Advertisement

Excitotoxicity in Cerebral Ischemia

  • Domenico E. Pellegrini-Giampietro
  • Elena Meli
  • Flavio Moroni

Abstract

The hypothesis that cerebral ischemia may recognize an excitoxic pathophysiological component is supported by a number of consolidated arguments, including the neuroprotective activity of glutamate receptor antagonists in experimental animal models and the use of anti-excitotoxic agents in clinical trials for stroke. Despite the dramatic results in the preclinical setting, phase III clinical trials with neuroprotective drugs have been generally unsuccessful so far. Several complicating variables have been put forward to explain this discrepancy, including population heterogeneity, morphological and functional differences between human and animal brain, and side-effects of the tested compounds that prevent reaching effective plasma concentrations. Fine-tuning in the design of clinical trials, the use of imaging techniques for the evaluation of human brain injury, and the development of more appropriate experimental animal models are among the strategies that need to be utilized in future clinical studies. Also, drugs with a better therapeutic index and aimed at alternative targets in the excitotoxic cascade appear to be required. In our laboratory, we have recently investigated two alternative mechanisms promoted by extracellular glutamate that lead to post-ischemic neuronal damage: (1) the stimulation of mGlu1 receptors and (2) the overactivation of poly(ADP-ribose) polymerase.

Keywords

cerebral ischemia stroke glutamate receptors free radicals poly(ADP-ribose) polymerase 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Alagarsamy S, Marino MJ, Rouse ST, Gereau RW, IV, Heinemann SF, Conn PJ (1999) Activation of NMDA receptors reverses desensitization of mGluR5 in native and recombinant systems. Nat Neurosci 2:234–240.PubMedCrossRefGoogle Scholar
  2. Attucci S, Carla V, Mannaioni G, Moroni F (2001) Activation of type 5 metabotropic glutamate receptors enhances NMDA responses in mice cortical wedges. Brit J Pharmacol 132:799–806.CrossRefGoogle Scholar
  3. Benveniste H, Drejer J, Schousboe A, Diemer N (1984) Elevation of extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis. J Neurochem 43: 1369–1374.PubMedCrossRefGoogle Scholar
  4. Bruno V, Battaglia G, Kingston AE, O’Neill MJ, Catania MV, Di Grezla R, Nicoletti F (1999) Neuroprotective activity of the potent and selective mGlu1a metabotropic glutamate receptor antagonist, (+)-2-methyl-4-carboxyphenylglycine (LY367385): comparison with LY357366, a broader spectrum antagonist with equal affinity for mGlu1a and mGlu5 receptors. Neuropharmacology 38: 199–207.PubMedCrossRefGoogle Scholar
  5. Bruno V, Ksiazek I, Battaglia G, Lukic S, Leonhardt T, Sauer D, Gasparini F, Kuhn R, Nicoletti F, Flor PJ (2000) Selective blockade of metabotropic glutamate receptor subtype 5 is neuroprotective. Neuropharmacology 39:2223–2230.PubMedCrossRefGoogle Scholar
  6. Buchan A, Pulsinelli WA (1990) Hypothermia but not the N-methyl-D-aspartate antagonist, MK-801, attenuates neuronal damage in gerbils subjected to transient global ischemia. J Neurosci 10:311–316.PubMedGoogle Scholar
