Apoptosis and Necrosis in Cerebrovascular Disease
B. JOY SNIDER,
FRANK J. GOTTRON,
DENNIS W. CHOI,
Corresponding Author
B. JOY SNIDER
Center for the Study of Nervous System Injury and the Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA
Address for correspondence: B. Joy Snider, Department of Neurology, Campus Box 8111, 660 S. Euclid, St. Louis, Missouri 63110. Phone: 314-747-2107; fax: 314-362-9462. e-mail: [email protected]Search for more papers by this authorFRANK J. GOTTRON
Center for the Study of Nervous System Injury and the Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA
Search for more papers by this authorDENNIS W. CHOI
Center for the Study of Nervous System Injury and the Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA
Search for more papers by this authorB. JOY SNIDER,
FRANK J. GOTTRON,
DENNIS W. CHOI,
Corresponding Author
B. JOY SNIDER
Center for the Study of Nervous System Injury and the Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA
Address for correspondence: B. Joy Snider, Department of Neurology, Campus Box 8111, 660 S. Euclid, St. Louis, Missouri 63110. Phone: 314-747-2107; fax: 314-362-9462. e-mail: [email protected]Search for more papers by this authorFRANK J. GOTTRON
Center for the Study of Nervous System Injury and the Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA
Search for more papers by this authorDENNIS W. CHOI
Center for the Study of Nervous System Injury and the Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA
Search for more papers by this authorAbstract
ABSTRACT: Neuronal death following ischemic insults has been thought to reflect necrosis. However, recent evidence from several labs suggests that programmed cell death, leading to apoptosis, might additionally contribute to this death. We have used both in vitro and in vivo models to study the role of apoptosis in ischemic cell death. Some features of apoptosis (TUNEL staining, internucleosomal DNA fragmentation, sensitivity to cycloheximide) were observed following transient focal ischemia in rats. Brief transient focal ischemia was followed by delayed infarction more than 3 days later; this delayed infarction was sensitive to cycloheximide. A cycloheximide-sensitive component of neuronal cell death was also observed in cultured murine neocortical neurons deprived of oxygen-glucose in the presence of glutamate receptor antagonists. This presumed ischemic apoptosis was attenuated by caspase inhibitors, or by homozygous deletion of the bax gene. Neurons may undergo both apoptosis and necrosis after ischemic insults, and thus it may be therapeutically desirable to block both processes.
REFERENCES
- 1
Kerr, J.F.R. & B.V. Harmon. 1991. Definition and incidence of apoptosis: an historical perspective. In Apoptosis: the Molecular Basis Of Cell Death. L. D. Tomei & F. O. Cope, Eds.: 5–29. Cold Spring Harbor Laboratory Press. Plainview, NY.
- 2
Kerr, J.F., A.H. Wyllie & A.R. Currie.
1972. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics.
Br. J. Cancer
26: 239–257.
- 3
Wyllie, A.H., J.F.R. Kerr & A.R. Currie.
1990. Cell death: the significance of apoptosis.
Int. Rev. Cytol.
68: 251–306.
- 4
Walker, N.I., B.V. Harmon, G.C. Gobe
et al.
1988. Patterns of cell death.
Methods Achiev. Exp. Pathol.
13: 18–54.
- 5
Johnson, E.M.Jr., & T.L. Deckwerth.
1993. Molecular mechanisms of developmental neuronal death.
Ann. Rev. Neurosci.
16: 31–46.
- 6
Hengartner, M.O. & H.R. Horvitz.
1994. Programmed cell death in Caenorhabditis elegans.
Curr Opin Genet Dev
4: 581–586.
- 7
Jacobson, M.D., M. Weil & M.C. Raff.
1997. Programmed cell death in animal development.
Cell
88: 347–354.
- 8
Vaux, D.L. & S.J. Korsmeyer.
1999. Cell death in development.
Cell
96: 245–254.
- 9
Charriaut-Marlangue, C. & Y. Ben-Ari.
1995. A cautionary note on the use of the TUNEL stain to determine apoptosis.
Neuroreport
7: 61–64.
- 10
Portera-Cailliau, C., J.C. Hedreen, D.L. Price
et al.
