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Cerebellar granule cells as a model to study mechanisms of neuronal apoptosis or survivalin vivo andin vitro

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Abstract

Granule cells of the cerebellum constitute the largest homogeneous neuronal population of mammalian brain. Due to their postnatal generation and the feasibility of well characterized primaryin vitro cultures, cerebellar granule cells are a model of election for the study of cellular and molecular correlates of mechanisms of survival/apoptosis and neurodegeneration/neuroprotection. The present review mainly deals with recent data on mechanisms and factors promoting survival or apoptotic elimination of cerebellar granule neurons, with a particular focus on the molecular correlates at the level of gene expression and induction of cellular signal pathways. Thein vivo development is first analysed with particular reference to the role played by several neurotrophic factors and by the NMDA subtype of glutamate receptor. Then, mechanisms of survival/apoptosis are examined in the model of primaryin vitro cultures, where the role of neurotrophins acting on cerebellar granule cells is followed by the large deal of data coming from the paradigm of potassium/serum withdrawal. The role of some key genes of the Bcl family, of some kinase systems and of transcriptional factors is primarily highlighted. Furthermore, the involvement of mitochondria, free radicals and proteases of the caspase family is considered. Finally, the use of cerebellar granule neurons in primary culture to experimentally address the issue of neurodegeneration and pharmacological neuroprotection is considered, with some comments on models at the borderline between necrosis and apoptosis, such as the excitotoxic neuronal damage. The overlapping of cellular signal pathways activated in granule neurons by apparently unrelated stimuli, such as neurotrophins and neurotransmitters/neuromodulators is stressed to put into light the special ‘trophic’ role played by activity in neurons. Finally, the advantage of designing and performing conceptually equivalent experiments on cerebellar granule neurons during developmentin vivo andin vitro, is stressed. On the basis of the reviewed material, it is concluded that cerebellar granule neurons have acquired a special position in modern neuroscience as one of the most reliable models for the study of neural development, function and pathology.

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References

  1. Nijhawan D, Hornarpour N, Wang X. Apoptosis in neural development and disease. Annu Rev Neurosci 2000; 23: 73–87.

    PubMed  CAS  Google Scholar 

  2. Brown MC, Hopkins WG, Keynes RJ. Essentials of neural development. Cambridge: Cambridge University Press, 1991.

    Google Scholar 

  3. Oppenheim RW. Cell death during development of the nervous system. Annu Rev Neurosci 1991; 14: 453–501.

    PubMed  CAS  Google Scholar 

  4. Henderson CE. Role of neurotrophic factors in neuronal development. Curr Opin Neurobiol 1996; 6: 64–70.

    PubMed  CAS  Google Scholar 

  5. Pettmann B, Henderson CE. Neuronal cell death. Neuron 1998; 20: 633–647.

    PubMed  CAS  Google Scholar 

  6. Cameron HT, Hazel TG, McKay RDG. Regulation of neurogenesis by growth factors and neurotransmitters. J Neurobiol 1998; 36: 287–306.

    PubMed  CAS  Google Scholar 

  7. Contestabile A. Roles of NMD A receptor activity and nitric oxide production in brain development. Brain Res Rev 2000; 32: 476–509.

    PubMed  CAS  Google Scholar 

  8. Raff MC, Barres BA, Burne JF, Coles HF, Ishizaki Y, Jacobson MD. Programmed cell death and the control of cell survival: lessons from the nervous system. Science 1993; 262: 695–699.

    PubMed  CAS  Google Scholar 

  9. Charriaut-Marlangue C, Aggoun-Zauaoui D, Represa A, Ben-Ari Y. Apoptotic features of selective neuronal death in ischemia, epilepsy and gp 120 toxicity. Trends Neurosci 1996; 19: 109–114.

    PubMed  CAS  Google Scholar 

  10. Leist M, Nicotera P. Apoptosis, excitotoxicity and neuropathology. Exp Cell Res 1998; 239: 183–201.

    PubMed  CAS  Google Scholar 

  11. Honig LS, Rosenberg RN. Apoptosis and neurologic disease. Physiol in Med 2000; 108: 317–330.

    CAS  Google Scholar 

  12. Kerr JF, Willie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 1972; 26: 239–257.

    PubMed  CAS  Google Scholar 

  13. Martin DP, Schmidt RE, Di Stefano PS, Lowry OH, Carter JG, Johnson EM Jr. Inhibitors of protein synthesis and RNA synthesis prevent neuronal death caused by nerve growth factor deprivation. J Cell Biol 1988; 106: 829–844.

    PubMed  CAS  Google Scholar 

  14. Majno G, Joris I. Apoptosis, oncosis and necrosis. An overview of cell death. Am J Pathol 1995; 146:3–15.

    PubMed  CAS  Google Scholar 

  15. Leist M, Nicotera P. The shape of cell death. Biochem Biophys Res Comm 1997; 236: 1–9.

    PubMed  CAS  Google Scholar 

  16. Steller H. Mechanisms and genes of cellular suicide. Science 1995; 267: 1445–1449.

    PubMed  CAS  Google Scholar 

  17. Hale AJ, Smith CA, Sutherland LC, et al. Apoptosis: molecular regulation of cell death. Eur J Biochem 1996; 236: 1–26.

    PubMed  CAS  Google Scholar 

  18. Song Z, Steller H. Death by design: mechanisms and control of apoptosis. Trends Cell Biol 1999; 9: M49–52.

    PubMed  CAS  Google Scholar 

  19. Merry DE, Korsmeyer SJ. Bcl-2 gene family in the nervous system. Annu Rev Neurosci 1997; 20: 245–267.

    PubMed  CAS  Google Scholar 

  20. Gorman AM, Orrenius S, Ceccatelli S. Apoptosis in neuronal cells: role of caspases. Neuroreport 1998; 9: 49–55.

    Google Scholar 

  21. Wolf BB, Green DR. Suicidal tendencies: apoptotic cell death by caspase family proteinases. J Biol Chem 1999; 274: 20049–20052.

    PubMed  CAS  Google Scholar 

  22. Mattson MP. Apoptosis in neurodegenerative disorders. Nature Rev Mol Cell Biol 2000; 1: 120–129.

    CAS  Google Scholar 

  23. Sastry PS, Rao KS. Apoptosis in the nervous system. J Neurochem 2000; 74: 1–20.

    PubMed  CAS  Google Scholar 

  24. Altman J. Morphological development of the rat cerebellum and some of its mechanisms. Exp Brain Res 1982; Suppl. 6: 8–49.

    Google Scholar 

  25. Altman J, Bayer SA. Development of the cerebellar system in relation to its evolution, structure and function. Boca Raton: CRC Press, 1997.

    Google Scholar 

  26. Gallo V, Ciotti MT, Coletti A, Aloisi F, Levi G. Selective release of glutamate from cerebellar granule cells differentiating in culture. Proc Natl Acad Sci 1982; 79: 7919–7923.

    PubMed  CAS  Google Scholar 

  27. Thangnipon W, Kingsbury A, Webb M, Balazs R. Observations on rat cerebellar cells in vitro: influence of substratum, potassium concentration and relationship between neurones and astrocytes. Brain Res 1983; 313: 177–189.

