Abstract
Ischemic stroke is a result of the disruption of blood flow in the cerebral circulation that leads to neuronal dysfunction and cell death. Approved treatment of ischemic stroke is limited to thrombolysis using TPA. The future of stroke therapy is focused on preventing cell death and enhancing endogenous recovery mechanisms to improve outcome. Erythropoietin has received considerable attention for its ability to promote neuronal survival following an insult. EPO mediated neuroprotection has been demonstrated in several in vitro and in vivo models relevant to ischemic stroke. While the neuroprotective function of EPO is thought to be primarily through the inhibition of apoptosis, more recent work has revealed additional functions for EPO that may contribute to its beneficial effects including the modulation of inflammation, preventing vascular dysfunction and enhancing angiogenesis and neurogenesis. This chapter will provide an overview of the pre-clinical research that supports the potential use of EPO in treating stroke. The effects of EPO on the mechanisms that contribute to damage following ischemic stroke will be discussed as well as more recent work describing the effect of EPO treatment on recovery of function.
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References
Aarts, M. M., and Tymianski, M. (2004). Molecular mechanisms underlying specificity of excitotoxic signaling in neurons. Curr Mol Med 4, 137–147.
Agnello, D., Bigini, P., Villa, P., Mennini, T., Cerami, A., Brines, M. L., and Ghezzi, P. (2002). Erythropoietin exerts an anti-inflammatory effect on the CNS in a model of experimental autoimmune encephalomyelitis. Brain Res 952, 128–134.
Assandri, R., Egger, M, Gassmann, M., Niggli, E., Bauer, C, Forster, I., and Gorlach, A. (1999). Erythropoietin modulates intracellular calcium in a human neuroblastoma cell line. J Physiol 516 (Pt 2), 343–352.
Bernaudin, M., Marti, H. H., Roussel, S., Divoux, D., Nouvelot, A., MacKenzie, E. T., and Petit, E. (1999). A potential role for erythropoietin in focal permanent cerebral ischemia in mice. J Cereb Blood Flow Metab 19, 643–651.
Brines, M. L., Ghezzi, P., Keenan, S., Agnello, D., de Lanerolle, N. C., Cerami, C., Itri, L. M., and Cerami, A. (2000). Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. Proc Natl Acad Sci U S A 97, 10526–10531.
Carlini, R. G., Alonzo, E. J., Dominguez, J., Blanca, I., Weisinger, J. R., Rothstein, M., and Bellorin-Font, E. (1999). Effect of recombinant human erythropoietin on endothelial cell apoptosis. Kidney Int 55, 546–553.
Chamorro, A., and Planas, A. M. (2004). Inflammation-mediated damage as a potential therapeutic target in acute ischemic stroke. Ernst Schering Res Found Workshop, 185–204.
Chen, J., Jin, K., Chen, M., Pei, W., Kawaguchi, K., Greenberg, D. A., and Simon, R. P. (1997). Early detection of DNA strand breaks in the brain after transient focal ischemia: implications for the role of DNA damage in apoptosis and neuronal cell death. J Neurochem 69, 232–245.
Chen, J., Zhang, Z. G., Li, Y., Wang, Y., Wang, L., Jiang, H., Zhang, C, Lu, M., Katakowski, M., Feldkamp, C. S., and Chopp, M. (2003). Statins induce angiogenesis, neurogenesis, and synaptogenesis after stroke. Ann Neurol 53, 743–751.
Choi, D. (1998). Antagonizing excitotoxicity: a therapeutic strategy for stroke? Mt Sinai J Med 65, 133–138.
Choi, D. W. (1990). Cerebral hypoxia: some new approaches and unanswered questions. J Neurosci 10, 2493–2501.
Choi, D. W., and Rothman, S. M. (1990). The role of glutamate neurotoxicity in hypoxic-ischemic neuronal death. Annu Rev Neurosci 13, 171–182.
Chong, Z. Z., Kang, J. Q., and Maiese, K. (2002). Erythropoietin is a novel vascular protectant through activation of Aktl and mitochondrial modulation of cysteine proteases. Circulation 106, 2973–2979.
Chong, Z. Z., Kang, J. Q., and Maiese, K. (2003a). Erythropoietin fosters both intrinsic and extrinsic neuronal protection through modulation of microglia, Aktl, Bad, and caspase-mediated pathways. Br J Pharmacol 138, 1107–1118.