1995. Evidence for apoptotic cell death in Huntington disease and excitotoxic animal models.
J. Neurosci
15: 3775–3787.
- 11
Petito, C.K., J. Torres-Munoz, B. Roberts
et al.
1997. DNA fragmentation follows delayed neuronal death in CA1 neurons exposed to transient global ischemia in the rat.
J. Cereb. Blood Flow Metab.
17: 967–976.
- 12
Portera-Cailliau, C., D.L. Price & L.J. Martin.
1997. Excitotoxic neuronal death in the immature brain is an apoptosis-necrosis morphological continuum.
J. Comp. Neurol.
378: 70–87.
- 13
Mehmet, H., X. Yue, J. Penrice
et al.
1998. Relation of impaired energy metabolism to apoptosis and necrosis following transient cerebral hypoxia-ischaemia.
Cell Death Differ.
5: 321–329.
- 14
Fukuda, T., H. Wang, H. Nakanishi
et al.
1999. Novel non-apoptotic morphological changes in neurons of the mouse hippocampus following transient hypoxic-ischemia.
Neurosci. Res.
33: 49–55.
- 15
Yue, X., H. Mehmet, J. Penrice
et al.
1997. Apoptosis and necrosis in the newborn piglet brain following transient cerebral hypoxia-ischaemia.
Neuropathol. Appl. Neurobiol.
23: 16–25.
- 16
Bonfoco, E., D. Krainc, M. Ankarcrona
et al.
1995. 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. Sci. USA
92: 7162–7166.
- 17
Li, Y., C. Powers, N. Jiang et al.
1998. Intact, injured, necrotic and apoptotic cells after focal cerebral ischemia in the rat.
J. Neurol. Sci.
156: 119–132.
- 18
Gwag, B.J., D. Lobner, J.Y. Koh
et al.
1995. Blockade of glutamate receptors unmasks neuronal apoptosis after oxygen-glucose deprivation in vitro.
Neuroscience
68: 615–619.
- 19
Meldrum, B., M. Evans, T. Griffiths
et al.
1985. Ischaemic brain damage: the role of excitatory activity and of calcium entry.
Br. J. Anaesth.
57: 44–46.
- 20
Rothman, S.M. & J.W. Olney.
1986. Glutamate and the pathophysiology of hypoxic-ischemic brain damage.
Ann. Neurol.
19: 105–111.
- 21
Choi, D.W.
1988. Calcium-mediated neurotoxicity: relationship to specific channel types and role in ischemic damage.
Trends Neurosci.
11: 465–469.
- 22
Siesjo, B. & F. Bengtsson.
1989. Calcium fluxes, calcium antagonists, and calcium-related pathology in brain ischemia, hypoglycemia, and spreading depression: a unifying hypothesis.
J. Cereb. Blood Flow Metab.
9: 127–140.
- 23
Choi, D.W.
1988. Glutamate neurotoxicity and diseases of the nervous system.
Neuron
1: 623–634.
- 24
Hall, E.D.
1997. Brain attack.
Acute therapeutic interventions. Free radical scavengers and antioxidants. Neurosurg. Clin. N. Am.
8: 195–206.
- 25
Samdani, A.F., T.M. Dawson & V.L. Dawson.
1997. Nitric oxide synthase in models of focal ischemia.
Stroke
28: 1283–1288.
- 26
Ikeda, J., S. Terakawa, S. Murota
et al.
1996. Nuclear disintegration as a leading step of glutamate excitotoxicity in brain neurons.
J. Neurosci. Res.
43: 613–622.
- 27
Gwag, B.J., J.-Y. Koh, J.A. Demaro
et al.
1997. Slowly-triggered excitotoxicity occurs by necrosis in cortical cultures.
Neuroscience
77: 393–401.
- 28
MacManus, J.P., I. Rasquinha, M.A. Black
et al.
1997. Glutamate-treated rat cortical neuronal cultures die in a way different from the classical apoptosis induced by staurosporine.
Exp. Cell Res.
233: 310–320.
- 29
Bonfoco, E., D. Krainc, M. Ankarcrona
et al.
1995. 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. Sci. USA
92: 7162–7166.