    PubMed  CAS  Google Scholar 

  28. Kingsbury A, Gallo V, Woodhams PL, Balazs R. Survival, morphology and adhesion properties of cerebellar interneurones cultured in chemically defined and serum-supplemented medium. Devel Brain Res 1985; 17: 17–25.

    Google Scholar 

  29. Wood KA, Dipasquale B, Youle RJ. In situ labeling of granule cells for apoptosis-associated DNA fragmentation reveals different mechanisms of cell loss in developing cerebellum. Neuron 1993; 11: 621–632.

    PubMed  CAS  Google Scholar 

  30. Lossi L, Zagzag D, Greco MA, Merighi A. Apoptosis of undifferentiated progenitors and granule cell precursors in the postnatal human cerebellar cortex correlates with expression of BCL-2, ICE and CPP32 proteins. J Comp Neurol 1998; 399: 359–372.

    PubMed  CAS  Google Scholar 

  31. Tanaka M, Marunouchi T. Immunohistochemical analysis of developmental stage of external granular layer neurons which undergo apoptosis in postnatal rat cerebellum. Neurosci Lett 1998; 242: 85–88.

    PubMed  CAS  Google Scholar 

  32. Chomez P, Neveu I, Mansen A et al. Increased cell death and delayed development in the cerebellum of mice lacking the reverbA(alpha) orphan receptor. Development 2000; 127: 1489–1498.

    PubMed  CAS  Google Scholar 

  33. Ohgoh M, Yamazaki K, Ogura H, Nishizawa Y, Tanaka I. Apoptotic cell death of cerebellar granule neurons in genetically ataxia (ax) mice. Neurosci Lett 2000; 288: 167–170.

    PubMed  CAS  Google Scholar 

  34. Wullner U, Loschmann PA, Weller M, Klockgether T. Apoptotic cell death in the cerebellum of mutant weaver and lurcher mice. Neurosci Lett 1995; 200: 109–112.

    PubMed  CAS  Google Scholar 

  35. Zanjani HS, Vogel MV, Delhaye-Bouchaud N, Martinou JC, Mariani J. Increased inferior olivary neuron and cerebellar granule cell number in transgenic mice overexpressing the human Bcl-2 gene. J Neurobiol 1997; 32: 502–516.

    PubMed  CAS  Google Scholar 

  36. Pennacchio LA, Bouley DM, Higgins KM, Scott MP, Noebels JL, Myers LM. Progressive ataxia, myoclonic epilepsy and cerebellar apoptosis in cystatin B-deficient mice. Nature Gen 1998; 20: 251–258.

    CAS  Google Scholar 

  37. Wullner U, Weller M, Schulz JB, Krajewski S, Reed JC, Klockgether T. Bcl-2, Bax and Bcl-x expression in neuronal apoptosis: a study of mutant weaver and lurcher mice. Acta Neuropathol 1998; 96: 233–238.

    PubMed  CAS  Google Scholar 

  38. Huard JM, Forster CC, Carter ML, Sicinski P, Ross ME. Cerebellar histogenesis is disturbed in mice lacking cyclin D2. Development 1999; 126: 1927–1935.

    PubMed  CAS  Google Scholar 

  39. Doughty ML, De Jager PL, Korsmeyer SJ, Heintz N. Neurode-generation in Lurcher mice occurs via mutiple cell death pathways. J Neurosci 2000; 20: 3687–3694.

    PubMed  CAS  Google Scholar 

  40. Selimi F, Doughty ML, Delhaye-Bouchaud N, Mariani J. Targetrelated and intrinsic neuronal death in lurcher mutant mice are both mediated by caspase-3 activation. J Neurosci 2000; 20: 992–1000.

    PubMed  CAS  Google Scholar 

  41. Selimi F, Vogel MW, Mariani J. Bax inactivation in lurcher mutants rescues cerebellar granule cells but not Purkinje cells or inferior olivary neurons. J Neurosci 2000; 20: 5339–5345.

    PubMed  CAS  Google Scholar 

  42. Selimi F, Campana A, Weitzman J, Vogel MW, Mariani J. Bax and p53 are differentially involved in the regulation of caspase-3 expression and activation during neurodegeneration in lurcher mice. C R Acad Sci III 2000; 323: 967–973.

    PubMed  CAS  Google Scholar 

  43. Chrysis D, Calikoglu AS, Ye P, D’Ercole AJ. Insulin-like growth factor-I overexpression attenuates cerebellar apoptosis by altering the expression of Bcl family proteins in a developmentally specific manner. J Neurosci 2001; 21: 1481–1489.

    PubMed  CAS  Google Scholar 

  44. Wood KA, Youle RJ. The role of free radicals and p53 in neuron apoptosis in vivo. J Neurosci 1995; 15: 5851–5857.

    PubMed  CAS  Google Scholar 

  45. Ferrer I. Role of caspases in ionizing-induced apoptosis in the developing cerebellum. J Neurobiol 1999; 41: 549–558.

    PubMed  CAS  Google Scholar 

  46. Ferrer I, Puig B, Goutan E, Gombau L, Munoz-Canoves P. Methylazoximethanol acetate-induced cell death in the granule cell layers of the developing mouse cerebellum is associated with caspase-3 activation, but does not depend on the tissue-type plasminogen activator. Neurosci Lett 2001; 299: 77–80.

    PubMed  CAS  Google Scholar 

  47. Smeyne RJ, Chu T, Lewin A, et al. Local control of granule cell generation by cerebellar Purkinje cells. Mol Cell Neurosci 1995; 6: 230–251.

    PubMed  CAS  Google Scholar 

  48. Dahmane N, Ruiz-i-Altaba A. Sonic hedgehog regulates the growth and patterning of the cerebellum. Development 1999; 126: 3089–3100.

    PubMed  Google Scholar 

  49. Kenney AM, Rowitch DH. Sonic hedgehog promotes G(l) cyclin expression and sustained cell cycle progression in mammalian neuronal precursors. Mol Cell Biol 2000; 20: 9055–9067.

    PubMed  CAS  Google Scholar 

  50. Schwartz PM, Borghesani PR, Levy RL, Pomeroy SL, Segal RA. Abnormal cerebellar development and foliation in BDNF -/- mice reveals a role for neurotrophins in CNS patterning. Neuron 1997; 19: 269–281.

    PubMed  CAS  Google Scholar 

  51. Cheng Y, Tao Y, Black IB, DiCicco-Bloom E. A single peripheral injection of basic fibroblast growth factor (bFGF) stimulates granule cell production and increases cerebellar growth in newborn ratss. J Neurobiol 2001; 46: 220–229.

    PubMed  CAS  Google Scholar 

  52. Vaudry D, Gonzalez BJ, Basille M, Pamantung TF, Fornier A, Vaudry K. PACAP acts as a neurotrophic factor during histogenesis of the rat cerebellar cortex. Ann N Y Acad Sci 2000; 921: 293–299.

    PubMed  CAS  Google Scholar 

  53. Tanaka M, Sawada M, Miura M, Marunouchi T. Insulin-like growth factor-I analogue prevents apoptosis mediated through an interleukin-1 beta converting enzyme (caspase l)-like protease of cerebellar external granule layer neurons: developmental stagespecific mechanisms of neuronal cell death. Neuroscience 1998; 84: 89–100.

