title: Mechanisms of neural cell death: implications for development of neuroprotective treatment strategies.
abstract: It has been increasingly recognized that cell death phenotypes and their molecular mechanisms are highly diverse. Necrosis is no longer considered a single entity, passively mediated by energy failure. Moreover, caspase-dependent apoptosis is not the only pathway involved in programmed cell death or even the only apoptotic mechanism. Recent experimental work emphasizes the diverse and interrelated nature of cell death mechanisms. Thus, there are both caspase-dependent and caspase-independent forms of apoptosis, which may differ morphologically as well as mechanistically. There are also necrotic-like phenotypes that require de novo protein synthesis and are, therefore, forms of programmed cell death. In addition, forms of cell death showing certain morphological features of both necrosis and apoptosis have been identified, leading to the term aponecrosis. Considerable experimental evidence also shows that modulation of one form of cell death may lead to another. Together, these observations underscore the need to substantially revise our conceptions about neuroprotection strategies. Use of multiple treatments that target different cell death cascades, or single agents that moderate multiple cell death pathways, is likely to lead to more effective neuroprotection for clinical disorders.
authors.affiliation: Department of Neuroscience, Georgetown University Medical Center, Washington, DC 20057, USA.
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Yakovlev
authors.forename: Alan I
authors.initials: AI
authors.lastname: Faden
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology*; D016923:Cell Death / Q000502:physiology*; D006801:Humans; D009474:Neurons / Q000473:pathology*; D018696:Neuroprotective Agents
chemical_list: D018696:Neuroprotective Agents
references.citation: J Neurosurg. 1993 Oct;79(4):500-7
references.pmid: 8410217
references.citation: J Biol Chem. 2000 Mar 10;275(10):7337-42
references.pmid: 10702305
references.citation: J Biol Chem. 2000 Mar 24;275(12):8461-8
references.pmid: 10722681
references.citation: Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3100-5
references.pmid: 10737788
references.citation: FASEB J. 2000 Apr;14(5):729-39
references.pmid: 10744629
references.citation: J Cell Biol. 2000 May 1;149(3):613-22
references.pmid: 10791975
references.citation: J Cell Biol. 2000 May 1;149(3):623-34
references.pmid: 10791976
references.citation: EMBO J. 2000 May 15;19(10):2237-46
references.pmid: 10811615
references.citation: Prog Neurobiol. 2000 Oct;62(3):273-95
references.pmid: 10840150
references.citation: Proc Natl Acad Sci U S A. 2000 Jul 5;97(14):8093-7
references.pmid: 10869421
references.citation: Cell. 2000 Jul 7;102(1):33-42
references.pmid: 10929711
references.citation: Nat Cell Biol. 2000 Aug;2(8):469-75
references.pmid: 10934466
references.citation: EMBO J. 2000 Aug 15;19(16):4310-22
references.pmid: 10944114
references.citation: J Cell Biol. 2000 Aug 21;150(4):887-94
references.pmid: 10953012
references.citation: Nat Cell Biol. 2000 Sep;2(9):645-52
references.pmid: 10980706
references.citation: J Cereb Blood Flow Metab. 2000 Sep;20(9):1294-300
references.pmid: 10994850
references.citation: Am J Med. 2000 Mar;108(4):317-30
references.pmid: 11014725
references.citation: J Neurotrauma. 2000 Oct;17(10):811-29
references.pmid: 11063050
references.citation: J Neurotrauma. 2000 Oct;17(10):843-55
references.pmid: 11063052
references.citation: J Cell Biol. 2000 Oct 30;151(3):483-94
references.pmid: 11062251
references.citation: J Biol Chem. 2000 Nov 17;275(46):36152-7
references.pmid: 10950947
references.citation: Proc Natl Acad Sci U S A. 2000 Dec 19;97(26):14376-81
references.pmid: 11121041
references.citation: J Cell Biochem. 2001;80(3):441-54
references.pmid: 11135374
references.citation: Cell Death Differ. 2000 Nov;7(11):1045-56
references.pmid: 11139277
references.citation: FASEB J. 2001 Mar;15(3):758-67
references.pmid: 11259394
references.citation: Expert Opin Investig Drugs. 2001 Apr;10(4):753-67
references.pmid: 11281824
references.citation: J Cell Biol. 2001 Apr 2;153(1):221-8
references.pmid: 11285287
references.citation: Br J Pharmacol. 2001 Apr;132(8):1691-8
references.pmid: 11309240
