Abstract
Recent studies have suggested a role for neuronal apoptosis in cell loss following acute CNS injury as well as in chronic neurodegeneration. Caspases are a family of cysteine requiring aspartate proteases with sequence similarity to Ced-3 protein of Caenorhabditis elegans. These proteases have been found to contribute significantly to the morphological and biochemical manifestations of apoptotic cell death. Caspases are translated as inactive zymogens and become active after specific cleavage. Of the 14 identified caspases, caspase-3 appears to be the major effector of neuronal apoptosis induced by a variety of stimuli. A role for caspase-3 in injury-induced neuronal cell death has been established using semispecific peptide caspase inhibitors. This article reviews the current literature relating to pathways regulating caspase activation in apoptosis associated with acute and chronic neurodegeneration, and suggests that identification of critical upstream caspase regulatory mechanisms may permit more effective treatment of such disorders.
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References
Faden A. I. (1996) Pharmacological treatment of central nervous system trauma. Pharmacol. Toxicol. 78, 12–17.
Trump B. F. and Bulger R. E. (1967) Studies of cellular injury in isolated flounder tubules. I. Correlation between morphology and function of control tubules and observations of autophagocytosis and mechanical cell damage. Lab. Invest. 16, 453–482.
Yakovlev A. G., Knoblach S. M., Fan L., Fox G. B., Goodnight R., and Faden A. I. (1997) Activation of CPP32-like caspases contributes to neuronal apoptosis and neurological dysfunction after traumatic brain injury. J. Neurosci. 17, 7415–7424.
Clark R. S., Kochanek P. M., Watkins S. C., et al. (2000) Caspase-3 mediated neuronal death after traumatic brain injury in rats. J. Neurochem. 74, 740–753.
Gillardon F., Bottiger B., Schmitz B., Zimmermann M., Hossmann K. A. (1997) Activation of CPP-32 protease in hippocampal neurons following ischemia and epilepsy. Brain Res. Mol. Brain Res. 50, 16–22.
Lipton P. (1999) Ischemic cell death in brain neurons. Physiol. Rev. 79, 1431–1568.
Snider B. J., Gottron F. J., Choi D. W. (1999) Apoptosis and necrosis in cerebrovascular disease. Ann. NY Acad. Sci. 893, 243–253.
Yamashima T. (2000) Implication of cysteine proteases calpain, cathepsin and caspase in ischemic neuronal death of primates. Prog. Neurobiol. 62, 273–295.
Selznick L. A., Holtzman D. M., Han B. H., et al. (1999) In situ immunodetection of neuronal caspase-3 activation in Alzheimer disease. J. Neuropathol. Exp. Neurol. 58, 1020–1026.
Portera-Cailliau C., Hedreen J. C., Price D. L., Koliatsos V. E. (1995) Evidence for apoptotic cell death in Huntington disease and excitotoxic animal models. J. Neurosci. 15, 3775–3787.
Jellinger K. A. (2000) Cell death mechanisms in Parkinson’s disease. J. Neural. Transm. 107, 1–29.
Hartmann A., Hunot S., Michel P. P., et al. (2000) Caspase-3: a vulnerability factor and final effector in apoptotic death of dopaminergic neurons in Parkinson’s disease. Proc. Natl. Acad. Sci. USA 97, 2875–2880.
Martin L. J. (1999) Neuronal death in amyotrophic lateral sclerosis is apoptosis: possible contribution of a programmed cell death mechanism. J. Neuropathol. Exp. Neurol. 58, 459–471.
Honig L. S. and Rosenberg R. N. (2000) Apoptosis and neurologic disease. Am. J. Med. 108, 317–330.
Wellington C. L. and Hayden M. R. (2000) Caspases and neurodegeneration: on the cutting edge of new therapeutic approaches. Clin. Genet. 57, 1–10.
Kerr J. F., Wyllie A. H., and Currie A. R. (1972) Apotosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer 26, 239–257.