  7. Cao X, Phillis JW (1994) α-Phenyl-tert-butyl-nitrone reduces cortical infarct and edema in rats subjected to focal ischemia. Brain Res 644:267–272.PubMedCrossRefGoogle Scholar
  8. Charriaut-Marlangue C, Aggoun-Zouaoui D, Represa A, Ben-Ari Y (1996) Apoptotic features of selective neuronal death in ischemia, epilepsy and gpl20 toxicity. Trends Neurosci 19:109–114.PubMedCrossRefGoogle Scholar
  9. Chauhan N, Zhao Z, Barber PA, Buchan AM (2003) Lessons in experimental ischemia for clinical stroke medicine. Curr Opin Neurol 16:65–71.PubMedCrossRefGoogle Scholar
  10. Chiarugi A (2002) Poly(ADP-ribose) polymerase: killer or conspirator? The ‘suicide hypothesis’ revisited. Trends Pharmacol Sci 23:122–129.PubMedCrossRefGoogle Scholar
  11. Chiarugi A, Meli E, Calvani M, Picca R, Baronti R, Camaioni E, Costantino G, Marinozzi M, Pellegrini-Giampiero DE, Pellicciari R, Moroni F (2003) Novel isoquinolinone-derived inhibitors of poly(ADP-ribose) polymerase-I: pharmacological characterization and neuroprotective effects in an in vitro model of cerebral ischemia. J Pharmacol Exp TherGoogle Scholar
  12. Choi D (1990) Cerebral hypoxia: some new approaches and unanswered questions. J Neurosci 10:2493–2501.PubMedGoogle Scholar
  13. Choi DW (1988) Glutamate neurotoxicity and diseases of the nervous system. Neuron 1:623–634.PubMedCrossRefGoogle Scholar
  14. Choi DW (1995) Calcium: still center-stage in hypoxic-ischemic neuronal death. Trends Neurosci 18:58–60.PubMedCrossRefGoogle Scholar
  15. Choi DW (1996) Ischemia-induced neuronal apoptosis. Curr Opin Neurobiol 6:667–672.PubMedCrossRefGoogle Scholar
  16. Clemens JA, Stephenson DT, Dixon EP, Smalstig EB, Mincy RE, Rash KS, Little SP (1997) Global cerebral ischemia activates nuclear factor-kappa B prior to evidence of DNA fragmentation. Brain Res Mol Brain Res 48:187–196.PubMedCrossRefGoogle Scholar
  17. Cosi C, Suzuki H, Milani D, Facci L, Menegazzi M, Vantini G, Kanai Y, Skaper SD (1994) Poly(ADP-ribose) polymerase: early involvement in glutamate-induced neurotoxicity in cultured cerebellar granule cells. J Neurosci Res 39:38–46.PubMedCrossRefGoogle Scholar
  18. Cregan SP, Fortin A, MacLaurin JG, Callaghan SM, Cecconi F, Yu SW, Dawson TM, Dawson VL, Park DS, Kroemer G, Slack RS (2002) Apoptosis-inducing factor is involved in the regulation of caspase-independent neuronal cell death. J Cell Biol 158:507–517.PubMedCrossRefGoogle Scholar
  19. Crumrine RC, Thomas AL, Morgan PF (1994) Attenuation of p53 expression protects against focal ischemic damage in transgenic mice. J Cereb Blood Flow Metab 14:887–891.PubMedCrossRefGoogle Scholar
  20. De Keyser J, Suiter G, Luiten PG (1999) Clinical trials with neuroprotective drugs in acute ischemic stroke: are we doing the right thing? Trends Neurosci 22:535–540.PubMedCrossRefGoogle Scholar
  21. de Murcia G, Schreiber V, Molinete M, Saulier B, Poch O, Masson M, Niedergang C, Ménissier-de Murcia j (1994) Structure and function of poly(ADP-ribose) polymerase. Mol Cell Biochem 138:15–24.Google Scholar