references.citation: J Cereb Blood Flow Metab. 2001 May;21(5):529-40
references.pmid: 11333363
references.citation: Brain Res. 2001 May 18;901(1-2):195-201
references.pmid: 11368967
references.citation: J Neurosci. 2001 Jul 1;21(13):4752-60
references.pmid: 11425902
references.citation: Nature. 2001 Jul 5;412(6842):95-9
references.pmid: 11452314
references.citation: Mol Med. 2001 Jan;7(1):36-48
references.pmid: 11474126
references.citation: Nat Cell Biol. 2001 Sep;3(9):839-43
references.pmid: 11533664
references.citation: Cell Death Differ. 2001 Jun;8(6):569-81
references.pmid: 11536007
references.citation: J Neurosci. 2001 Oct 1;21(19):7439-46
references.pmid: 11567033
references.citation: Mol Cell. 2001 Sep;8(3):613-21
references.pmid: 11583623
references.citation: J Biol Chem. 2001 Dec 21;276(51):48404-9
references.pmid: 11606588
references.citation: Cell Death Differ. 2001 Dec;8(12):1136-42
references.pmid: 11753562
references.citation: Biochim Biophys Acta. 2001 Dec 19;1541(3):231-8
references.pmid: 11755217
references.citation: J Biol Chem. 2002 Jan 4;277(1):432-8
references.pmid: 11606597
references.citation: Stroke. 2002 Jan;33(1):308-9
references.pmid: 11779930
references.citation: Mol Neurobiol. 2001 Aug-Dec;24(1-3):131-44
references.pmid: 11831549
references.citation: J Biol Chem. 2002 Apr 19;277(16):13430-7
references.pmid: 11832478
references.citation: Mol Cell Biol. 2002 May;22(10):3509-17
references.pmid: 11971981
references.citation: J Neurochem. 2002 Jul;82(1):181-91
references.pmid: 12091479
references.citation: EMBO Rep. 2002 Jul;3(7):604-9
references.pmid: 12101090
references.citation: Cell Death Differ. 2002 Aug;9(8):807-17
references.pmid: 12107824
references.citation: J Cell Physiol. 2002 Aug;192(2):131-7
references.pmid: 12115719
references.citation: Brain Pathol. 2002 Jul;12(3):385-90
references.pmid: 12146806
references.citation: Acta Neuropathol. 2002 Sep;104(3):267-72
references.pmid: 12172912
references.citation: Science. 2002 Aug 23;297(5585):1352-4
references.pmid: 12193789
references.citation: Anat Histol Embryol. 2002 Aug;31(4):214-23
references.pmid: 12196263
references.citation: Nat Rev Cancer. 2002 Sep;2(9):647-56
references.pmid: 12209154
references.citation: Cell Death Differ. 2002 Oct;9(10):1031-42
references.pmid: 12232790
references.citation: Nature. 2002 Sep 26;419(6905):367-74
references.pmid: 12353028
references.citation: Neuroreport. 2002 Oct 28;13(15):1985-8
references.pmid: 12395105
references.citation: Nature. 2002 Oct 31;419(6910):939-44
references.pmid: 12410314
references.citation: Curr Opin Neurol. 2002 Dec;15(6):707-12
references.pmid: 12447109
references.citation: Science. 2003 Jan 10;299(5604):223-6
references.pmid: 12522243
references.citation: Exp Cell Res. 2003 Feb 1;283(1):1-16
references.pmid: 12565815
references.citation: Mech Ageing Dev. 1989 Dec;50(3):215-25
references.pmid: 2630833
references.citation: Anat Embryol (Berl). 1990;181(3):195-213
references.pmid: 2186664
references.citation: Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):2628-32
references.pmid: 8464868
references.citation: Science. 1993 Aug 6;261(5122):765-9
references.pmid: 7688144
references.citation: Ann N Y Acad Sci. 1999;893:243-53
references.pmid: 10672241
references.citation: J Cereb Blood Flow Metab. 2003 Mar;23(3):342-54
references.pmid: 12621309
references.citation: J Cereb Blood Flow Metab. 2003 Mar;23(3):355-63
references.pmid: 12621310
references.citation: Science. 2003 Apr 4;300(5616):135-9
references.pmid: 12624178
references.citation: Br J Cancer. 1972 Aug;26(4):239-57
references.pmid: 4561027
references.citation: Teratology. 1973 Jun;7(3):253-66
references.pmid: 4807128
references.citation: FASEB J. 1994 Aug;8(11):814-22
references.pmid: 8070630
references.citation: Cerebrovasc Brain Metab Rev. 1994 Summer;6(2):109-62
references.pmid: 7915532
references.citation: Stroke. 1994 Nov;25(11):2265-70
references.pmid: 7974554
references.citation: Am J Pathol. 1994 Dec;145(6):1271-9
references.pmid: 7992831
references.citation: Science. 1995 Mar 10;267(5203):1506-10
references.pmid: 7878471
references.citation: Development. 1994 Oct;120(10):3033-42
references.pmid: 7607090
references.citation: Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7162-6
references.pmid: 7638161
references.citation: J Neurotrauma. 1995 Jun;12(3):235-43