- 30
Bortner, C.D., F.M. Hughes, JR. & J.A. Cidlowski.
1997. A primary role for K+ and Na+ efflux in the activation of apoptosis.
J. Biol. Chem.
272: 32436–32442.
- 31
Yu, S.P., C.H. Yeh, S.L. Sensi
et al.
1997. Mediation of neuronal apoptosis by enhancement of outward potassium current.
Science
278: 114–117.
- 32
Ratan, R.R., T.H. Murphy & J.M. Baraban.
1994. Oxidative stress induces apoptosis in embryonic cortical neurons.
J. Neurochem.
62: 376–379.
- 33
Whittemore, E.R., D.T. Loo & C.W. Cotman.
1994. Exposure to hydrogen peroxide induces cell death via apoptosis in cultured rat cortical neurons.
Neuroreport
5: 1485–1488.
- 34
Greenlund, L.J., T.L. Deckwerth & E.M. Johnson, JR.
1995. Superoxide dismutase delays neuronal apoptosis: a role for reactive oxygen species in programmed neuronal death.
Neuron
14: 303–315.
- 35
Adams, J.H. & L.W. Duchen. 1992. Greenfield's Neuropathology: 1557. Oxford University Press. New York.
- 36
MacManus, J.P., A.M. Buchan, I.E. Hill
et al.
1993. Global ischemia can cause DNA fragmentation indicative of apoptosis in rat brain.
Neurosci. Lett.
164: 89–92.
- 37
Gillardon, F., B. Bottiger, B. Schmitz
et al.
1997. Activation of CPP-32 protease in hippocampal neurons following ischemia and epilepsy.
Brain Res. Mol. Brain Res.
Z50: 16–22.
- 38
Chen, J., T. Nagayama, K. Jin
et al.
1998. Induction of caspase-3-like protease may mediate delayed neuronal death in the hippocampus after transient cerebral ischemia.
J. Neurosci.
18: 4914–4928.
- 39
Nunez, G., M.A. Benedict, Y. Hu
et al.
1998. Caspases: the proteases of the apoptotic pathway.
Oncogene
17: 3237–3245.
- 40
Krajewski, S., M. Krajewska, L.M. Elleerby
et al.
1999. Release of caspase-9 from mitochondria during neuronal apoptosis and cerebral ischemia.
Proc. Natl. Acad. Sci. USA
96: 5752–5757.
- 41
Colbourne, F., G.R. Sutherland & R.N. Auer.
1999. Electron micoscopic evidence against apoptosis as the mechanism of neuronal death in global ischemia.
J. Neurosci.
19: 4200–4210.
- 42
Degirlami, U., R.M. Crowell & F.W. Marcoux.
1984. Selective necrosis and total necrosis in focal cerebral ischemia.
Neuropathologic observations on experimental middle cerebral artery occlusion in the macaque monkey. J. Neuropathol. Exp. Neurol.
43: 57–71.
- 43
Nakano, S., K. Kogure & H. Fujikura.
1990. Ischemia-induced slowly progressive neuronal damage in the rat brain.
Neuroscience
38: 115–124.
- 44
Garcia, J.H., K.F. Liu & J.K. Relton.
1995. Interleukin-1 receptor antagonist decreases the number of necrotic neurons in rats with middle cerebral artery occlusion.
Am. J. Pathol.
147: 1477–1486.
- 45
Dereski, M.O., M. Chopp, R.A. Knight et al.
1993. The heterogeneous temporal evolution of focal ischemic neuronal damage in the rat.
Acta Neuropathol.
85: 327–333.
- 46
Tominaga, T., S. Kure, K. Narisawa
et al.
1993. Endonuclease activation following focal ischemic injury in the rat brain.
Brain Res.
608: 21–26.
- 47
Li Y., M. Chopp, N. Jiang
et al.
1995. Induction of DNA fragmentation after 10 to 120 minutes of focal cerebral ischemia in rats.
Stroke
26: 1252–1257;discussion 7–8.
- 48
Linnik, M.D., J.A. Miller, J. Sprinkle-Cavallo
et al.