  22. Dirnagl U, Iadecola C, Moskowitz MA (1999) Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci 22:391–397.PubMedCrossRefGoogle Scholar
  23. Doble A (1999) The role of excitotoxicity in neurodegenerative disease: implications for therapy. Pharmacol Ther 81:163–221.PubMedCrossRefGoogle Scholar
  24. Doherty AJ, Palmer MJ, Henley JM, Collingridge GL, Jane DE (1997) (RS)-2-Chloro-5 hydroxyphenylglycine (CHPG) activates mGlu5, but not mGlu1, receptors expressed in CHO cells and potentiates NMDA responses in the hippocampus. Neuropharmacology 36:265–267.PubMedCrossRefGoogle Scholar
  25. Ehrenreich H, Hasselblatt M, Dembowski C, Cepek L, Lewczuk P, Stiefel M, Rustenbeck HH, Breiter N, Jacob S, Knerlich F, Bohn M, Poser W, Ruther E, Kochen M, Gefeller O, Gleiter C, Wessel TC, De Ryck M, Itri L, Prange H, Cerami A, Brines M, Siren AL (2002) Erythropoietin therapy for acute stroke is both safe and beneficial. Mol Med 8:495–505.PubMedGoogle Scholar
  26. Eliasson MJL, Sampei K, Mandir AS, Hurn PD, Traystman RJ, Bao J, Pieper A, Wang Z-Q, Dawson TM, Snyder SH, Dawson VL (1997) Poly(ADP-ribose) polymerase gene disruption renders mice resistant to cerebral ischemia. Nat Med 3:1089–1095.PubMedCrossRefGoogle Scholar
  27. Endres M, Wang Z-Q, Namura S, Waeber C, Moskowitz MA (1997) Ischemic brain injury is mediated.by the activation of poly(ADP-ribose) polymerase. J Cereb Blood Flow Metab 17:1143–1151.PubMedCrossRefGoogle Scholar
  28. Gasparini F, Lingenhöhl K, Stoehr N, Flor PJ, Heinrich M, Vranesic I, Biollaz M, Allgeier H, Heckendorn R, Urwyler S, Varney MA, Johnson EC, Hess SD, Rao SP, Sacaan AI, Santori EM, Veliçelebi G, Kuhn R (1999) 2-Methyl-6-(phenylethynyl)-pyridine (MPEP), a potent, selective and systemically active mGlu5 receptor antagonist. Neuropharmacology 38:1493–1503.PubMedCrossRefGoogle Scholar
  29. Ginsberg MD, Pulsinelli WA (1994) The ischemic penumbra, injury thresholds, and the therapeutic window for acute stroke. Ann Neurol 36:553–554.PubMedCrossRefGoogle Scholar
  30. Gladstone DJ, Black SE, Hakim AM (2002) Toward wisdom from failure: lessons from neuroprotective stroke trials and new therapeutic directions. Stroke 33:2123–2136.PubMedCrossRefGoogle Scholar
  31. Grotta J (2002) Neuroprotection is unlikely to be effective in humans using current trial designs. Stroke 33:306–307.PubMedGoogle Scholar
  32. Ha HC, Snyder SH (1999) Poly(ADP-ribose) polymerase is a mediator of necrotic cel1 death by ATP depletion. Proc Natl Acad Sci USA 96: 13978–13982.PubMedCrossRefGoogle Scholar
  33. Ha HC, Snyder SH (2000) Poly(ADP-ribose) polymerase-1 in the nervous system. Neurobiol Dis 7:225–239.PubMedCrossRefGoogle Scholar
  34. Herceg Z, Wang ZQ (2001) Functions of poly(ADP-ribose) polymerase (PARP) in DNA repair, genomic integrity and cell death. Mutat Res 477:97–110.PubMedCrossRefGoogle Scholar
  35. Huang Z, Huang PL, Panahian N, Dalkara T, Fishman MC, Moskowitz MA (1994) Effects of cerebral ischemia in mice deficient in neuronal nitric oxid synthase. Science 265: 1883–1885.PubMedCrossRefGoogle Scholar
  36. Kinouchi H, Epstein CJ, Mizui T, Carlson E, Chen SF, Chan PH (1991) Attenuation of focal cerebral ischemic injury in transgenic mice overexpressing CuZn superoxide dismutase. Proc Natl Acad Sci USA 88:11158–11162.PubMedCrossRefGoogle Scholar