Bredesen D. E. (1995) Neural apoptosis. Ann. Neurol 38, 839–851.
Wyllie A. H., Kerr J. F., and Currie A. R. (1980) Cell death: the significance of apoptosis. Int. Rev. Cytol. 68, 251–306.
Horvitz H. R. (1999) Genetic control of programmed cell death in the nematode Caenorhabditis elegans. Cancer Res. 59, 1701s-1706s.
Yuan J., Shaham S., Ledoux S., Ellis H. M., and Horvitz H. R. (1993) The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1 beta-converting enzyme. Cell 75, 641–652.
Yuan J. and Horvitz H. R. (1992) The Caenorhabditis elegans cell death gene ced-4 encodes a novel protein and is expressed during the period of extensive programmed cell death. Development 116, 309–320.
Hengartner M. O. and Horvitz H. R. (1994) Programmed cell death in Caenorhabditis elegans. Curr. Opin. Genet. Dev. 4, 581–586.
Hengartner M. O. (1999) Programmed cell death in the nematode C. elegans. Recent Prog. Horm. Res. 54, 213–222.
Hengartner M. (1998) Apoptosis. Death by crowd control [comment]. Science 281, 1298–1299.
Alnemri E. S., Livingston D. J., Nicholson D. W., et al. (1996) Human ICE/CED-3 protease nomenclature [letter]. Cell 87, 171.
Thornberry N. A., Rano T. A., Peterson E. P., et al. (1997) A combinatorial approach defines specificities of members of the caspase family and granzyme B. Functional relationships established for key mediators of apoptosis. J. Biol. Chem. 272, 17,907–17,911.
Thornberry N. A. and Lazebnik Y. (1998) Caspases: enemies within. Science 281, 1312–1316.
Martin S. J. and Green D. R. (1995) Protease activation during apoptosis: death by a thousand cuts? Cell 82, 349–352.
Zhivotovsky B., Burgess D. H., and Orrenius S. (1996) Proteases in apoptosis. Experientia 52, 968–978.
Cohen G. M. (1997) Caspases: the executioners of apoptosis. Biochem. J. 326, 1–16.
Miura M., Zhu H., Rotello R., Hartwieg E. A., and Yuan J. (1993) Induction of apoptosis in fibroblasts by IL-1 beta-converting enzyme, a mammalian homolog of the C. elegans cell death gene ced-3. Cell 75, 653–660.
Fernandes-Alnemri T., Litwack G., and Alnemri E. S. (1994) CPP32, a novel human apoptotic protein with homology to Caenorhabditis elegans cell death protein Ced-3 and mammalian interleukin-1 beta- converting enzyme. J. Biol. Chem. 269, 30,761–30,764.
Kuida K., Zheng T. S., Na S., et al. (1996) Decreased apoptosis in the brain and premature lethality in CPP32- deficient mice. Nature 384, 368–372.
Gottron F. J., Ying H. S., and Choi D. W. (1997) Caspase inhibition selectively reduces the apoptotic component of oxygen-glucose deprivation-induced cortical neuronal cell death. Mol. Cell Neurosci. 9, 159–169.
Fink K., Zhu J., Namura S., et al. (1998) Prolonged therapeutic window for ischemic brain damage caused by delayed caspase activation. J. Cereb. Blood Flow Metab. 18, 1071–1076.
Eldadah B. A., Yakovlev A. G., and Faden A. I. (1997) The role of CED-3-related cysteine proteases in apoptosis of cerebellar granule cells. J. Neurosci. 17, 6105–6113.
Namura S., Zhu J., Fink K., et al. (1998) Activation and cleavage of caspase-3 in apoptosis induced by experimental cerebral ischemia. J. Neurosci. 18, 3659–3668.
Clark R. S., Kochanek P. M., Chen M., et al. (1999) Increases in Bc1-2 and cleavage of caspase-1 and caspase-3 in human brain after head injury. FASEB J. 13, 813–821.