1995. Apoptotic DNA fragmentation in the rat cerebral cortex induced by permanent middle cerebral artery occlusion.
Brain Res. Mol. Brain Res.
32: 116–124.
- 49
Du, C., R. Hu, C.A. Csernansky
et al.
1996. Very delayed infarction after mild focal cerebral ischemia: a role for apoptosis? J.
Cereb. Blood Flow Metab.
16: 195–201.
- 50
Martin-Villalba, A., I. Herr, I. Jeremias
et al.
1999. CD95 ligand (Fas-L/APO-1L) and tumor necrosis factor-related apoptosis-inducing ligand mediate ischemia-induced apoptosis in neurons.
J. Neurosc.i
19: 3809–3817.In press.
- 51
Fujimura, M., Y. Morita-Fujimura, K. Murakami
et al.
1998. Cytosolic redistribution of cytochrome c after transient focal cerebral ischemia in rats.
J. Cereb. Blood Flow Metab.
18: 1239–1247.
- 52
Namura, S., J. Zhu, K. Fink
et al.
1998. Activation and cleavage of caspase-3 in apoptosis induced by experimental cerebral ischemia.
J. Neurosci.
18: 3659–3668.
- 53
Linnik. M.D., R.H. Zobrist & M.D. Hatfield.
1993. Evidence supporting a role for programmed cell death in focal cerebral ischemia in rats.
Stroke
24: 2002–2008.
- 54
Du, C., R. Hu, C.A. Csernansky
et al.
1996. Additive neuroprotective effects of dextrorphan and cycloheximide in rats subjected to transient focal cerebral ischemia.
Brain Res.
718: 233–236.
- 55
Ratan, R.R., T.H. Murphy & J.M. Baraban.
1994. Macromolecular synthesis inhibitors prevent oxidative stress-induced apoptosis in embryonic cortical neurons by shunting cysteine from protein synthesis to glutathione.
J. Neurosci.
14: 4385–4392.
- 56
Nam, M.J., C. Thore & D. Busija.
1995. Rapid induction of prostaglandin synthesis in piglet astroglial cells by interleukin 1 alpha.
Brain Res. Bull.
36: 215–218.
- 57
Veltkamp, R., F. Domoki, F. Bari
et al.
1999. Inhibitors of protein synthesis preserve the N-methyl-D-aspartate-induced cerebral arteriolar dilation after ischemia in piglets.
Stroke
30: 148–152.
- 58
Loddick, S.A., A. MacKenzie & N.J. Rothwell.
1996. An ICE inhibitor, z-VAD-DCB attenuates ischaemic brain damage in the rat.
Neuroreport
7: 1465–1468.
- 59
Hara, H., R.M. Friedlander, V. Gagliardini
et al.
1997. Inhibition of interleukin 1 beta converting enzyme family proteases reduces ischemic and excitotoxic neuronal damage.
Proc. Natl. Acad. Sci. USA
94: 2007–2012.
- 60
Schielke, G.P., G.Y. Yang, B.D. Shivers
et al.
1998. Reduced ischemic brain injury in interleukin-1 beta converting enzyme- deficient mice.
J. Cereb. Blood Flow Metab.
18: 180–185.
- 61
Fink, K., J. Zhu, S. Namura
et al.
1998. Prolonged therapeutic window for ischemic brain damage caused by delayed caspase activation.
J. Cereb. Blood Flow Metab.
18: 1071–1076.
- 62
Relton, J.K. & N.J. Rothwell.
1992. Interleukin-1 receptor antagonist inhibits ischaemic and excitotoxic neuronal damage in the rat.
Brain Res. Bull.
29: 243–246.
- 63
Yamasaki, Y., T. Suzuki, H. Yamaya
et al.
1992. Possible involvement of interleukin-1 in ischemic brain edema formation.
Neurosci. Lett.
142: 45–47.
- 64
Yang, E. & S.J. Korsmeyer.
1996. Molecular thanatopsis: a discourse on the BCL2 family and cell death.
Blood
88: 386–401.
- 65
Martinou, J.C., M. Dubois-Dauphin, J.K. Staple
et al.
1994. Overexpression of BCL-2 in transgenic mice protects neurons from naturally occurring cell death and experimental ischemia.
