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The Genetic Control of Ischemic Neuronal Cell Death

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Cerebral Blood Flow

Part of the book series: Update in Intensive Care Medicine ((UICMSOFT,volume 37))

Abstract

Apoptosis is the final envent in programmed cell death, the mechanism by which neurons die during development. Whether neurons die by apoptosis or necrosis after cerebral ischemia remains controversial. Strictly speaking, apoptosis includes certain key morphologic features: condensation and cleavage of nuclear chromatin, and the formation of budding cytoplasmic appendages known as apoptotic bodies. In addition, intracellular membranes and the plasma membrane remain intact until very late in apoptotic cell death, and there is little inflammation.

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References

  1. Ellis HM, Horvitz HR. Genetic control of programmed cell death in the nematode C. elegans. Cell 1986;44(6):817–29.

    Article  PubMed  CAS  Google Scholar 

  2. Ellis RE, Jacobson DM, Horvitz HR. Genes required for the engulfment of cell corpses during programmed cell death in Caenorhabditis elegans. Genetics 1991;129(1):79–94.

    Google Scholar 

  3. Hengartner MO, Horvitz HR. G. elegans cell survival gene ced-9 encodes a functional homolog of the mammalian proto-oncogene bcl-2. Cell 1994;76(4):665–76.

    Article  PubMed  CAS  Google Scholar 

  4. Reed JC. Bcl-2 family proteins. Oncogene 1998;17(25):3225–36.

    Article  PubMed  Google Scholar 

  5. Yuan J, Shaham S, Ledoux S, Ellis HM, Horvitz HR. The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1 beta-converting enzyme. Cell 1993;75(4):641–52.

    Article  PubMed  CAS  Google Scholar 

  6. Zou H, Henzel WJ, Liu X, Lutschg A, Wang X. Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3. Cell 1997; 90(3):405–13.

    Article  PubMed  CAS  Google Scholar 

  7. Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, et al. Cytochrome c and dATP-dependent formation of Apaf-l/caspase-9 complex initiates an apoptotic protease cascade. Cell 1997;91(4):479–89.

    Article  PubMed  CAS  Google Scholar 

  8. Thornberry NA, Lazebnik Y. Caspases: enemies within. Science 1998;281(5381):1312–6.

    Article  PubMed  CAS  Google Scholar 

  9. Enari M, Sakahira H, Yokoyama H, Okawa K, Iwamatsu A, Nagata S. A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature 1998;391(6662):43–50.

    Article  PubMed  CAS  Google Scholar 

  10. Colbourne F, Sutherland GR, Auer RN. Electron microscopic evidence against apoptosis as the mechanism of neuronal death in global ischemia. J Neurosci 1999;19(11):4200–10.

    PubMed  CAS  Google Scholar 

  11. Chen D, Stetler RA, Cao G, Pei W, O’Horo C, Yin XM, et al. Characterization of the rat DNA fragmentation factor 35/Inhibitor of caspase-activated DNase (Short form). The endogenous inhibitor of caspase-dependent DNA fragmentation in neuronal apoptosis. J Biol Chem 2000;275(49):38508–17.

    Article  PubMed  CAS  Google Scholar 

  12. Hossmann KA. Disturbances of cerebral protein synthesis and ischemic cell death. Prog Brain Res 1993;96:161–77.

    Article  PubMed  CAS  Google Scholar 

  13. Hockenbery D, Nunez G, Milliman C, Schreiber RD, Korsmeyer SJ. Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature 1990;348(6299):334–6.

    Article  PubMed  CAS  Google Scholar 

  14. Graham SH, Chen J, Clark RS. Bcl-2 family gene products in cerebral ischemia and traumatic brain injury. J Neurotrauma 2000;17(10):831–41.

    Article  PubMed  CAS  Google Scholar 

  15. Chen J, Graham SH, Chan PH, Lan J, Zhou RL, Simon RP. bcl-2 is expressed in neurons that survive focal ischemia in the rat. Neuroreport 1995;6(2):394–98.