Allen J. W., Knoblach S. M., and Faden A. I. (1999) Combined mechanical trauma and metabolic impairment in vitro induces NMDA receptor-dependent neuronal cell death and caspase-3-dependent apoptosis. FASEB J. 13, 1875–1882.
Scaffidi C., Fulda S., Srinivasan A., et al. (1998) Two CD95 (APO-1/Fas) signaling pathways. EMBO J. 17, 1675–1687.
Li P., Nijhawan D., Budihardjo I., et al. (1997) Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91, 479–489.
Slee E. A., Harte M. T., Kluck R. M., et al. (1999) Ordering the cytochrome c-initiated caspase cascade: hierarchical activation of caspases-2, -3, -6, -7, -8, and-10 in a caspase-9-dependent manner. J. Cell Biol. 144, 281–292.
Ashkenazi A. and Dixit V. M. (1998) Death receptors: signaling and modulation. Science 281, 1305–1308.
Aravind L., Dixit V. M., and Koonin E. V. (1999) The domains of death: evolution of the apoptosis machinery. Trends Biochem Sci. 24, 47–53.
Nagata S. (1997) Apoptosis by death factor. Cell 88, 355–365.
Boldin M. P., Goncharov T. M., Goltsev Y. V., and Wallach D. (1996) Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death. Cell 85, 803–815.
Fernandes-Alnemri T., Armstrong R. C., Krebs J., et al. (1996) In vitro activation of CPP32 and Mch3 by Mch4, a novel human apoptotic cysteine protease containing two FADD-like domains. Proc. Natl. Acad. Sci. USA 93, 7464–7469.
Muzio M., Chinnaiyan A. M., Kischkel F. C., et al. (1996) FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex. Cell 85, 817–827.
Kischkel F. C., Hellbardt S., Behrmann I., et al. (1995) Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor. EMBO J. 14, 5579–5588.
Woo M., Hakem A., Elia A. J., et al. (1999) In vivo evidence that caspase-3 is required for Fas-mediated apoptosis of hepatocytes. J. Immunol. 163, 4909–4916.
Li H., Zhu H., Xu C. J., and Yuan J. (1998) Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94, 491–501.
Murphy K. M., Streips U. N., and Lock R. B. (1999) Bax membrane insertion during Fas(CD95)-induced apoptosis precedes cytochrome c release and is inhibited by Bcl-2. Oncogene 18, 5991–5999.
Luo X., Budihardjo I., Zou H., Slaughter C., and Wang X. (1998) Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 94, 481–490.
Kudla G., Montessuit S., Eskes R., et al. (2000) The destabilization of lipid membranes induced by the C-terminal fragment of caspase 8-cleaved bid is inhibited by the N-terminal fragment. J. Biol. Chem. 275, 22,713–22,718.
Irmler M., Thome M., Hahne M., et al. (1997) Inhibition of death receptor signals by cellular FLIP [see comments]. Nature 388, 190–195.
Zou H., Henzel W. J., Liu X., Lutschg A., and Wang X. (1997) Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3 [see comments]. Cell 90, 405–413.
Zou H., Li Y., Liu X., and Wang X. (1999) An APAF-1. cytochrome c multimeric complex is a functional apoptosome that activates procaspase-9. J. Biol. Chem. 274, 11,549–11,556.
Kulms D. and Schwarz T. (2000) Molecular mechanisms of UV-induced apoptosis. Photodermatol. Photoimmunol. Photomed. 16, 195–201.
Robertson J. D. and Orrenius S. (2000) Molecular mechanisms of apoptosis induced by cytotoxic chemicals. Crit. Rev. Toxicol. 30, 609–627.
Richter C. and Ghafourifar P. (1999) Ceramide induces cytochrome c release from isolated mitochondria. Biochem. Soc. Symp. 66, 27–31.