references.pmid: 7473798
references.citation: Ann Neurol. 1995 Dec;38(6):839-51
references.pmid: 8526456
references.citation: J Biol Chem. 1996 Mar 15;271(11):6306-12
references.pmid: 8626425
references.citation: Pharmacol Toxicol. 1996 Jan;78(1):12-7
references.pmid: 8685080
references.citation: Oncogene. 1996 May 16;12(10):2045-50
references.pmid: 8668329
references.citation: Cell. 1996 Oct 18;87(2):171
references.pmid: 8861900
references.citation: Nature. 1996 Nov 28;384(6607):368-72
references.pmid: 8934524
references.citation: J Neurosci. 1997 Mar 15;17(6):1911-8
references.pmid: 9045720
references.citation: J Neurosci. 1997 May 1;17(9):3112-9
references.pmid: 9096145
references.citation: J Neurotrauma. 1997 Mar;14(3):121-34
references.pmid: 9104930
references.citation: Cell. 1997 Apr 18;89(2):175-84
references.pmid: 9108473
references.citation: Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):3668-72
references.pmid: 9108035
references.citation: Cancer Res. 1997 May 15;57(10):1835-40
references.pmid: 9157970
references.citation: Biochem J. 1997 Aug 15;326 ( Pt 1):1-16
references.pmid: 9337844
references.citation: Cell. 1997 Oct 17;91(2):231-41
references.pmid: 9346240
references.citation: Nature. 1997 Oct 30;389(6654):974-8
references.pmid: 9353121
references.citation: J Child Neurol. 1998 Jan;13(1):2-15
references.pmid: 9477242
references.citation: Cell. 1998 Feb 20;92(4):501-9
references.pmid: 9491891
references.citation: J Biol Chem. 1998 Apr 3;273(14):7787-90
references.pmid: 9525868
references.citation: EMBO J. 1998 Apr 15;17(8):2215-23
references.pmid: 9545235
references.citation: Genes Dev. 1998 May 1;12(9):1304-14
references.pmid: 9573047
references.citation: EMBO J. 1998 Jul 15;17(14):3878-85
references.pmid: 9670005
references.citation: Cell. 1998 Aug 7;94(3):325-37
references.pmid: 9708735
references.citation: Cell. 1998 Aug 21;94(4):481-90
references.pmid: 9727491
references.citation: Oncogene. 1998 Sep 10;17(10):1295-304
references.pmid: 9771973
references.citation: Biochem Biophys Res Commun. 1998 Oct 9;251(1):379-87
references.pmid: 9790964
references.citation: Science. 1998 Nov 13;282(5392):1318-21
references.pmid: 9812896
references.citation: J Cell Biol. 1999 Jan 25;144(2):281-92
references.pmid: 9922454
references.citation: Proc Soc Exp Biol Med. 1999 Feb;220(2):64-72
references.pmid: 9933500
references.citation: Nature. 1999 Feb 4;397(6718):441-6
references.pmid: 9989411
references.citation: Genes Dev. 1999 Feb 1;13(3):239-52
references.pmid: 9990849
references.citation: Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):2508-13
references.pmid: 10051673
references.citation: Cancer Res. 1999 Mar 1;59(5):999-1002
references.pmid: 10070954
references.citation: Trends Biochem Sci. 1999 Feb;24(2):47-53
references.pmid: 10098397
references.citation: Science. 1999 Apr 9;284(5412):339-43
references.pmid: 10195903
references.citation: Ann Neurol. 1999 Jun;45(6):724-35
references.pmid: 10360764
references.citation: J Biol Chem. 1999 Jun 18;274(25):17484-90
references.pmid: 10364179
references.citation: J Comp Neurol. 1999 Jul 5;409(3):339-57
references.pmid: 10379822
references.citation: Cell Death Differ. 1999 Jun;6(6):508-15
references.pmid: 10381653
references.citation: Proc Natl Acad Sci U S A. 1999 Aug 17;96(17):9683-8
references.pmid: 10449754
references.citation: Toxicol Pathol. 1999 Jul-Aug;27(4):484-90
references.pmid: 10485836
references.citation: J Neurochem. 1999 Oct;73(4):1773-6
references.pmid: 10501228
references.citation: FASEB J. 1999 Oct;13(13):1875-82
references.pmid: 10506592
references.citation: Am J Physiol. 1999 Oct;277(4 Pt 2):R1196-204
references.pmid: 10516262
references.citation: Cell. 1995 Jan 27;80(2):285-91
references.pmid: 7834748
references.citation: Stroke. 1999 Dec;30(12):2704-12; discussion 2712
references.pmid: 10583001
references.citation: Nature. 2000 Jan 6;403(6765):98-103
references.pmid: 10638761
references.citation: Biochem Biophys Res Commun. 1999 Oct 22;264(2):550-5
references.pmid: 10529400
references.citation: Recent Prog Horm Res. 1999;54:213-22; discussion 222-4
references.pmid: 10548877
references.citation: Tanpakushitsu Kakusan Koso. 1999 Nov;44(14):2091-100
references.pmid: 10554602
references.citation: J Cell Physiol. 2000 Jan;182(1):41-9
references.pmid: 10567915