    PubMed  CAS  Google Scholar 

  54. Tanaka M, Momoi T, Marunouchi T. In situ detection of activated caspase-3 in apoptotic granule neurons in the developing cerebellum in slice cultures and in vivo. Devel Brain Res 2000; 121: 223–228.

    CAS  Google Scholar 

  55. Inamura N, Araki T, Enokido Y, Nishio C, Aizawa S, Hatanaka H. Role of p53 in DNA strand break-induced apoptosis in organotypic slice culture from mouse cerebellum. J Neurosci Res 2000; 60: 450–457.

    PubMed  CAS  Google Scholar 

  56. Tanaka M, Yoshida S, Yano M, Hanaoka F. Roles of endogenous nitric oxide in cerebellar cortical development in slice cultures. Neuroreport 1994; 5: 2049–2052.

    PubMed  CAS  Google Scholar 

  57. Virgili M, Monti B, LoRusso A, Bentivogli M, Contestabile A. Developmental effects of in vivo and in vitro inhibition of nitric oxide synthase. Brain Res 1999; 839: 164–172.

    PubMed  CAS  Google Scholar 

  58. Monti B, Contestabile A. Blockade of the NMDA receptor increases developmental apoptotic elimination of granule neurons and activates caspases in the rat cerebellum. Eur J Neurosci 2000; 12: 3117–3123.

    PubMed  CAS  Google Scholar 

  59. Virgili M, Facchinetti F, Sparapani M et al. Neuronal nitric oxide synthase is permanently decreased in the cerebellum of rats subjected to chronic neonatal blockade of N-methyl-D-aspartate receptors. Neurosci Lett 1998; 258: 1–4.

    PubMed  CAS  Google Scholar 

  60. Tregnago M, Virgili M, Monti B, Guarnieri T, Contestabile A. Alteration of neuronal nitric oxide synthase activity and expression in the cerebellum and the forebrain of microencephalic rats. Brain Res 1998; 793: 54–60.

    PubMed  CAS  Google Scholar 

  61. Kaltschmidt B, Kaltschmidt C. DNA array analysis of the developing rat cerebellum: trasforming growth factor-beta2 inhibits constitutively activated NF-kappaB in granule neurons. Mechan Devel 2001; 101: 11–19.

    CAS  Google Scholar 

  62. Ramon Y, Cajal S. Studies on vertebrate neurogenesis (Translated by Guth L.). Springfield, Illinois: Charles C. Thomas Publisher, 1960.

    Google Scholar 

  63. Gallo V, Kingsbury A, Balazs R, Jorgensen OS. The role of depolarization in the survival and differentiation of cerebellar granule cells in culture. J Neurosci 1987; 7: 2203–2213.

    PubMed  CAS  Google Scholar 

  64. Balazs R, Gallo V, Kingsbury A. Effect of depolarization on the maturation of cerebellar granule cells in culture. Devel Brain Res 1988; 40: 269–276.

    CAS  Google Scholar 

  65. D’Mello SR, Anelli R, Calissano P. Lithium induces apoptosis in immature cerebellar granule cells but promotes survival of mature neurons. Exp Cell Res 1994; 211: 332–338.

    PubMed  CAS  Google Scholar 

  66. Copani A, Bruno VMG, Barresi V, Battaglia G, Condorelli DF, Nicoletti F. Activation of metabotropic glutamate receptors prevents neuronal apoptosis in culture. J Neurochem 1994; 64: 101–108.

    Google Scholar 

  67. Sparapani M, Virgili M, Bardi G. Ornithine decarboxylase activity during development of cerebellar granule neurons. J Neurochem 1998; 71: 1898–1904.

    PubMed  CAS  Google Scholar 

  68. Balazs R, Hack N, Jorgensen OS. Stimulation of the N-methyl-D- aspartate receptor has a trophic effect on differentiating cerebellar granule cells. Neurosci Lett 1988; 87: 80–86.

    PubMed  CAS  Google Scholar 

  69. Balazs R, Jorgensen OS, Hack N. N-methyl-D-aspartate promotes the survival of cerebellar granule cells in culture. Neuroscience 1988; 27: 437–451.

    PubMed  CAS  Google Scholar 

  70. Balazs A, Hack N, Jorgensen OS. Selective stimulation of excitatory amino acid receptor subtypes and the survival of cerebellar granule cells in culture: Effect of kainic acid. Neuroscience 1990; 37: 251–258.

    PubMed  CAS  Google Scholar 

  71. Balazs R, Hack N, Jorgensen OS. Interactive effects involving different classes of excitatory amino acid receptors and the survival of cerebellar granule cells in culture. Int J Devel Neurosci 1990; 8: 347–359.

    CAS  Google Scholar 

  72. Copani A., Casabona V., Bruno A et al. The metabotropic glutamate receptor mGlu5 controls the onset of developmental apoptosis in cultured cerebellar neurons. Eur J Neurosci 1998; 10: 2173–2184.

    PubMed  CAS  Google Scholar 

  73. Yan GM., Lin SZ., Irwin RP., Paul SM. Activation of muscarinic cholinergic receptor blocks apoptosis of cultured cerebellar granule neurons. Mol Pharmacol 1995; 47: 248–257.

    PubMed  CAS  Google Scholar 

  74. Burgoyne RD., Graham ME., Cambray-Deakin M. Neurotrophic effects of NMDA receptor activation on developing cerebellar granule cells. J Neurocytol 1993; 22: 689–695.

    PubMed  CAS  Google Scholar 

  75. Hack N., Hidaka H., Wakefield MJ., Balazs R. Promotion of granule cell survival by high K+ or excitatory amino acid treatment and Ca2+/calmodulin-dependent protein kinase activity. Neuroscience 1993; 57: 9–20.

    PubMed  CAS  Google Scholar 

  76. Mattson MP. Calcium and free radicals: mediators of neurotrophic factor and excitatory transmitter-regulated developmental plasticity and cell death. Perspect Dev Neurobiol 1996; 3: 79–91.

    PubMed  CAS  Google Scholar 

  77. Ciani E., Rizzi S., Paulsen RE., Contestabile A. Chronic pre-explant blockade of the NMDA receptor affects survival of cerebellar granule cells explanted in vitro. Devel Brain Res 1997; 99: 112–117.

    CAS  Google Scholar 

  78. Bhave SV., Ghoda L., Hoffman PL. Brain-derived neurotrophic factor mediates the anti-apoptotic effect of NMDA in cerebellar granule neurons: signal transduction cascade and site of ethanol action. J Neurosci 1999; 19: 3277–3286.

    PubMed  CAS  Google Scholar 

  79. Shimoke K., Kubo T., Numakawa T et al. Involvement of phosphatidylinositol-3 kinase in prevention of low K+-induced apoptosis of cerebellar granule neurons. Devel Brain Res 1997; 101: 197–206.

    CAS  Google Scholar 

  80. Shimoke K., Yamagishi S., Yamada M., Ikeuchi T., Hatanaka H. Inhibition of phosphatidylinositol 3-kinase activity elevates c-Jun N-terminal kinase activity in apoptosis of cultured cerebellar granule neurons. Devel Brain Res 1999; 112: 245–253.

    CAS  Google Scholar 

  81. Segal RA., Takahashi H., McKay RD. Changes in neurotrophin responsiveness during the development of cerebellar granule neurons. Neuron 1992; 9: 1041–1052.