Brown G. C. and Borutaite V. (1999) Nitric oxide, cytochrome c and mitochondria. Biochem. Soc. Symp. 66, 17–25.
Hakem R., Hakem A., Duncan G. S., et al. (1998) Differential requirement for caspase 9 in apoptotic pathways in vivo. Cell 94, 339–352.
Cecconi F., Alvarez-Bolado G., Meyer B. I., Roth K. A., and Gruss P. (1998) Apaf1 (CED-4 homolog) regulates programmed cell death in mammalian development. Cell 94, 727–737.
Yoshida H., Kong Y. Y., Yoshida R., et al. (1998) Apaf1 is required for mitochondrial pathways of apoptosis and brain development. Cell 94, 739–750.
Honarpour N., Du C., Richardson J. A., Hammer R. E., Wang X., and Herz J. (2000) Adult Apaf-1-deficient mice exhibit male infertility. Dev. Biol. 218, 248–258.
Kuida K., Haydar T. F., Kuan C. Y., et al. (1998) Reduced apoptosis and cytochrome c-mediated capsase activation in mice lacking caspase 9. Cell 94, 325–337.
Gonzalez-Garcia M., Perez-Ballestero R., Ding L., et al. (1994) bcl-XL is the major bcl-x mRNA form expressed during murine development and its product localizes to mitochondria. Development 120, 3033–3042.
Motoyama N., Wang F., Roth K. A., et al. (1995) Massive cell death of immature hematopoietic cells and neurons in Bcl-x- deficient mice. Science 267, 1506–1510.
Pan G., O’Rourke K., and Dixit V. M. (1998) Caspase-9, Bcl-XL, and Apaf-1 form a ternary complex. J. Biol. Chem. 273, 5841–5845.
Moriishi K., Huang D. C., Cory S., and Adams J. M. (1999) Bcl-2 family members do not inhibit apoptosis by binding the caspase activator Apaf-1. Proc. Natl. Acad. Sci. USA 96, 9683–9688.
Hausmann G., O’Reilly L. A., van Driel R., et al. (2000) Pro-apoptotic apoptosis protease-activating factor 1 (Apaf-1) has a cytoplasmic localization distinct from Bcl-2 or Bcl-x(L). J. Cell. Biol. 149, 623–634.
Shimizu S., Konishi A., Kodama T., and Tsujimoto Y. (2000) BH4 domain of antiapoptotic Bcl-2 family members closes voltage-dependent anion channel and inhibits apoptotic motochondrial canges and cell death [published erratum appears in Proc. Natl. Acad. Sci. USA 2000 Aug 1;97(16):9347]. Proc. Natl. Acad. Sci. USA 97, 3100–3105.
Fujita N., Nagahashi A., Nagashima K., Rokudai S., and Tsuruo T. (1998) Acceleration of apoptotic cell death after the cleavae of Bcl-XL protein by caspase-3-like proteases. Oncogene 17, 1295–1304.
Hsu Y. T., Wolter K. G., and Youle R. J. (1997) Cytosol-to-membrane redistribution of Bax and Bcl-X(L) during apotposis. Proc. Natl. Acad. Sci. USA 94, 3668–3672.
Wolter K. G., Hsu Y. T., Smith C. L., Nechustan A., Xi X. G., and Youle R. J. (1997) Movement of Bax from the cytosol to mitochondria durin apoptosis. J. Cell Biol. 139, 1281–1292.
Goping I. S., Gross A., Lavoie J. N., et al. (1998) Regulated targeting of BAX to mitochondria. J. Cell Biol. 143, 207–215.
Chinnaiyan A. M. (1999) The apoptosome: heart and soul of the cell death machine. Neoplasia 1, 5–15.
Eskes R., Antonsson B., Osen-Sand A., et al. (1998) Bax-induced cytochrome C release from mitochondria is independent of the permeability transition pore but highly dependent on Mg2+ ions. J. Cell Biol. 143, 217–224.