    Article  PubMed  CAS  Google Scholar 

  16. Chen J, Graham SH, Nakayama M, Zhu RL, Jin KL, Stetler RA, et al. Apoptosis repressor genes bcl-2 and bcl-x-long are expressed in the rat brain following global ischemia. J. Cerebr. Blood Flow MetaboL 1997;17:1–10.

    Google Scholar 

  17. Shimazaki K, Ishida A, Kawai N. Increase in bcl-2 oncoprotein and the tolerance to ischemiainduced neuronal death in the gerbil hippocampus. Neuroscience Research 1994;20(1):95–99.

    Article  PubMed  CAS  Google Scholar 

  18. Boise LH, Gonzalez-Garcia M, Postema CE, Ding L, Lindsten T, Turka LA, et al. bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell 1993;74(4):597–608.

    Article  PubMed  CAS  Google Scholar 

  19. Oltvai ZN, MiUiman CL, Korsmeyer S J. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 1993;74(4):609–19.

    Article  PubMed  CAS  Google Scholar 

  20. Jurgensmeier JM, Xie Z, Deveraux Q, Ellerby L, Bredesen D, Reed JC. Bax directly induces release of cytochrome c from isolated mitochondria. Proc Natl Acad Sei U S A 1998;95(9):4997–5002.

    Article  CAS  Google Scholar 

  21. Krajewski S, Mai JK, Krajewska M, Sikorska M, Mossakowski MJ, Reed JC. Upregulation of Bax protein levels in neurons following cerebral ischemia. Journal Of Neuroscience 1995; 15(10):6364–76.

    Google Scholar 

  22. Chen J, Zhu RL, Nakayama M, Kawaguchi K, Jin K, Stetler RA, et al. Expression of the apoptosis-effector gene, Bax, is up-regulated in vulnerable hippocampal CAl neurons following global ischemia. J. Neurochem. 1996;67(1):64–71.

    Article  PubMed  CAS  Google Scholar 

  23. Cao G, Minami M, Yan C, Chen D, Pei W, O’Horo C, et al. Intracellular Bax translocation following transient cerebral ischemia: Implications for a role of the mitochondrial apoptotic-signaling pathway in ischemic neuronal death. J. Cerebral Blood Flow Metabol. 2001;(in press).

    Google Scholar 

  24. Gillardon F, Lenz C, Waschke KF, Krajewski S, Reed JC, Zimmermann M, et al. Altered expression of Bcl-2, Bcl-X, Bax, and c-Fos colocalizes with DNA fragmentation and ischemic cell damage following middle cerebral artery occlusion in rats. Brain Res Mol Brain Res 1996;40(2):254–60.

    Article  PubMed  CAS  Google Scholar 

  25. Martinou JC, Dubois-Dauphin M, Staple JK, Rodriguez I, Frankowski H, Missotten M, et al. Overexpression of BCL-2 in transgenic mice protects neurons from naturally occurring cell death and experimental ischemia. Neuron 1994;13(4):1017–30.

    Article  PubMed  CAS  Google Scholar 

  26. Linnik MD, Zahos P, Geschwind MD, Federoff HJ. Expression of bcl-2 from a defective herpes simplex virus-1vector limits neuronal death in focal cerebral ischemia. Stroke 1995;26(9):1670–4.

    Article  PubMed  CAS  Google Scholar 

  27. Lawrence MS, McLaughlin JR, Sun GH, Ho DY, Mcintosh L, Kunis DM, et al. Herpes simplex viral vectors expressing Bcl-2 are neuroprotective when delivered after a stroke. J Cereb Blood FlowMetab 1997;17(7):740–4.

    Article  CAS  Google Scholar 

  28. Antonawich FJ, Federoff HJ, Davis JN. BCL-2 transduction, using a herpes simplex virus amplicon, protects hippocampal neurons from transient global ischemia. Exp Neurol 1999;156(1):130–7.