  37. Koroshetz WJ, Moskowitz MA (1996) Emerging treatments for stroke in humans. Trends Pharmacol Sci 17:227–233.PubMedCrossRefGoogle Scholar
  38. Lee J-M, Zipfel GJ, Choi DW (1999) The changing landscape of ischaemic brain injury mechanisms. Nature 399 (supp.):A7–A14PubMedCrossRefGoogle Scholar
  39. Leker RR, Shohami E (2002) Cerebral ischemia and trauma-different etiologies yet similar mechanisms: neuroprotective opportunities. Brain Res Brain Res Rev 39:55–73.PubMedCrossRefGoogle Scholar
  40. Lipton P (1999) Ischemic cell death in brain neurons. Physiol Rev 79:1431–1568.PubMedGoogle Scholar
  41. Lipton SA, Rosenberg PA (1994) Excitatory amino acids as a final common pathway for neurological disorders. N Engl J Med 330:613–622.PubMedCrossRefGoogle Scholar
  42. Lossi L, Merighi A (2003) In vivo cellular and molecular mechanisms of neuronal apoptosis in the mammalian CNS. Prog Neurobiol 69:287–312.PubMedCrossRefGoogle Scholar
  43. Mannaioni G, Attucci S, Missanelli A, Pellicciari R, Corradetti R, Moroni F (1999) Biochemical and electrophysiological studies on (S)-(+)-2-(3′-carboxybicyclo[1.1.1]pentyl)glycine (CBPG), a novel mGlu5 receptor agonist endowed with mGLu1 receptor antagonist activity. Neuropharmacology 38:917–926.PubMedCrossRefGoogle Scholar
  44. Martinou J-C, Dubois-Dauphin M, Staple JK, Rodriguez I, Frankowski H, Missotten M, Albertini P, Talabot D, Catsicas S, Pietra C, Huarte J (1994) Overexpression of BCL-2 in transgenic mice protects neurons from naturally occurring cell death and experimental ischemia. Neuron 13:1017–1030.PubMedCrossRefGoogle Scholar
  45. Meldrum BS (2000) Glutamate as a neurotransmitter in the brain: review of physiology and pathology. J Nutr 130:1007S–1015S.PubMedGoogle Scholar
  46. Meli E, Pangallo M, Baronti R, Chiarugi A, Cozzi A, Pellegrini-Giampietro DE, Moroni F (2003) Poly(ADP-ribose) polymerase as a key player in excitotoxicity and post-ischemic brain damage. Toxicol Lett 193:153–162.CrossRefGoogle Scholar
  47. Meli E, Picca R, Attucci S, Cozzi A, Peruginelli F, Moroni F, Pellegrini-Giampietro DE (2002) Activation of mGlu1 but not mGlu5 metabotropic glutamate receptors contributes to post-ischemic neuronal injury in vitro and in vivo. Pharmacol Biochem Behav 73:439–446.PubMedCrossRefGoogle Scholar
  48. Moroni F, Lombardi G, Thomsen C, Leonardi P, Attucci S, Peruginelli F, Albani Torregrossa S, Pellegrini-Giampietro DE, Luneia R, Pellicciari R (1997) Pharmacological characterization of 1-aminoindan-1,5-dicarboxylic acid, a potent mGluR1 antagonist. J Pharmacol Exp Ther 281:721–729.Google Scholar
  49. Moroni F, Meli E, Peruginelli F, Chiarugi A, Cozzi A, Picca R, Romagnoli P, Pellicciari R, Pellegrini-Giampietro DE (2001) Poly(ADP-ribose) polymerase inhibitors attenuate necrotic but not apoptotic neuronal death in experimental models of cerebral ischemia. Cell Death Differ 8:921–932.PubMedCrossRefGoogle Scholar