Priault M., Chaudhuri B., Clow A., Camougrand N., and Manon S. (1999) Investigation of bax-induced release of cytochrome c from yeast mitochondria permeability of motochondrial membranes, role of VDAC and ATP requirement. Eur. J. Biochem. 260, 684–691.
Gross A., Jockel J., Wei M. C., and Korsmeyer S. J. (1998) Enforced dimerization of BAX results in its translocation, mitochondrial dysfunction and apoptosis. EMBO J. 17, 3878–3885.
Shindler K. S., Latham C. B., and roth K. A. (1997) Bax deficiency prevents the increased cell death of immature neurons in bcl-x-deficient mice. J. Neurosci. 17, 3112–3119.
Sedlak T. W., Oltvai Z. N., Yang E., et al. (1995) Multiple Bcl-2 family members demonstrate selective dimerizations with Bax. Proc. Natl. Acad. Sci. USA 92, 7834–7838.
Knudson C. M., Tung K. S., tourtellotte W. G., Brown G. A., and Korsmeyer S. J. (1995) Baxdeficient mice with lymphoid hyperplasia and male erm cell death. Science 270, 96–99.
Deckwerth T. L., Elliott J. L., Knudson C. M., Johnson E. M., Jr., Snider W. D., and Korsmeyer S. J. (1996) BAX is required for neuronal death after trophic factor deprivation and during development. Neuron 17, 401–411.
Minn A. J., Boise L. H., and Thompson C. B. (1996) Bcl-x(S) anatagonizes the protective effects of Bcl-x(L). J. Biol. Chem. 271, 6306–6312.
Yang X. F., Weber G. F., and Cantor H. (1997) A novel Bcl-x isoform connected to the T cell receptor regulates apoptosis in T cells. Immunity 7, 629–639.
Srinivasula S. M., Ahmad M., Guo Y., et al. (1999) Identification of an endogenous dominant-negative short isoform of caspase-9 that can regulate apoptosis. Cancer Res. 59, 999–1002.
Benedict M. A., Hu Y., Inohara N., and Nunez G. (2000) Expression and functional analysis of Apaf-1 isoforms. Extra Wd-40 repeat is required for cytochrome c binding and regulated activation of procaspase-9. J. Biol. Chem. 275, 8461–8468.
Jiang Z. H. and Wu J. Y. (1999) Alternative splicing and programmed cell death. Proc. Soc. Exp. Biol. Med. 220, 64–72.
Cardone M. H., Roy N., Stennicke H. R., et al. (1998) Regulation of cell death protease caspase-9 by phosphorylation [see comments]. Science 282, 1318–1321.
Fujita E. Jinbo A., Matuzaki H., Konishi H., Kikkawa U., and Momoi T. (1999) Akt phosphorylation site found in human caspase-9 is absent in mouse caspase-9. Biochem. Biophys. Res. Commun. 264, 550–555.
Zhou H. Li X. M., Meinkoth J., and Pittman R. N. (2000) Akt regulates cell survival and apoptosis at a postmitochondrial level [In Process Citation]. J. Cell Biol. 151, 483–494.
Datta S.R., Dudek H., Tao X., et al. (1997) Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91, 231–241.
Wang H. G., Pathan N., Ethell I. M., et al. (1999) Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD. Science 284, 339–343.
Ayllon V., Martinez A. C., Garcia A., Cayla X., and Rebollo A. (2000) Protein phosphatase 1alpha is a Ras-activated Bad phosphatase that regulates interleukin-2 deprivation-induced apoptosis. EMBO J. 19, 2237–2246.
Yang E., Zha J., Jockel J., Boise L. H., Thompson C. B., and Korsmeyer S. J. (1995) Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death. Cell 80, 285–291.
Francois F. and Grimes M. L. (1999) Phosphorylation-dependent Akt cleavage in neural cell in vitro reconstitution of apoptosis. J. Neurochem. 73, 1773–1776.