    PubMed  CAS  Google Scholar 

  82. Lindholm D., Dechant G., Heisenberg CP., Thoenen H. Brainderived neurotrophic factor is a survival factor for cultured rat cerebellar granule neurons and protects them against glutamateinduced neurotoxicity. Eur J Neurosci 1993; 5: 1455–1464.

    PubMed  CAS  Google Scholar 

  83. Gao WQ., Zheng JL., Karihaloo M. Neurotrophin-4/5 (NT-4/5) and brain-derived neurotrophic factor (BDNF) act at later stages of cerbellar granule cell differentiation. J Neurosci 1995; 15: 2656–2667.

    PubMed  CAS  Google Scholar 

  84. Courtney MJ., Akerman KEO., Coffey ET. Neurotrophins protect cultured cerebellar granule neurons against the early phase of cell death by a two-component mechanism. J Neurosci 1997; 17: 4201–4211.

    PubMed  CAS  Google Scholar 

  85. Lin X., Bulleit RF. Insulin-like growth factor I (IGF-I) is a critical trophic factor for developing cerebellar granule cells. Devel Brain Res 1997; 99: 234–242.

    CAS  Google Scholar 

  86. Miller TM., Tansey MG., Johnson EM Jr., Creedon DJ. Inhibition of phosphatidylinositol 3-kinase activity blocks depolarization- and insulin-like growth factor I-mediated survival of cerebellar granule cells. J Biol Chem 1997; 272: 9847–9853.

    PubMed  CAS  Google Scholar 

  87. Suzuki K., Koike T. Brain-derived neurotrophic factor suppresses programmed death of cerebellar granule cells through a posttranslational mechanism. Mol Chem Neuropathol 1997; 30: 101–124.

    PubMed  CAS  Google Scholar 

  88. Muller Y., Tangre K., Clos J. Autocrine regulation of apoptosis and bcl-2 expression by nerve growth factor in early differentiating cerebellar granule neurons involves low affinity neurotrophin receptor. Neurochem Int 1997; 31: 177–191.

    PubMed  CAS  Google Scholar 

  89. Wu G., Xie X., Lu ZH., Ledeen RW. Cerebellar neurons lacking complex gangliosides degenerate in the presence of depolarizing levels of potassium. Proc Natl Acad Sci USA 2001; 98: 307–312.

    PubMed  CAS  Google Scholar 

  90. D’Mello SR., Galli C., Ciotti T., Calissano P. Induction of apoptosis in cerebellar granule neurons by low potassium: inhibition of death by insulin-like growth factor I and cAMP. Proc Natl Acad Sci USA 1993; 90: 10989–10993.

    PubMed  CAS  Google Scholar 

  91. Nardi N., Avidan G., Daily D., Zilkha-Falb R., Barzilai A. Biochemical and temporal analysis of events associated with apoptosis induced by lowering the extracellular potassium concentration in mouse cerebellar granule neurons. J Neurochem 1997; 68: 750–759.

    PubMed  CAS  Google Scholar 

  92. Schulz JB., Beinroth S., Weller M., Wullner U., Klockgether T. Endonucleolytic DNA fragmentation is not required for apoptosis of cultured rat cerebellar granule neurons. Neurosci Lett 1998; 27: 9–12.

    Google Scholar 

  93. Armstrong RC., Aja TJ., Hoang KD et al. Activation of CED3/ICE-related protease CPP32 in cerebellar granule neurons undergoing apoptosis but not necrosis. J Neurosci 1997; 17: 553–562.

    PubMed  CAS  Google Scholar 

  94. Eldadah BA., Yakoviev AG., Faden AI. The role of CED-3-related cysteine proteases in apoptosis of cerebellar granule cells. J Neurosci 1997; 17:6105–6113.

    PubMed  CAS  Google Scholar 

  95. Harada J., Sugimoto M. Inhibitors of interleukin-1 beta-converting enzyme family proteases (caspases) prevent apoptosis without affecting decreased cellular ability to reduce 3-(4,5-dimethylthia-zole-2-yl)-2,5-diphenyltetrazolium bromide in cerebellar granule neurons. Brain Res 1998; 793: 231–243.

    PubMed  CAS  Google Scholar 

  96. Marks N., Berg MJ., Guidotti A., Saito M. Activation of caspase-3 and apoptosis in cerebellar granule cells. J Neurosci Res 1998; 52: 334–341.

    PubMed  CAS  Google Scholar 

  97. Allsopp TE., McLuckie J., Kerr LE., MacLeod M., Sharkey J., Kelly JS. Caspase 6 activity initiates caspase 3 activation in cerebellar granule cell apoptosis. Cell Death Differ 2000; 7: 984–993.

    PubMed  CAS  Google Scholar 

  98. Eldadah BA., Ren RF., Faden AI. Ribozyme-mediated inhibition of caspase-3 protects cerebellar granule cells from apoptosis induced by serum-potassium deprivation. J Neurosci 2000; 20: 179–186.

    PubMed  CAS  Google Scholar 

  99. Miller TM., Moulder KL., Knudson CM, et al. Bax deletion further orders the cell death pathway in cerebellar granule cells and suggests a caspase-independent pathway to cell death. J Cell Biol 1997; 139:205–217.

    PubMed  CAS  Google Scholar 

  100. Cregan SP., MacLaurin JG., Craig CG et al. Bax-dependent caspase-3 activation is a key determinant in p53-induced apoptosis in neurons. J Neurosci 1999; 19: 7860–7869.

    PubMed  CAS  Google Scholar 

  101. D’Mello SR., Kuan CY., Flavell RA., Rakic P. Caspase-3 is required for apoptosis-associated DNA fragmentation but not for cell death in neurons deprived of potassium. J Neurosci Res 2000; 59: 24–31.

    PubMed  CAS  Google Scholar 

  102. Robertson GS., Crocker SJ., Nicholson DW., Schulz JB. Neuroprotection by the inhibition of apoptosis. Brain Pathol 2000; 10: 283–292.

    PubMed  CAS  Google Scholar 

  103. Simons R., Beinroth S., Gleichmann M et al. Adenovirus-mediated gene transfer of inhibitors of apoptosis protein delays apoptosis in cerebellar granule neurons. J Neurochem 1999; 72: 292–301.

    PubMed  CAS  Google Scholar 

  104. Tanabe H., Eguchi Y., Kamada S., Martinou JC., Tsujimoto Y. Susceptibility of cerebellar granule neurons derived from Bcl-2-deficient and transgenic mice to cell death. Eur J Neurosci 1997; 9: 848–856.

    PubMed  CAS  Google Scholar 

  105. Gleichmann M., Beinroth S., Reed JC et al. Potassium deprivation-induced apoptosis of cerebellar granule neurons: cytochrome c release in the absence of altered expression of Bcl-2 family proteins. Cell Physiol Biochem 1998; 8: 194–201.

    PubMed  CAS  Google Scholar 

  106. Watson A., Eilers A., Lallemaand D., Kyriakis J., Rubin LL., Ham J. Phosphorylation of c-Jun is necessary for apoptosis induced by survival signal withdrawal in cerebellar granule neurons. J Neurosci 1998; 18: 751–762.