    Article  PubMed  CAS  Google Scholar 

  29. Chen J, Simon RP, Nagayama T, Zhu R, Loeffert JE, Watkins SC, et al. Suppression of endogenous bcl-2 expression by antisense treatment exacerbates ischemic neuronal death (rapid communication). J Cereb Blood Flow Metab 2000;20(7):1033–9.

    Article  PubMed  CAS  Google Scholar 

  30. Eldadah BA, Faden AI. Caspase pathways, neuronal apoptosis, and CNS injury. J Neurotrauma 2000;17(10):811–29.

    Article  PubMed  CAS  Google Scholar 

  31. Hara H, Friedlander RM, Gaghardini V, Ayata C, Fink K, Huang Z, et al. Inhibition of interleukin Ibeta converting enzyme family proteases reduces ischemic and excitotoxic neuronal damage. Proc Natl Acad Sei U S A 1997;94(5):2007–12

    Article  CAS  Google Scholar 

  32. Ma J, Endres M, Moskowitz MA. Synergistic effects of caspase inhibitors and MK-801 in brain injury after transient focal cerebral ischaemia in mice, Br J Pharmacol 1998; 124(4):756–62.

    CAS  Google Scholar 

  33. Endres M, Namura S, Shimizu-Sasamata M, Waeber C, Zhang L, Gomez-Isla T, et al. Attenuation of delayed neuronal death after mild focal ischemia in mice by inhibition of the cas-pase family J Cereb Blood Flow Metab 1998;18(3):238–47.

    Article  PubMed  CAS  Google Scholar 

  34. Li H, Colbourne F, Sun P, Zhao Z, Buchau AM, ladecola C. Caspase inhibitors reduce neuronal injury after focal but not global cerebral ischemia in rats. Stroke 2000;31(1): 176–82.

    Article  PubMed  CAS  Google Scholar 

  35. Chen J, Nagayama T, Jin K, Stetler RA, Zhu RL, Graham SH, et al. Induction of caspase-3-like protease may mediate delayed neuronal death in the hippocampus after transient cerebral ischemia. J Neurosci 1998;18(13):4914–28.

    PubMed  CAS  Google Scholar 

  36. Gillardon F, Kiprianova I, Sandkuhler J, Hossmann KA, Spranger M. Inhibition of caspases prevents cell death of hippocampal CAl neurons, but not impairment of hippocampal longterm potentiation following global ischemia. Neuroscience 1999;93(4): 1219–22

    Article  PubMed  CAS  Google Scholar 

  37. Hara H, Fink K, Endres M, Friedlander RM, Gagliardini V, Yuan J, et al. Attenuation of transient focal cerebral ischemic injury in transgenic mice expressing a mutant ICE inhibitory protein. J Cereb Blood Flow Metab 1997;17(4):370–5.

    Article  PubMed  CAS  Google Scholar 

  38. Liu XH, Kwon D, Schielke GP, Yang GY, Silverstein FS, Barks JD. Mice deficient in interleukin-1 converting enzyme are resistant to neonatal hypoxic-ischemic brain damage. J Cereb Blood FlowMetab 1999;19(10):1099–108.

    Article  CAS  Google Scholar 

  39. Friedlander RM, Gaghardini V, Hara H, Fink KB, Li W, MacDonald G, et al. Expression of a dominant negative mutant of interleukin-1 beta converting enzyme in transgenic mice prevents neuronal cell death induced by trophic factor withdrawal and ischemic brain injury. J Exp Med 1997;185(5):933–40.

    Article  PubMed  CAS  Google Scholar 

  40. Schielke GP, Yang GY, Shivers BD, Betz AL. Reduced ischemic brain injury in interleukin-1 beta converting enzyme-deficient mice. J Cereb Blood Flow Metab 1998;18(2):180–5.

    Article  PubMed  CAS  Google Scholar 

  41. u D, Bureau Y, Mclntyre DC, Nicholson DW, Liston P, Zhu Y, et al. Attenuation of ischemiainduced cellular and behavioral deficits by X chromosome-linked inhibitor of apoptosis protein overexpression in the rat hippocampus. J Neurosci 1999;19(12):5026–33.