Pandey P., Saleh A., Nakazawa A., et al. (2000) Negative regulation of cytochrome c-mediated oligomerization of apaf-1 and activation of procaspase-9 by heat shock protein 90 [In Process Citation]. EMBO J. 19, 4310–4322.
Beere H. M., Wolf B. B., Cain K., et al. (2000) Heat-shock protein 70 inhibits apoptosis by preventing recruitment of procaspase-9 to the Apaf-1 apoptosome. Nat. Cell Biol. 2, 469–475.
Bruey J. M., Ducasse C., Bonniaud P., et al. (2000) Hsp27 negatively regulates cell death by interacting with cytochrome c. Nat. Cell Biol. 2, 645–652.
Hay B. A. (2000) Understanding IAP function and regulation: a view from Drosophila. Cell Death Differ 7, 1045–1056.
Du C., Fang M., Li Y., Li L., and Wang X. (2000) Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating 1AP inhibition. Cell 102, 33–42.
Nakagawa T., Zhu H., Morishima N., et al. (2000) Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature 403, 98–103.
Bitko V. and Barik S. (2001) An endoplasmic reticulum-specific stress-activated caspase (caspase-12) is implicated in the apoptosis of A549 epithelial cells by respiratory syncytial virus. J. Cell Biochem. 80, 441–454.
Nakagawa T. and Yuan J. (2000) Cross-talk between two cysteine protease families. Activation of caspase-12 by calpain in apoptosis. J. Cell Biol. 150, 887–894.
Wang S., Miura M., Jung Y. K., Zhu H., Li E., and Yuan J. (1998) Murine caspase-11, an ICE-interacting protease, is essential for the activation of ICE. Cell 92, 501–509.
Kang S. J., Wang S., Hara H., et al. (2000) Dual role of caspase-11 in mediating activation of caspase-1 and caspase-3 under pathological conditions. J. Cell Biol. 149, 613–622.
Schotte P., Van Criekinge W., Van de Craen M., et al. (1998) Cathepsin B-mediated activation of the proinflammatory caspase-11. Biochem. Biophys. Res. Commun. 251, 379–387.
Hall K. E. and Wiley J. W. (1998) Neural injury, repair and adaptation in the GI tract. I. New insights into neuronal injury: a cautionary tale. Am. J. Physiol. 274, G978–983.
Krajewski S., Krajewska M., Ellerby L. M., et al. (1999) Release of caspase-9 from mitochondria during neuronal apoptosis and cerebral ischemia. Proc. Natl. Acad. Sci. USA 96, 5752–5757.
Morita-Fujimura Y., Fujimura M., Kawase M., Chen S. F., and Chan P. H. (1999) Release of mitochondrial cytochrome c and DNA fragmentation after cold injury-induced brain trauma in mice: possible role in neuronal apoptosis. Neurosci. Lett. 267, 201–205.
Buki A., Okonkwo D. O., Wang K. K., and Povlishock J. T. (2000) Cytochrome c release and caspase activation in traumatic axonal injury. J. Neurosci. 20, 2825–2834.
Tamatani M., Mitsuda N., Matsuzaki H., et al. (2000) A pathway of neuronal apoptosis induced by hhpoxia/reoxygenation: roles of nuclear factor-kappaB and Bcl-2. J. Neurochem. 75, 683–693.
Ouyang Y. B., He Q. P., Li P. A., Janelidze S., Wang G. X., and Siesjo B. K. (2000) Is neuronal injury caused by hypoglycemic coma of the necrotic or apoptotic type? [In Process Citation]. Neurochem. Res. 25, 661–667.
Deshmukh M., Kuida K., and Johnson E. M., Jr. (2000) Caspase inhibition extends the commitment to neuronal death beyond cytochrome c release to the point of mitochondrial depolarization. J. Cell Biol. 150, 131–143.