Neuron
13: 1017–1030.
- 66
Kitagawa, K., M. Matsumoto, Y. Tsujimoto
et al.
1998. Amelioration of hippocampal neuronal damage after global ischemia by neuronal overexpression of BCL-2 in transgenic mice.
Stroke
29: 2616–2621.
- 67
Linnik, M.D., P. Zahos, M.D. Geschwind
et al.
1995. Expression of bcl-2 from a defective herpes simplex virus-1 vector limits neuronal death in focal cerebral ischemia.
Stroke
26: 1670–1674;discussion 5.
- 68
Ma, J., M. Endres & M.A. Mskowitz.
1998. Synergistic effects of caspase inhibitors and MK-801 in brain injury after transient focal cerebral ischaemia in mice.
Br. J. Pharmacol.
124: 756–762.
- 69
Schulz, J.B., M. Weller, R.T. Matthews
et al.
1998. Extended therapeutic window for caspase inhibition and synergy with MK-801 in the treatment of cerebral histotoxic hypoxia.
Cell Death Differ.
5: 847–857.
- 70
Goldberg, M.P., J.H. Weiss, P.C. Pham
et al.
1987. N-methyl-D-aspartate receptors mediate hypoxic neuronal injury in cortical culture.
J. Pharmacol. Exp.Ther.
243: 784–791.
- 71
Gottron, F.J., H.S. Ying & D.W. Choi.
1997. Caspase inhibition selectively reduces the apoptotic component of oxygen-glucose deprivation-induced cortical neuronal cell death.
Mol. Cell. Neurosci.
9: 159–169.
- 72
Thornberry, N.A., T.A. Rano, E.P. Peterson
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: 17907–17911.
- 73
Snider, B.J., D. Lobner, K. Yamada
et al.
1998. Conditioning heat stress reduces excitotoxic and apoptotic components of oxygen-glucose deprivation-induced neuronal death in vitro.
J. Neurochem.
77: 120–129.
- 74
Goldberg, M.P. & D.W. Choi.
1993. Combined oxygen and glucose deprivation in cortical cell culture: calcium-dependent and calcium-independent mechanisms of neuronal injury.
J. Neurosci.
13: 3510–3524.
- 75
Beck, T., D. Lindholm, E. Castren
et al.
1994. Brain-derived neurotrophic factor protects against ischemic cell damage in rat hippocampus.
J. Cereb. Blood Flow Metab.
14: 689–692.
- 76
Chan, K.M., D.T. Lam, K. Pong
et al.
1996. Neurotrophin-4/5 treatment reduces infarct size in rats with middle cerebral artery occlusion.
Neurochem. Res.
21: 763–767.
- 77
Pringle, A.K., L.E. Sundstrom, G.J. Wilde
et al.
1996. Brain-derived neurotrophic factor, but not neurotrophin-3, prevents ischaemia-induced neuronal cell death in organotypic rat hippocampal slice cultures.
Neurosci. Lett.
211: 203–206.
- 78
Tagami, M., K. Yamagata, K. Ikeda
et al.
1998. Vitamin E prevents apoptosis in cortical neurons during hypoxia and oxygen reperfusion.
Lab. Invest.
78: 1415–1429.
- 79
Ravati, A., V. Junker, M. Kouklei
et al.
1999. Enalapril and moexipril protect from free radical-induced neuronal damage in vitro and reduce ischemic brain injury in mice and rats.
Eur. J. Pharmacol.
373: 21–33.
- 80
Tagami, M., K. Ikeda, K. Yamagata
et al.
1999. Vitamin E prevents apoptosis in hippocampal neurons caused by cerebral ischemia and reperfusion in stroke-prone spontaneously hypertensive rats.
Lab. Invest.
79: 609–615.
- 81
Johnson, E.M.Jr., T. Koike & J. Franklin.
1992. A “calcium set-point hypothesis” of neuronal dependence on neurotrophic factor.
Exp. Neurol.
115: 163–166.
- 82
Deckwerth, T.L., J.L. Elliott, C.M. Knudson
et al.
1996. BAX is required for neuronal death after trophic factor deprivation and during development.
Neuron
17: 401–411.