    PubMed  CAS  Google Scholar 

  107. Harada J., Sugimoto M. An inhibitor of p38 and JNK MAP kinases prevents activation of caspase and apoptosis of cultured cerebellar granule neurons. Jpn J Pharmacol 1999; 79: 369–378.

    PubMed  CAS  Google Scholar 

  108. Yamagishi S., Yamada M., Ishikawa Y., Matsumoto T., Ikeuchi T., Hatanaka H. P38 mitogen-activated protein kinase regulates low potassium-induced c-Jun phosphorylation and apoptosis in cultured cerebellar granule neurons. J Biol Chem 2001; 276: 5129–5133.

    PubMed  CAS  Google Scholar 

  109. Gunn-More FJ., Tavare JM. Apoptosis of cerebellar granule cells induced by serum withdrawal, glutamate or beta-amyloid, is independent on Jun kinase or p38 mitogen activated protein kinase activation. Neurosci Lett 1998; 250: 53–56.

    Google Scholar 

  110. Le-Niculescu H., Bonfoco E., Kasuya Y., Claret FX., Green DR., Karin M. Withdrawal of survival factors results in activation of the JNK pathway in neuronal cells leading to Fas ligand induction and cell death. Mol Cell Biol 1999; 19: 751–763.

    PubMed  CAS  Google Scholar 

  111. Ginham R., Harrison DC., Facci L., Skaper S., Philpott KL. Upregulation of death pathway molecules in rat cerebellar granule neurons undergoing apoptosis. Neurosci Lett 2001; 302: 113–116.

    PubMed  CAS  Google Scholar 

  112. Galli C., Meucci O., Scorziello A., Werge TM., Calissano P., Schettini G. Apoptosis in cerebellar granule cells is blocked by high KC1, forskolin and IGF-I trhough distinct mechanisms of action: the involvement of intracellular calcium and RNA synthesis. J Neurosci 1995; 15: 1172–1179.

    PubMed  CAS  Google Scholar 

  113. Kubo T., Nonomura T., Enokido Y., Hatanaka H. Brain derived neurotrophic factor (BDNF) can prevent apoptosis of rat cerebellar granule neurons in culture. Devel Brain Res 1995; 85: 249–258.

    CAS  Google Scholar 

  114. Ikeuchi T., Shimoke K., Kubo T., Yamada M., Hatanaka H. Apoptosis-inducing and-preventing signal transduction pathways in cultured cerebellar granule neurons. Hum Cell 1998; 11: 125–140.

    PubMed  CAS  Google Scholar 

  115. Roschier M., Kuusisto E., Suuronen T., Korhonen P., Kyrylenko S., Salminen A. Insulin-like growth factor binding protein 5 and type-1 insulin-like growth factor receptor are differentially regulated during apoptosis in cerebellar granule cells. J Neurochem 2001; 76: 11–20.

    PubMed  CAS  Google Scholar 

  116. D’Mello SR., Borodezt K., Soltoff SP. Insulin-like growth factor and potassium depolarization maintain neuronal survival by distinct pathways: possible involvement of PI 3-kinase in IGF-I signaling. J Neurosci 1997; 17: 1548–1560.

    PubMed  CAS  Google Scholar 

  117. Dudek H., Datta SR., Franke TF, et al. Regulation of neuronal survival by the serine-threonine protein kinase Akt. Science 1997; 275: 661–665.

    PubMed  CAS  Google Scholar 

  118. Brunet A., Bonni A., Zigmond MJ et al. Akt promotes cell survival by phosphorylating and inhibiting a forkhead transcription factor. Cell 1999; 96: 857–868.

    PubMed  CAS  Google Scholar 

  119. Zheng WH., Kar S., Quirion R. Insulin-like growth factor-1-induced phosphorylation of the forkhead family transcription factor FKHRL1 is mediated by Akt kinase in PC 12 cells. J Biol Chem 2000; 275: 39152–39158.

    PubMed  CAS  Google Scholar 

  120. Chang JY., Korolev VV., Wang JZ. Cyclic AMP and pituitary adenylate cyclase-activating polypeptide (PACAP) prevent programmed cell death of cultured cerebellar granule cells. Neurosci Lett 1996; 206: 181–184.

    PubMed  CAS  Google Scholar 

  121. Campard PK., Crochemore C., Rene F., Monnier D., Koch B., Loeffler JP. PACAP type I receptor activation promotes cerebellar neuron survival through the cAMP/PKA signaling pathway. DNA Cell Biol 1997; 16: 323–333.

    CAS  Google Scholar 

  122. Cavallaro S., Copani A., D’Agata V, et al. Pituitary adenylate cyclase activating polypeptide prevents apoptosis in cultured cerebellar granule neurons. Mol Pharmacol 1996; 50: 60–66.

    PubMed  CAS  Google Scholar 

  123. Villalba M., Bockaert J., Journot L. Pituitary adenylate cyclase-activating polypeptide (PACAP-38) protects cerebellar granule neurons from apoptosis by activating the mitogen-activated protein kinase (MAP kinase) pathway. J Neurosci 1997; 17: 83–90.

    PubMed  CAS  Google Scholar 

  124. Journot L., Villalba M., Bockaert J. PACAP-38 protects cerebellar granule cells from apoptosis. Ann N Y Acad Sci 1998; 865: 100–110.

    PubMed  CAS  Google Scholar 

  125. Koulich E., Nguyen T., Johnson K., Giardina C., D’Mello S. NF-kappaB is involved in the survival of cerebellar granule neurons: association of NF-kappabeta phosphorylation with cell survival. J Neurochem 2001; 76: 1188–1198.

    PubMed  CAS  Google Scholar 

  126. Tabuchi A., Koizumi M., Nakatsubo J., Yaguchi T., Tsuda M. Involvement of endogenous PACAP expression in the activity-dependent survival of mouse cerebellar granule cells. Neurosci Res 2001; 39: 85–93.

    PubMed  CAS  Google Scholar 

  127. See V., Boutillier AR., Bito H., Loeffler JP. Calcium/calmodulin-dependent protein kinase IV (CaMKIV) inhibits apoptosis induced by potassium deprivation in cerebellar granule neurons. FASEB J 2001; 15: 134–144.

    PubMed  CAS  Google Scholar 

  128. Monti B., Ciani E., Muzzi P., Marri L., Wanke E., Contestabile A. NMDA receptor-mediated Akt and CREB activation during cerebellar granule cell development. Soc Neurosci Abstr 2001.

  129. Yao CJ., Lin CW., Lin-Shiau SY. Altered intracellular calcium level in association with neuronal death induced by lithium chloride. J Formos Med Assoc 1999; 98: 820–826.

    PubMed  CAS  Google Scholar 

  130. Grignon S., Levy N., Couraud F., Bruguerolle B. Tyrosine kinase inhibitors and cychloeximide inhibit Li+ protection of cerebellar granule neurons switched to non-depolarizing medium. Eur J Pharmacol 1996; 315: 111–114.

    PubMed  CAS  Google Scholar 

  131. Chen RW., Chuang DM. Long term lithium treatment suppresses p53 and Bax expression and increases Bcl-2 expression. A prominent role in neuroprotection against excitotoxicity. J Biol Chem 1999; 274: 6039–6042.

