Abstract
Neuronal death following cardiac arrest or stroke is a primary cause of delayed morbidity and mortality. In cardiac arrest, neurologic compromise is primarily the result of delayed neuronal death which develops over 24 to 72 h following resuscitation. In the case of stroke, the cells at the core of the lesion die acutely. However, the cells at the penumbra are at risk in subsequent days, and it is their fate that can determine survival or the degree of debilitation of the victim. The mechanisms underlying delayed neuronal death following cerebral ischemia and reperfusion are not fully understood. Amelioration of in vivo damage through the administration of excitatory amino acid antagonists of the NMDA and especially non-NMDA type have met with success. As well, inhibitors of free-radical induced damage such as antioxidants or heavy metal chelators have been found to inhibit delayed neuronal death. However, no treatment has been found to completely prevent the deleterious effects of ischemia/reperfusion, due either to a complex interplay of multiple degradative mechanisms1, or to a lack of appreciation of the sequence and relative importance of events in the death pathway.
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References
Siesjö, B.K., Pathophysiology and treatment of focal cerebral ischemia. J. Neurosurg. 77:337–354 (1992).
Heron, A., Pollard, H., Dessi, F., Moreau, J., Lasbennes, Ben-Ari, Y., and Charriaut-Marlangue, C, Regional variability in DNA fragmentation after global ischemia evidenced by combined histological and gel electrophoresis observations in the rat brain. J. Neurochem. 61:1973–1976 (1993).
Linnik, M.D., Zobrist, R.H., and Hatfield, M.D., Evidence supporting a role for programmed cell death in focal cerebral ischemia in rats. Stroke 24:2002–2009 (1993).
Okamoto, M., Matsumoto, M., Ohtsuki, T., Taguchi, A., Mikoshiba, K., Yanagihara, T., and Kamada, T., Internucleosomal DNA cleavage involved in ischemia-induced neuronal death. Biochem. Biophys. Res. Commun. 196:1356–1362 (1993).
Sci Y., Von Lubitz D.K.J.E., Basile A.S., Borner M.M., Lin R.C.-S., Skolnick P., and Fossom L.H., Internucleosomal DNA fragmentation in gerbil hippocampus following forebrain ischemia. Neurosci. Lett. 171, 179–182 (1994).
Nitatori, T., Sato, N., Waguri, S., Karasawa, Y., Araki, H., Shibanai, K., Kominami, E., and Uchiyama, Y., Delayed neuronal death in the CA1 pyramidal cell layer of the gerbil hippocampus following transient ischemia is apoptosis. J. Neurosci. 15:1001–1011 (1995).
MacManus, J.P., Hill, I.E., Preston, E., Rasquinha, I., Walker, T., and Buchan, A.M., Differences in DNA fragmentation following transient cerebral or decapitation ischemia in rats. J. Cereb. Blood Flow Metab. 15:728–737 (1995).
Kihara S., Shiraishi T., Nakagawa S., Toda K., and Tabuchi K., Visualization of DNA double strand breaks in the gerbil hippocampal CA1 following transient ischemia. Neurosci. Lett. 175, 133–136 (1994).
Deshpande, J., Bergstedt, K., Linden, T., Kalimo, H., and Wieloch, T., Ultrastructural changes in the hippocampal CA1 region following transient cerebral ischemia: evidence against programmed cell death. Exp. Brain Res. 88:91–105 (1992).
Lennon, S.V., Martin, S.J., and Cotter, T.G., Dose-dependent induction of apoptosisin human tumour cell lines by widely diverging stimuli. Cell Prolif. 24:203–214 (1991).
Buttke, T.M., and Sandstrom, P.A., Oxidative stress as a mediator of apoptosis. Immun. Today 15:7–10 (1994).
Reed, J.C., Bcl-2 and the regulation of programmed cell death. J. Cell Biol. 124:1–6 (1994).
Hockenbery, D.M., Nunez, G., Milliman, C, Schreiber, R.D., and Korsmeyer, S.J., Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature 348:334–336 (1990).
Hockenbery, D.M., Oltvai, Z.N., Yin, X.-M., Milliman, C.L., and Korsmeyer, S.J. Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Cell 75:241–251 (1993).
Zhong, L.-T., Sarafian, T., Kane, D.J., Charles, A.C., Mah, S.P., Edwards, R.H., and Bredesen, D.E., bcl-2 inhibits death of central neural cells induced by multiple agents. Proc. Natl. Acad. Sci. USA, 90:4533–4537 (1993).
Kane, D.J., Sarafian, T.A., Anton, R., Hahn, H., Gralla, E.B., Valentine, J.S., Örd, T., and Bredesen, D.E., Bcl-2 inhibition of neural death: Decreased generation of reactive oxygen species, Science 262:1274–1277 (1993).
Mah, S.P., Zhong, L.T., Liu, Y., Roghani, A., Edwards, R.H., and Bredesen, D.E. The protooncogene bcl-2 inhibits apoptosis in PC12 cells. J. Neurochem. 60:1183–1186 (1993).
Lam M., Dubyak G., Chen L., Nunez G., Miesfeld R.L., and Distelhorst C.W., Evidence that BCL-2 represses apoptosis by regulating endoplasmic reticulum-associated Ca2+ fluxes. Proc. Natl. Acad. Sci. USA. 91, 6569–6573 (1994).
Dubois-Dauphin M., Frankowski H., Tsujimoto Y., Huarte J., and Martinou J.-C., Neonatal motoneurons overexpressing the bcl-2 protooncogene in transgenic mice are protected from axotomy-induced cell death. Proc. Natl. Acad. Sci. USA 91, 3309–3313 (1994).