  50. Movsesyan VA, O’Leary OM, Fan L, Bao W, Mullins PGM, Knoblach SM, Faden AI (2001) mGluR5 antagonists 2-methyl-6-(phenylethynyl)-pyridine and (E)-2-methyl-6(phenylethynyl)-pyridine reduce traumatic neuronal injury in vivo and in vitro by antagonizing N-methyl-D-aspartate receptors. J Pharmacol Exp Ther 296:41–47.PubMedGoogle Scholar
  51. Muir KW (2002) Heterogeneity of stroke pathophysiology and neuroprotective clinical trial design. Stroke 33:1545–1550.PubMedCrossRefGoogle Scholar
  52. Mukhin A, Fan L, Faden AI (1996) Activation of metabotropic glutamate receptor mGluRI contributes to post-traumatic neuronal injury. J Neurosci 16:6012–6020.PubMedGoogle Scholar
  53. Namura S, Zhu J, Fink K, Endres M, Srinivasan A, Tomaselli KJ, Yuan J, Moskowitz MA (1998) Activation and cleavage of caspase-3 in apoptosis induced by experimental cerebral ischemia. J Neurosci 18:3659–3668.PubMedGoogle Scholar
  54. Nellgard B, Wieloch T (1992) Post ischemic blockade of AMPA but not NMDA receptors mitigates neuronal damage in the rat brain following transient severe forebrain ischemia. J Cereb Blood Flow Metab 12:1–11.CrossRefGoogle Scholar
  55. Nicoletti F, Bruno V, Catania MV, Battaglia G, Copani A, Barbagallo G, Ceña V, Sánchez-Prieto J, Spano PF, Pizzi M (1999) Group-I metabotropic glutamate receptors: hypotheses to explain their dual role in neurotoxicity and neuroprotection. Neuropharmacology 38:1477–1484.PubMedCrossRefGoogle Scholar
  56. Nicotera P, Leist M, Manzo L (1999) Neuronal cell death: a demise with different shapes. Trends Pharmacol Sci 20:46–51.PubMedCrossRefGoogle Scholar
  57. Olney JW (1990) Excitotoxic amino acids and neuropsychiatric disorders. Annu Rev Pharmacol Toxicol 30:47–71.PubMedCrossRefGoogle Scholar
  58. Pellegrini-Giampietro DE, Cherici G, Alesiani M, Carlà V, Moroni F (1990) Excitatory amino acid release and free radical formation may cooperate in the genesis of ischemiainduced neuronal damage. J Neurosci 10:1035–1041.PubMedGoogle Scholar
  59. Pellegrini-Giampietro DE, Cozzi A, Peruginelli F, Leonardi P, Meli E, Pellicciari R, Moroni F (1999a) 1-Amino-1,5-dicarboxylic acid and (8)-(+)-2-(3′-carboxybicyclo[1.1.1]pentyl)glycine, two mGlu1 receptor-preferring antagonists, reduce neuronal death in in vitro and in vivo models of cerebral ischemia. Eur J Neurosci 11:3637–3647.PubMedCrossRefGoogle Scholar
  60. Pellegrini-Giampietro DE, Gorter JA, Bennett MVL, Zukin RS (1997) The GluR2 (GluR-B) hypothesis: Ca2+-permeable AMPA receptors in neurological disorders. Trends Neurosci 20:464–470.PubMedCrossRefGoogle Scholar
  61. Pellegrini-Giampietro DE, Peruginelli F, Meli E, Cozzi A, Albani Torregrossa S, Pellicciari R, Moroni F (1999b) Protection with metabotropic glutamate I receptor antagonists in models of ischemic neuronal death: time-course and mechanisms. Neuropharmacology 38:1607–1619.PubMedCrossRefGoogle Scholar
  62. Pieper AA, Brat DJ, Krug DK, Watkins CC, Gupta A, Blackshaw S, Verma A, Wang ZQ, Snyder SH (1999) Poly(ADP-ribose) polymerase-deficient mice are protected from streptozotocin-induced diabetes. Proc Natl Acad Sci USA 96:3059–3064.PubMedCrossRefGoogle Scholar
  63. Pulsinelli WA, Brierley JB, Plum F (1982) Temporal profile of neuronal damage in a model of transient forebrain ischemia. Ann Neurol 11:491–498.PubMedCrossRefGoogle Scholar