    CAS  Google Scholar 

  132. Chalecka-Franaszek E., Chuang DM. Lithium activates the serine/threonine kinase Akt-1 and suppresses glutamate-induced inhibition of Akt-1 activity in neurons. Proc Natl Acad Sci USA 1999; 96: 8745–8750.

    PubMed  CAS  Google Scholar 

  133. Oka T., Kubo T., Enokido Y., Hatanaka H. Expression of cyclin A decreases during neuronal apoptosis in cultured rat cerebellar granule neurons. Devel Brain Res 1996; 97: 96–106.

    CAS  Google Scholar 

  134. O’Hare MJ., Hou ST., Morris EJ, et al. Induction and modulation of cerebellar granule neuron death by E2F-1. J Biol Chem 2000; 275: 25358–25364.

    PubMed  CAS  Google Scholar 

  135. Padmanabhan J., Park DS., Greene LA., Shelanski ML. Role of cell cycle regulatory proteins in cerebellar granule neuron apoptosis. J Neurosci 1999; 19: 8747–8756.

    PubMed  CAS  Google Scholar 

  136. Sakai K., Suzuki K., Tanaka S., Koike T. Up-regulation of cyclin D1 occurs in apoptosis of immature but not mature cerebellar granule neurons in culture. J Neurosci Res 1999; 58: 396–406.

    PubMed  CAS  Google Scholar 

  137. Martin-Romero FJ., Santiago-Josefat B., Correa-Bordes J., Gutierrez-Merino C., Fernandez-Saiguero P. Potassium-induced apoptosis in rat cerebellar granule cells involves cell-cycle blockade at the G1/S transition. J Mol Neurosci 2000; 15: 155–165.

    PubMed  CAS  Google Scholar 

  138. Tomomura M., Fernandez-Gonzales A., Yano R., Yuzaki M. Characterization of the apoptosis-associated tyrosine kinase (AATYK) expressed in the CNS. Oncogene 2001; 20: 1022–1032.

    PubMed  CAS  Google Scholar 

  139. Courtney MJ., Coffey ET. The mechanism of Ara-C-induced apoptosis of differentiating cerebellar granule neurons. Eur J Neurosci 1999; 11: 1073–1084.

    PubMed  CAS  Google Scholar 

  140. Green DR., Reed JC. Mitochondria and apoptosis. Science 1998; 281: 1309–1312.

    PubMed  CAS  Google Scholar 

  141. Susin SA., Lorenzo HK., Zamzani N, et al. Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 1999; 397: 441–446.

    PubMed  CAS  Google Scholar 

  142. McGinnis KM., Gnegy ME., Wang KK. Endogenous bax translocation in SH-SY5Y human neurobalstoma cells and cerebellar granule neurons undergoing apoptosis. J Neurochem 1999; 72: 1899–1906.

    PubMed  CAS  Google Scholar 

  143. Gleichmann M., Weller M., Schulz JB. Insulin-like growth factor-1-mediated protection from neuronal apoptosis is linked to phosphorylation of the pro-apoptotic protein BAD but not to inhibition of cytochrome c translocation in rat cerebellar neurons. Neurosci Lett 2000; 282: 69–72.

    PubMed  CAS  Google Scholar 

  144. Atlante A., Gagliardi S., Marra E., Calissano P. Neuronal apoptosis in rats is accompanied by rapid impairment of cellular respiration and is prevented by scavengers of reactive oxygen species. Neurosci Lett 1998; 245: 127–130.

    PubMed  CAS  Google Scholar 

  145. Schulz JB., Weller M., Klockgether T. Potassium deprivation-induced apoptosis of cerebellar granule neurons: a sequential requirement for new mRNA and protein synthesis, ICE-like protease activity, and reactive oxygen species. J Neurosci 1996; 16: 4696–4706.

    PubMed  CAS  Google Scholar 

  146. Isaev NK., Stemashook EV., Halle A. Inhibition of Na+, K+- ATPase activity in cultured rat cerbellar granule cells prevents the onset of apoptosis induced by low potassium. Neurosci Lett 2000; 283: 41–44.

    PubMed  CAS  Google Scholar 

  147. Vitolo OV., Ciotti MT., Galli C., Borsello T., Calissano P. Adenosine and ADP prevent apoptosis in cultured rat cerebellar granule cells. Brain Res 1998; 809: 297–301.

    PubMed  CAS  Google Scholar 

  148. Ishitani R., Sunaga K., Hirano A., Saunders P., Katsube N., Chuang DM. Evidence that glyceraldehyde-3-phosphate dehydrogenase is involved in age-induced apoptosis in mature cerebellar neurons in culture. J Neurochem 1996; 66: 928–935.

    PubMed  CAS  Google Scholar 

  149. Ishitani R., Sunaga K., Tanaka M., Aishita H., Chuang DM. Overexpression of glyceraldehyde-3-phosphate dehydrogenase is involved in low K+-induced apoptosis but not necrosis of cultured cerebellar granule cells. Mol Pharmacol 1997; 51: 542–550.

    PubMed  CAS  Google Scholar 

  150. Ishitani R., Tanaka M., Sunaga K., Katsube N., Chuang DM. Nuclear localization of overexpressed glyceraldehyde-3-phosphate dehydrogenase in cultured cerebellar neurons undergoing apoptosis. Mol Pharmacol 1998; 53: 701–707.

    PubMed  CAS  Google Scholar 

  151. Saunders PA., Chen RW., Chuang DM. Nuclear translocation of glyceraldehyde-3-phosphate dehydrogenase isoforms during neuronal apoptosis. J Neurochem 1999; 72: 925–932.

    PubMed  CAS  Google Scholar 

  152. Chiang LW., Grenier JM., Ettwiller L, et al. An orchestrated gene expression component of neuronal programmed cell death revealed by cDNA array analysis. Proc Natl Acad Sci USA 2001; 98: 2814–2819.

    PubMed  CAS  Google Scholar 

  153. Bartus RT., Elliot PJ., Hayward NJ. Calpain as a novel target for treating acute neurodegenerative disorders. Neurol Res 1995; 17: 249–258.

    PubMed  CAS  Google Scholar 

  154. Canu N., Barbato C., Ciotti MT., Serafino A., Dus L., Calissano P. Proteasome involvement and accumulation of ubiquinated proteins in cerebellar granule neurons undergoing apoptosis. J Neurosci 2000; 20: 589–599.

    PubMed  CAS  Google Scholar 

  155. Wang KK. Calpain and caspase: can you tell the difference? Trends Neurosci 2000; 23: 20–26.

    PubMed  Google Scholar 

  156. Monti B., Sparapani M., Contestabile A. Differential toxicity of protease inhibitors in cultures of cerebellar granule neurons. Exp Neurol 1998; 153: 335–341.

    PubMed  CAS  Google Scholar 

  157. Pasquini LA., Besio Moreno M., Adamo AM., Paquini JM., Soto EF. Lactacystin, a specific inhibitor of the proteasome, induces apoptosis and activates caspase-3 in cultured cerebellar granule cells. J Neurosci Res 2000; 59: 601–611.

    PubMed  CAS  Google Scholar 

  158. Schwarz A., Futerman AH. Distinct roles for ceramide and glucosylceramide at different stages of neuronal growth. J Neurosci 1997; 19: 2929–2938.