Knoblach S. M., Fan L., Huang X., Krajewski S., Reed J. C., and Faden A. I. (2000) Activation of caspases 3 and 9 after traumatic brain injury in the rat: treatment with a pan-caspase inhibitor improves outcome. Soc. Neurosci. Abst.
Endres M., Namura S., Shimizu-Sasamata M., et al. (1998) Attenuation of delayed neuronal death after mild focal ischemia in mice by inhibition of the caspase family. J. Cereb. Blood Flow Metab. 18, 238–247.
Bossenmeyer-Pourie C., Koziel V., and Daval J. L. (1999) CPP32/CASPASE-3-like proteases in hypoxia-induced apoptosis indeveloping brain neurons. Brain Res. Mol. Brain Res. 71, 225–237.
Kondratyev A. and Gale K. (2000) Intracerebral injection of caspase-3 inhibitor prevents neuronal apoptosis after kainic acid-evoked status epilepticus. Brain Res. Mol. Brain Res. 75, 216–224.
Kermer P., Klocker N., and Bahr M. (1999) Long-term effect of inhibition of ced 3-like caspases on the survival of axotomized retinal ganglion cells in vivo. Exp. Neurol. 158, 202–205.
Springer J. E., Azbill R. D., and Knapp P. E. (1999) Activation of the caspase-3 apoptotic cascade in traumatic spinal cord injury. Nat. Med. 5, 943–946.
Sanchez I., Xu C. J., Juo P., Kakizaka A., Blenis J., and Yuan J. (1999) Caspase-8 is required for cell death induced by expanded polyglutamine repeats [see comments]. Neuron 22, 623–633.
Ivins K. J., Thornton P. L., Rohn T. T., and Cotman C. W. (1999) Neuronal apoptosis induced by beta-amyloid is mediated by caspase-8. Neurobiol. Dis. 6, 440–449.
Felderhoff-Mueser U., Taylor D. L., Greenwood K., et al. (2000) Fas/CD95/APO-1 can function as a death receptor for neuronal cells in vitro and in vivo and is upregulated following cerebral hypoxic-ischemic injury to the developing rat brain. Brain Pathol. 10, 17–29.
Matsushita K., Wu Y., Qiu J., et al. (2000) Fas receptor and neuronal cell death after spinal cord ischemia. J. Neurosci. 20, 6879–6887.
Velier J. J., Ellison J. A., Kikly K. K., Spera P. A., Barone F. C., and Feuerstein G. Z. (1999) Caspase-8 and caspase-3 are expressed by different populations of cortical neurons undergoing delayed cell death after focal stroke in the rat. J. Neurosci. 19, 5932–5941.
Bittigau P., Sifringer M., Pohl D., et al. (1999) Apoptotic neurodegeneration following trauma is markedly enhanced in the immature brain. Ann. Neurol. 45, 724–735.
Pohl D., Bittigau P., Ishimaru M. J., et al. (1999) N-Methyl-D-aspartate antagonists and apoptotic cell death triggered by head trauma in developing rat brain. Proc. Natl. Acad. Sci. USA 96, 2508–2513.
de Bilbao F., Guarin E., Nef P., Vallet P., Giannakopoulos P., and Dubois-Dauphin M. (1999) Postnatal distribution of cpp32/caspase 3 mRNA in the mouse central nervous system: an in situ hybridization study. J. Comp. Neurol. 409, 339–357.
Hu B. R., Liu C. L., Ouyang Y., Blomgren K., and Siesjo B. K. (2000) Involvement of caspase-3 in cell death after hypoxia-ischemia declines during brain maturation. J. Cereb. Blood Flow Metab. 20, 1294–1300.
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Yakovlev, A.G., Faden, A.I. Caspase-dependent apoptotic pathways in CNS injury. Mol Neurobiol 24, 131–144 (2001). https://doi.org/10.1385/MN:24:1-3:131
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DOI: https://doi.org/10.1385/MN:24:1-3:131