    PubMed  Google Scholar 

  42. Bonfoco E, Krainc D, Ankarcrona M, Nicotera P, Lipton SA. Apoptosis and necrosis: two distinct events induced, respectively, by mild and intense insults with N-methyl-D-aspartate or nitric oxide/superoxide in cortical cell cultures. Proc Natl Acad Sei U S A 1995;92(16):7162–6.

    Article  CAS  Google Scholar 

  43. Ankarcrona M, Dypbukt JM, Bonfoco E, Zhivotovsky B, Orrenius S, Lipton SA, et al. Glutamate-induced neuronal death: a succession of necrosis or apoptosis depending on mito-chondrial function. Neuron 1995;15(4):961–73.

    Article  PubMed  CAS  Google Scholar 

  44. White MJ, Chen J, Zhu RL, Irvin S, Sinor A, DiCaprio MJ, et al. A bcl-2 antisense oligodeoxynucleotide increases AMPA toxicity in cultured cortical neurons, submitted 1996.

    Google Scholar 

  45. Massa SM, Swanson RA, Sharp FR. The stress gene response in brain. Cerebrovasc Brain Metab Rev 1996;8(2):95–158.

    PubMed  CAS  Google Scholar 

  46. Nicotera P, Leist M, Manzo L. Neuronal cell death: a demise with different shapes. Trends Pharmacol Sei 1999;20(2):46–51.

    Article  CAS  Google Scholar 

  47. Charriaut-Marlangue C, Margaill I, Represa A, Popovici T, Plotkine M, Ben-Ari Y. Apoptosis and necrosis after reversible focal ischemia: an in situ DNA fragmentation analysis. J Cereb Blood Flow Metab 1996;16(2):186–94.

    Article  PubMed  CAS  Google Scholar 

  48. Charriaut-Marlangue C, Aggoun-Zouaoui D, Represa A, Ben-Ari Y. Apoptotic features of selective neuronal death in ischemia, epilepsy and gp 120 toxicity. Trends Neurosci 1996; 19(3):109–14.

    Article  PubMed  CAS  Google Scholar 

  49. Charriaut-Marlangue C, Ben-Ari Y. A cautionary note on the use of the TUNEL stain to determine apoptosis. Neuroreport 1995;7(1):61–4.

    PubMed  CAS  Google Scholar 

  50. Leist M, Single B, Castoldi AF, Kuhnle S, Nicotera P. Intracellular adenosine triphosphate (ATP) concentration: a switch in the decision between apoptosis and necrosis. J Exp Med 1997;185(8):1481–6.

    Article  PubMed  CAS  Google Scholar 

  51. Eguchi Y, Shimizu S, Tsujimoto Y. Intracellular ATP levels determine cell death fate by apoptosis or necrosis. Cancer Res 1997;57(10):1835–40.

    PubMed  CAS  Google Scholar 

  52. Lorenzo HK, Susin SA, Penninger J, Kroemer G. Apoptosis inducing factor (AIP): a phylogenetically old, caspase-independent effector of cell death. Cell Death Differ 1999;6(6):516–24.

    Article  PubMed  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

    Steven H. Graham MD, PhD (Associate Professor) & Robert W Hickey MD (Assistant Professor)

  2. Geriatric Research Educational and Clinical Center, Veterans Affairs Pittsburgh Health System, Pittsburgh, Pennsylvania, USA

    Steven H. Graham MD, PhD (Associate Professor)

Authors
  1. Steven H. Graham MD, PhD
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  2. Robert W Hickey MD
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© 2003 Kluwer Academic/Plenum Publishers, New York

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Graham, S.H., Hickey, R.W. (2003). The Genetic Control of Ischemic Neuronal Cell Death. In: Cerebral Blood Flow. Update in Intensive Care Medicine, vol 37. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-56036-1_8

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  • DOI: https://doi.org/10.1007/978-3-642-56036-1_8

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-540-42684-4

  • Online ISBN: 978-3-642-56036-1

  • eBook Packages: Springer Book Archive

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