    Google Scholar 

  159. Ariga T., Jarvis WD., Yu RK. Role of sphingolipid-mediated cell death in neurodegenerative diseases. J Lip Res 1998; 39: 1–16.

    CAS  Google Scholar 

  160. Manev H., Cogoli C. Ceramide-mediated and isoquinolinesulphonamide-sensitive pathways of neuronal death: anything in common? Neurochem Int 1997; 31: 203–206.

    PubMed  CAS  Google Scholar 

  161. Centeno F., Mora A., Fuentes JM., Soler G., Claro E. Partial lithium-associated protection against apoptosis induced by C2-ceramide in cerebellar granule neurons. Neuroreport 1998; 4199–4203.

  162. Monti B., Zanghellini P., Contestabile A. Characterization of ceramide-induced apoptotic death in cerebellar granule cells in culture. Neurochem Int 2001; 39: 11–18.

    PubMed  CAS  Google Scholar 

  163. Ramos B., Salido GM., Campo ML., Claro E. Inhibition of phosphatidylcholine synthesis precedes apoptosis induced by C2-ceramide: protection by exogenous phosphatidylcholine. Neuroreport 2000; 11: 3103–3108.

    PubMed  CAS  Google Scholar 

  164. Gorman AM., Bonfoco E., Zhivotovsky B., Orrenius S., Ceccatelli S. Cytochrome c release and caspase-3 activation during colchicine-induced apoptosis of cerebellar granule cells. Eur J Neurosci 1999; 11: 1067–072.

    PubMed  CAS  Google Scholar 

  165. Kaida A., Zharkovsky A. Metabotropic glutamate receptor agonists protect from oxygen-glucose deprivation and cholchicineinduced apoptosis in primary cultures of cerebellar granule cells. Neuroscience 1999; 92: 7–14.

    Google Scholar 

  166. Allen JW., Eldadah BA., Faden AI. Beta-amyloid-induced apoptosis of cerebellar granule cells and cortical neurons: exacerbation by selective inhibition of group I metabotropic glutamate receptors. Neuropharmacology 1999; 38: 243–252.

    Google Scholar 

  167. Canu N., Dus L., Barbato C, et al. Tau cleavage and dephosphorylation in cerebellar granule neurons undergoing apoptosis. J Neurosci 1998; 18: 7061–7074.

    PubMed  CAS  Google Scholar 

  168. Galli C., Piccini A., Ciotti MT et al. Increased amyloidogenic secretion in cerebellar granule cells undergoing apoptosis. Proc Natl Acad Sci USA 1998; 95: 1247–1252.

    PubMed  CAS  Google Scholar 

  169. Piccini A., Ciotti MT., Vitolo OV., Calissano P., Tabaton M., Galli C. Endogenous APP derivatives oppositely modulate apoptosis through an autocrine loop. Neuroreport 2000; 11: 1375–1379.

    PubMed  CAS  Google Scholar 

  170. Chiesa R., Drisaldi B., Quaglio E, et al. Accumulation of proteaseresistant prion protein (PrP) and apoptosis of cerebellar granule cells in transgenic mice expressing a PrP insertional mutation. Proc Natl Acad Sci USA 2000; 97: 5574–5579.

    PubMed  CAS  Google Scholar 

  171. Thellung S., Florio T., Villa V, et al. Apoptotic cell death and impairment of L-type voltage-sensitive calcium channel activity in rat cerebellar granule cells treated with the prion protein fragment 106-126. Neurobiol Dis 2000; 7: 299–309.

    PubMed  CAS  Google Scholar 

  172. Moulder KL., Onodera O., Burke JR., Strittmatter WJ., Johnson EM. Generation of neuronal intranuclear inclusions by polyglutamine-GFP: analysis of inclusion clearance and toxicity as a function of polyglutamine length. J Neurosci 1999; 19: 705–715.

    PubMed  CAS  Google Scholar 

  173. Maggirwar SB., Tong N., Ramirez S., Gelbard HA., Dewhurst S. HIV-1 Tat-mediated activation of glycogen synthase kinase-3beta contributes to Tat-mediated neurotoxicity. J Neurochem 1999; 73: 578–586.

    PubMed  CAS  Google Scholar 

  174. Menegon A., Leoni C., Benfenati F., Valtorta F. Tat protein from HIV-1 activates MAP kinase in granular neurons and glial cells from rat cerebellum. Biochem Biophys Res Commun 1997; 238: 800–805.

    PubMed  CAS  Google Scholar 

  175. Ransom RW., Stec NL. Cooperative modulation of3H-MK-801 binding to the N-methyl-D-aspartate receptor-ion channel complex by L-glutamate, glycine and polyamines. J Neurochem 1988; 51: 830–836.

    PubMed  CAS  Google Scholar 

  176. Williams K., Romano C., Dichter MA., Molinoff PB. Modulation of the NMDA receptor by polyamines. Life Sci 1991; 48: 469–498.

    PubMed  CAS  Google Scholar 

  177. Bowie D., Mayer ML. Inward rectification of both AMPA and kainate subtype glutamate receptors generated by polyamine-mediated ion channel block. Neuron 1995; 15: 453–462.

    PubMed  CAS  Google Scholar 

  178. Fakler B., Brandle U., Glowatzki E., Weidemann S., Zenner HP., Ruppersberg JP. Strong voltage-dependent inward rectification of inward rectifier K+ channels is caused by intracellular spermine. Cell 1995; 80: 149–154.

    PubMed  CAS  Google Scholar 

  179. Bourdiol F., Fage D., Serrano A., Carter C., Benavides J., Scatton B. Neurotoxic effects of the intrastriatal injection of spermine and spermidine: lack of involvement of NMDA receptors. Brain Res 1992; 596: 183–188.

    PubMed  CAS  Google Scholar 

  180. Virgili M., Sparapani M., Facchinetti F., Ciani E., Dall’Olio R., Contestabile A. In vitro and in vivo evidence for spermine and spermidine neurotoxicity. Neurodegeneration 1992; 1: 273–279.

    Google Scholar 

  181. Sparapani M., Dall’Olio R., Gandolfi O., Ciani E., Contestabile A. Neurotoxicity of polyamines and pharmacological neuroprotection in cultures of rat cerebellar granule cells. Exp Neurol 1997; 148: 157–166.

    PubMed  CAS  Google Scholar 

  182. Segal JA., Skolnick P. Spermine-induced toxicity in cerebellar granule neurons is independent of its actions at NMDA receptors. J Neurochem 2000; 74: 60–69.

    PubMed  CAS  Google Scholar 

  183. Behl C. Vitamin E protects neurons against oxidative cell death in vitro more effectively than 17-beta estradiol and induces the activity of the transcription factor NF-kappaB. J Neural Transm 2000; 107: 393–407.

    PubMed  CAS  Google Scholar 

  184. Xin W., Wei T., Chen C., Ni Y., Zhao B., Hou J. Mechanisms of apoptosis in rat cerebellar granule cells induced by hydroxyl radicals and the effects of Egb761 and its constituents. Toxicology 2000; 148: 103–110.