Linnik M.D., Zahos P., Geschwind M.D., Federoff H.J., Expression of bcl-2 from a defective herpes simplex virus-1 vector limits neuronal death in focal cerebral ischemia. Stroke 26, 1670–1675 (1995).
Shimazaki, K., Ishida, A., and Kawai, N., Increase in bcl-2 oncoprotein and the tolerance to ischemia-induced neruonal death in the gerbil hippocampus. Neurosci. Res. 20:95–99 (1994).
Chen, J., Graham, S.H., Chan, P.H., Lan, J., and Simon, R.P., Bcl-2 is expressed in neurons that survive focal ischemia in the rat. Neuroreport 6:394–398. (1995).
Krajewski, S., Mai, J.K., Krajewska, M, Sikorska, M., Mossakowski, M.J., and Reed, J.C., Upregulation of Bax protein levels in neurons following cerebral ischemia. J. Neurosci. 15:6364–6367 (1995).
Jacobson M.D., and Raff M.C., Programmed cell death and Bcl-2 protection in very low oxygen. Nature 374, 814–816 (1995).
Shimizu S., Eguchi Y., Kosaka H., Kamiike W., Matsuda H., and Tsujimoto Y., Prevention of hypoxia-induced cell death by Bcl-2 and Bcl-xL. Nature 374, 811–813 (1995).
Chen-Levy, Z., Nourse, J., and Cleary, M.L., The Bcl-2 candidate proto-oncogene product is a 24-kilodalton integral-membrane protein highly expressed in lymphoid cell lines and lymphomas carrying the t(14;18). Mol Cell. Biol. 9:701–710 (1989).
Krajewski, S., Tanaka, S., Takayama, S., Schibier, M.J., Fenton, W., and Reed, J.C., Investigation of the subcellular distribution of the bcl-2 oncoprotein: residence in the nuclear envelope, endoplasmic reticulum, and outer mitochondrial membranes. Cancer Res. 53:4701–4714 (1993).
Newmeyer, D.D., Farschon, D.M., and Reed, J.C., Cell-free apoptosis in Xenopus egg extracts: inhibition by Bcl-2 and requirement for an organelle fraction enriched in mitochondria. Cell 79, 353–364 (1994).
Cross, A.R., and Jones, O.T.G., Enzymic mechanisms of Superoxide production. Biochim. Biophys. Acta 1057:281–298 (1991).
Gunter, T.E., Gunter, K.K., Sheu, S.-S., and Gavin, C.E., Mitochondrial calcium transport: physiological and pathological relevance. Am. J. Physiol. 267:C313–C339 (1994).
Gunter, T.E., and Pfeiffer, D.R., Mechanisms by which mitochondria transport calcium. Am. J. Physiol. 258:C755–C786 (1990).
Sciammanna, M.A., Zinkel, J., Fabi, A.Y., Lee, C.P., Ischemic injury to rat forebrain mitochondria and cellular calcium homeostasis, Biochem Biophys. Acta. 1134:223–232, 1992.
Sun D., and Gilboe D.D., Ischemia-induced changes in cerebral mitochondrial free fatty acids, phospholipids, and respiration in the rat. J. Neurochem. 62, 1921–1928 (1994).
White, R.J., and Reynolds, I.J., Mitochondria and Na+/Ca2+ exchange buffer glutamate-induced calcium loads in cultured cortical neurons. J. Neurosci. 15:1318–1328 (1995).
Reynolds, I.J., and Hastings, T.G., Glutamate induces the production of reactive oxygen species in cultured forebrain neurons following NMDA receptor activation. J. Neurosci. 15:3318–3327 (1995).
Dugan, L.L., Sensi, S.L., Canzoniero, L.M.T., Handran, S.D., Rothman, S.M., T.-S. Lin, Goldberg, M.P., and Choi, D.W., Mitochondrial production of reactive oxygen species in cortical neurons following exposure to N-methyl-d-aspartate. J. Neurosci. 15:6377–6388 (1995).
Myers, K.M., Fiskum, G., Liu, Y., Simmens, S.J., Bredesen, D.E., and Murphy, A.N., Bcl-2 protects neural cells from cyanide/aglycemia induced lipid oxidation, mitochondrial injury, and loss of viability, J. Neurochem. 22 555(1995, in press).
Nishijima, M.K., Koehler, R.C., Hum, P.D., Eleff, S.M., Norris, S., Jacobus, W.E., and Traystman, R.J., Postischemic recovery rate of cerebral ATP, phosphocreatine, pH, and evoked potentials. Am. J. Physiol. 257, H1860–H1870 (1989).
Murphy, A.N., Bredesen, D.E., and Fiskum, G., Bcl-2 protects neural cell mitochondria from Ca2+ overload and Ca2+-induced respiratory inhibition. Soc. for Neurosci. Abst. 21 (3):1728 (1995).
Wang L., Miura M., Bergeron L., Zhu H., and Yuan J., Ich-1, an Ice/ced-3-related gene, encodes both positive and negative regulators of programmed cell death. Cell 78, 739–750 (1994).
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Murphy, A.N., Bredesen, D.E., Fiskum, G. (1996). Bcl-2 Protection of Mitochondrial Function Following Chemical Hypoxia/Aglycemia. In: Fiskum, G. (eds) Neurodegenerative Diseases. GWUMC Department of Biochemistry and Molecular Biology Annual Spring Symposia. Springer, Boston, MA. https://doi.org/10.1007/978-1-4899-0209-2_51
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DOI: https://doi.org/10.1007/978-1-4899-0209-2_51
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