  64. Ray AM, Owen DE, Evans ML, Davis JB, Benham CD (2000) Caspase inhibitors are functionally neuroprotective against oxygen glucose deprivation induced CA1 death in rat organotypic hippocampal slices. Brain Res 867:62–69.PubMedCrossRefGoogle Scholar
  65. Shall S, de Murcia G (2000) Poly(ADP-ribose) polymerase-1: what have we learned from the deficient mouse model? Mutat Res 460:1–15.PubMedCrossRefGoogle Scholar
  66. Silver IA, Erecinska M (1992) Ion homeostasis in rat brain in vivo: intra-and extracellular [Ca2+] and [H+] in the hippocampus during recovery from short-term, transient ischemia. J Cereb Blood Flow Metab 12:759–772.PubMedCrossRefGoogle Scholar
  67. Simbulan-Rosenthal CM, Rosenthal DS, Iyer S, Boulares AH, Smulson ME (1998) Transient poly(ADP-ribosyl)ation of nuclear proteins and role of poly(ADP-ribose) polymerase in the early stages of apoptosis. J Biol Chem 273: 13703–13712.PubMedCrossRefGoogle Scholar
  68. Smith S (2001) The world according to PARP. Trends Biochem Sci 26:174–179.PubMedCrossRefGoogle Scholar
  69. Strasser U, Lobner D, Behrens MM, Canzoniero LMT, Choi DW (1998) Antagonists for group I mGluRs attenuate excitotoxic neuronal death in cortical cultures. Eur J Neurosci 10:2848–2855.PubMedCrossRefGoogle Scholar
  70. Szabö C, Dawson VL (1998) Role of poly(ADP-ribose) synthetase in inflammation and ischaemia-reperfusion. Trends Pharmacol Sci 19:287–298.PubMedCrossRefGoogle Scholar
  71. Szatkowski M, Attwell D (1994) Triggering and execution of neuronal death in brain ischemia: two phases of glutamate release by different mechanisms. Trends Neurosci 17:359–365.PubMedCrossRefGoogle Scholar
  72. Takahashi K, Greenberg JH, Jackson P, Maclin K, Zhang J (1997) Neuroprotective effects of inhibiting poly(ADP-ribose) synthetase on focal cerebral ischemia in rats. J Cereb Blood Flow Metab 17:1137–1142.PubMedCrossRefGoogle Scholar
  73. Takei N, Endo Y (1994) Ca2+ ionophore-induced apoptosis on cultured embryonic rat cortical neurons. Brain Res 652:65–70.PubMedCrossRefGoogle Scholar
  74. Traynelis S, Cull-Candy S (1990) Proton inhibition of N-methyl-D-aspartate receptors in cerebellar neurons. Nature 345:347–350.PubMedCrossRefGoogle Scholar
  75. Ugolini A, Corsi M, Bordi F (1999) Potentiation of NMDA and AMPA responses by the specific mGluRs agonist CHPG in spinal cord motoneurons. Neuropharmacology 38:1569–1576.PubMedCrossRefGoogle Scholar
  76. Virag L, Szabo C (2002) The therapeutic potential of poly(ADP-Ribose) polymerase inhibitors. Pharmacol Rev 54:375–429.PubMedCrossRefGoogle Scholar
  77. Wang KKW (2000) Calpain and caspase: can you tell the difference? Trends Neurosci 23:20–26.PubMedCrossRefGoogle Scholar
  78. Zhang J, Dawson VL, Dawson TM, Snyder SH (1994) Nitric oxide activation of poly(ADPribose) synthetase in neurotoxicity. Science 263:687–689.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2004

Authors and Affiliations

  • Domenico E. Pellegrini-Giampietro
    • 1
  • Elena Meli
    • 1
  • Flavio Moroni
    • 1
  1. 1.Dipartimento di Fannacologia Preclinica e ClinicaFirenzeItaly

Personalised recommendations