    PubMed  CAS  Google Scholar 

  185. Contestabile A. Antioxidant strategies for neurodegenerative diseases. Exp Opin Ther Patents 2001; 11: 573–585.

    CAS  Google Scholar 

  186. Callaway JK., Beart PM., Jarrot B., Giardina SF. Incorporation of sodium channel blocking and free radical scavenging activities into a single drug, AM-36, results in profound inhibition of neuronal apoptosis. Br J Pharmacol 2001; 132: 1691–1698.

    PubMed  CAS  Google Scholar 

  187. Leist M., Volbracht C., Kuhnle S., Fava E., Ferrando-May E., Nicotera P. Caspase-mediated apoptosis in neuronal excitotoxicity triggered by nitric oxide. Mol Med 1997; 3: 750–764.

    PubMed  CAS  Google Scholar 

  188. Wei T., Chen C., Hou J., Xin W., Mori A. Nitric oxide induces oxidative stress and apoptosis in neuronal cells. Biochim Biophys Acta 2000; 1498: 72–79.

    PubMed  CAS  Google Scholar 

  189. Heneka MT., Feinstein DL., Galea E., Gleichmann M., Wullner U., Klockgether T. Peroxisome proliferator-activated receptor gamma agonists protect cerebellar granule cells from cytokine-induced apoptotic cell death by inhibition of inducible nitric oxide synthase. J Neuroimmunol 1999; 100: 156–168.

    PubMed  CAS  Google Scholar 

  190. Kim WK., Ko KH. Potentiation of N-methyl-D-aspartate-mediated neurotoxicity by immunostimulated murine microglia. J Neurosci Res 1998; 54: 17–26.

    PubMed  CAS  Google Scholar 

  191. Prickaerts J., De Vente J., Markering-Van Ittersum M., Steinbusch HWM. Behavioural, neurochemical and neuroanatomical effects of chronic postnatal N-nitro-L-arginine methyl ester treatment in neonatal and adult rats. Neuroscience 1998; 87: 181–195.

    PubMed  CAS  Google Scholar 

  192. Ciani E., Virgili M., Contestabile A. Akt pathway mediates a cGMP-dependent survival role of nitric oxide in cerebellar neurons. J Neurochem. (Submitted).

  193. Choi DW. Glutamate neurotoxicity and diseases of the nervous system. Neuron 1988; 1: 623–634.

    PubMed  CAS  Google Scholar 

  194. Coyle JT., Puttfarcken P. Oxidative stress, glutamate and neurodegenerative disorders. Science 1993; 262: 689–693.

    PubMed  CAS  Google Scholar 

  195. Dessi F., Ben Ari Y., Charriault-Marlangue C. Increased synthesis of specific proteins during glutamate-induced neural death in cerebellar cultures. Brain Res 1994; 654: 27–33.

    PubMed  CAS  Google Scholar 

  196. Ciani E., Groneng L., Voltattorni M., Veslemoy R., Contestabile A., Paulsen RE. Inhibition of free radical production or free radical scavenging protects from the excitotoxic death mediated by glutamate in cultures of cerebellar granule neurons. Brain Res 1996; 728: 1–6.

    PubMed  CAS  Google Scholar 

  197. Dessi F., Charriault-Marlangue C., Khrestchatisky M., Ben Ari Y. Glutamate-induced neuronal death is not a programmed cell death in cerebellar cultures. J Neurochem 1993; 60: 1953–1955.

    PubMed  CAS  Google Scholar 

  198. Ankarcrona M., Dypbukt JM., Bonfoco E, et al. Glutamateinduced neuronal death: a succession of necrosis or apoptosis depending on mitochondrial function. Neuron 1995; 15: 961–973.

    PubMed  CAS  Google Scholar 

  199. Walker PR., Sikorska M. New aspects of the mechanism of DNA fragmentation in apoptosis. Biochem Cell Biol 1997; 75: 287–299.

    PubMed  CAS  Google Scholar 

  200. Slagsvold HH., Marvik OJ., Eidem G., Kristoffersen N., Paulsen RE. Detection of high molecular weight DNA fragments characteristic of early stage apoptosis in cerebellar granule cells exposed to glutamate. Exp Brain Res 2000; 135: 173–178.

    PubMed  CAS  Google Scholar 

  201. Simonian NA., Getz RL., Leveque JC., Konradi C., Coyle JT. Kainic acid induces apoptosis in neurons. Neuroscience 1996; 75: 1047–1055.

    PubMed  CAS  Google Scholar 

  202. Du Y., Bales KR., Dodel RC, et al. Activation of a caspase 3- related cysteine protease is required for glutamate-mediated apoptosis of cultured cerebellar granule neurons. Proc Natl Acad Sci USA 1997; 94: 11657–11662.

    PubMed  CAS  Google Scholar 

  203. Kawasaki K., Morooka T., Shimoama S, et al. Activation and involvement of p38 mitogen-activated protein kinase in glutamate-induced apoptosis in rat cerebellar granule cells. J Biol Chem 1997; 272: 18518–18521.

    PubMed  CAS  Google Scholar 

  204. Cheung NS., Carrol FY., Larm JA., Beart PM., Giardina SF. Kainate-induced apoptosis correlates with c-Jun activation in cultured cerebellar granule cells. J Neurosci Res 1998; 52: 69–82.

    PubMed  CAS  Google Scholar 

  205. Giardina SF., Cheung NS., Reid MT., Beart PM. Kainate-induced apoptosis in cultured murine cerebellar granule cells elevates expression of the cell cycle gene cyclin Dl. J Neurochem 1998; 71: 1325–1328.

    PubMed  CAS  Google Scholar 

  206. Uberti D., Belloni M., Grilli M., Spano P., Memo M. Induction of tumor-suppressor phosphoprotein p53 in the apoptosis of cultured rat cerebellar neurones triggered by excitatory amino acids. Eur J Neurosci 1998; 10: 246–254.

    PubMed  CAS  Google Scholar 

  207. Wood AM., Bristow DR. N-methyl-D-aspartate receptor desensitisation is neuroprotective by inhibiting glutamate-induced apoptotic-like death. J Neurochem 1998; 70: 677–687.

    PubMed  CAS  Google Scholar 

  208. Chalecka-Franaszek E., Chuang DM. Lithium activates the serine/threonine kinase Akt-1 and suppresses glutamate-induced inhibition of Akt-1 activity in neurons. Proc Natl Acad Sci USA 1999; 96: 8745–8750.

    PubMed  CAS  Google Scholar 

  209. Chen RW., Chuang DM. Long term lithium treatment suppresses p53 and Bax expression but increases Bcl-2 expression. A prominent role in neuroprotection against excitotoxicity. J Biol Chem 1999; 274: 6039–6042.

    CAS  Google Scholar 

  210. Atlante A., Gagliardi S., Marra E., Calissano P., Passarella S. Glutamate neurotoxicity in rat cerebellar granule cells involves cytochrome c release from mitochondria and mitochondrial shuttle impairment. J Neurochem 1999; 73: 237–246.

    PubMed  CAS  Google Scholar 

  211. Uberti D., Grilli M., Memo M. Induction of p53 in the glutamateinduced cell death program. Amino Acids 2000; 19: 253–261.

    PubMed  CAS  Google Scholar 

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Contestabile, A. Cerebellar granule cells as a model to study mechanisms of neuronal apoptosis or survivalin vivo andin vitro . Cerebellum 1, 41–55 (2002). https://doi.org/10.1080/147342202753203087

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