Lett 273:191–194

    Article  PubMed  CAS  Google Scholar 

  165. Sabelhaus CF, Schröder UH, Breder J, Henrich-Noack P, Reymann KG (2000) Neuroprotection against hypoxic/hypoglycaemic injury after the insult by the group III metabotropic glutamate receptor agonist (R,S)-4-phosphonophenylglycine. Br J Pharmacol 131:655–658

    Article  PubMed  CAS  Google Scholar 

  166. Kohara A, Takahashi M, Yatsugi S et al (2008) Neuroprotective effects of the selective type 1 metabotropic glutamate receptor antagonist YM-202074 in rat stroke models. Brain Res 1191:168–179

    Article  PubMed  CAS  Google Scholar 

  167. Aronowski J, Strong R, Grotta JC (1996) Combined neuroprotection and reperfusion therapy for stroke. Effect of lubeluzole and diaspirin cross-linked hemoglobin in experimental focal ischemia. Stroke 27:1571–1576

    Article  PubMed  CAS  Google Scholar 

  168. Bach A, Eildal JN, Stuhr-Hansen N et al (2011) Cell-permeable and plasma-stable peptidomimetic inhibitors of the postsynaptic density-95/N-methyl-d-aspartate receptor interaction. J Med Chem 54:1333–1346

    Article  PubMed  CAS  Google Scholar 

  169. Duzenli S, Bakuridze K, Gepdiremen A (2005) The effects of ruthenium red, dantrolen and nimodipine alone or in combination, in NMDA-induced neurotoxicity of cerebella granular cell culture of rats. Toxicol In Vitro 19:589–594

    Article  PubMed  CAS  Google Scholar 

  170. Funato H, Katsuki Y, Yano T et al (1996) Effects of lacidipine, a new dihydropyridipine derivative, on various cerebral ischemia models. Nippon Yakurigaku Zasshi 108:243–257

    Article  PubMed  CAS  Google Scholar 

  171. Choi SK, Lee GJ, Choi S, Kim YJ, Park HK, Park BJ (2011) Neuroprotective effects by nimodipine treatment in the experimental global ischemic rat model: real time estimation of glutamate. J Korean Neurosurg Soc 49:1–7

    Article  PubMed  CAS  Google Scholar 

  172. Kiewert C, Hartmann J, Stoll J, Thekkumkara TJ, Van der Schyf CJ, Klein J (2006) NGP1-01 is a brain-permeable dual blocker of neuronal voltage- and ligand-operated calcium channels. Neurochem Res 31:395–399

    Article  PubMed  CAS  Google Scholar 

  173. Ginsberg MD (2008) Neuroprotection for ischemic stroke: past, present and future. Neuropharmacology 55:363–389

    Article  PubMed  CAS  Google Scholar 

  174. Hoyte L, Barber PA, Buchan AM, Hill MD (2004) The rise and fall of NMDA antagonists for ischemic stroke. Curr Mol Med 4:131–136

    Article  PubMed  CAS  Google Scholar 

  175. Walters MR, Kaste M, Lees KR et al (2005) The AMPA antagonist ZK 200775 in patients with acute ischaemic stroke: a double-blind, multicentre, placebo-controlled safety and tolerability study. Cerebrovasc Dis 20:304–309

    Article  PubMed  CAS  Google Scholar 

  176. Elting JW, Sulter GA, Kaste M et al (2002) AMPA antagonist ZK200775 in patients with acute ischemic stroke: possible glial cell toxicity detected by monitoring of S-100B serum levels. Stroke 33:2813–2818

    Article  PubMed  CAS  Google Scholar 

  177. Byrnes KR, Loane DJ, Faden AI (2009) Metabotropic glutamate receptors as targets for multipotential treatment of neurological disorders. Neurotherapeutics 6:94–107

    Article  PubMed  CAS  Google Scholar 

  178. Matsumoto Y, Yamamoto S, Suzuki Y et al (2004) Na+/H+ exchanger inhibitor, SM-20220, is protective against excitotoxicity in cultured cortical neurons. Stroke 35:185–190

    Article  PubMed  CAS  Google Scholar 

  179. Govoni S, Trabucchi M, Battaini F, Magnoni MS, Paoletti R (1986) Vascular and neuronal mechanisms of calcium antagonists. Significance in neurological therapy. Minerva Med 77:1053–1058

    PubMed  CAS  Google Scholar 

  180. Alps BJ (1992) Drugs acting on calcium channels: potential treatment for ischemic stroke. Br J Clin Pharmacol 34:199–206

    PubMed  CAS  Google Scholar 

  181. Dawson VL, Kizushi VM, Huang PL, Snyder SH, Dawson TM (1996) Resistance to neurotoxicity in cortical cultures from neuronal nitric oxide synthase-deficient mice. J Neurosci 16:2479–2487

    PubMed  CAS  Google Scholar 

  182. Rothwell PM, Algra A, Amarenco P (2011) Medical treatment in acute and long-term secondary prevention after transient ischaemic attack and ischaemic stroke. Lancet 377:1681–1692

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Botros B. Kostandy.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kostandy, B.B. The role of glutamate in neuronal ischemic injury: the role of spark in fire. Neurol Sci 33, 223–237 (2012). https://doi.org/10.1007/s10072-011-0828-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10072-011-0828-5

Keywords

Navigation