Chong, Z. Z., Lin, S. H., Kang, J. Q., and Maiese, K. (2003b). Erythropoietin prevents early and late neuronal demise through modulation of Aktl and induction of caspase 1, 3, and 8. J Neurosci Res 71, 659–669.
del Zoppo, G. J., and Hallenbeck, J. M. (2000). Advances in the vascular pathophysiology of ischemic stroke. Thromb Res 98, 73–81.
Digicaylioglu, M., and Lipton, S. A. (2001). Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-kappaB signalling cascades. Nature 412, 641–647.
Ehrenreich, H., Hasselblatt, M., Dembowski, C., Cepek, L., Lewczuk, P., Stiefel, M., Rustenbeck, H. H., Breiter, N., Jacob, S., Knerlich, F., et al. (2002). Erythropoietin therapy for acute stroke is both safe and beneficial. Mol Med 8, 495–505.
Eid, T., Brines, M. L., Cerami, A., Spencer, D. D., Kim, J. H., Schweitzer, J. S., Ottersen, O. P., and de Lanerolle, N. C. (2004). Increased expression of erythropoietin receptor on blood vessels in the human epileptogenic hippocampus with sclerosis. J Neuropathol Exp Neurol 63, 73–83.
Felling, R. J., and Levison, S. W. (2003). Enhanced neurogenesis following stroke. J Neurosci Res 73, 277–283.
Ferrer, I., and Planas, A. M. (2003). Signaling of cell death and cell survival following focal cerebral ischemia: life and death struggle in the penumbra. J Neuropathol Exp Neurol 62, 329–339.
Gorio, A., Gokmen, N., Erbayraktar, S., Yilmaz, O., Madaschi, L., Cichetti, C., Di Giulio, A. M., Vardar, E., Cerami, A., and Brines, M. (2002). Recombinant human erythropoietin counteracts secondary injury and markedly enhances neurological recovery from experimental spinal cord trauma. Proc Natl Acad Sci U S A 99, 9450–9455.
Grasso, G., Buemi, M., Alafaci, C., Sfacteria, A., Passalacqua, M., Sturiale, A., Calapai, G., De Vico, G., Piedimonte, G., Salpietro, F. M., and Tomasello, F. (2002). Beneficial effects of systemic administration of recombinant human erythropoietin in rabbits subjected to subarachnoid hemorrhage. Proc Natl Acad Sci U S A 99, 5627–5631.
Hakim, A. M. (1998). Ischemic penumbra: the therapeutic window. Neurology 51, S44–46.
Hansen, A. J., and Nedergaard, M. (1988). Brain ion homeostasis in cerebral ischemia. Neurochem Pathol 9, 195–209.
Ishikawa, M., Zhang, J. H., Nanda, A., and Granger, D. N. (2004). Inflammatory responses to ischemia and reperfusion in the cerebral microcirculation. Front Biosci 9, 1339–1347.
Juul, S. E., McPherson, R. J., Farrell, F. X., Jolliffe, L., Ness, D. J., and Gleason, C. A. (2004). Erytropoietin concentrations in cerebrospinal fluid of nonhuman primates and fetal sheep following high-dose recombinant erythropoietin. Biol Neonate 85, 138–144.
Kawakami, M., Sekiguchi, M., Sato, K., Kozaki, S., and Takahashi, M. (2001). Erythropoietin receptor-mediated inhibition of exocytotic glutamate release confers neuroprotection during chemical ischemia. J Biol Chem 276, 39469–39475.
Kawamata, T., Dietrich, W. D., Schallert, T., Gotts, J. E., Cocke, R. R., Benowitz, L. I., and Finklestein, S. P. (1997). Intracisternal basic fibroblast growth factor enhances functional recovery and up-regulates the expression of a molecular marker of neuronal sprouting following focal cerebral infarction. Proc Natl Acad Sci U S A 94, 8179–8184.
Koshimura, K., Murakami, Y., Sohmiya, M., Tanaka, J., and Kato, Y. (1999). Effects of erythropoietin on neuronal activity. J Neurochem 72, 2565–2572.
Koury, M. J., and Bondurant, M. C. (1990). Erythropoietin retards DNA breakdown and prevents programmed death in erythroid progenitor cells. Science 248, 378–381.
Kuriyama, S., Hopp, L., Yoshida, H., Hikita, M., Tomonari, H., Hashimoto, T., and Sakai, O. (1996). Evidence for amelioration of endothelial cell dysfunction by erythropoietin therapy in predialysis patients. Am J Hypertens 9, 426–431.
Lewczuk, P., Hasselblatt, M., Kamrowski-Kruck, H., Heyer, A., Unzicker, C, Siren, A. L., and Ehrenreich, H. (2000). Survival of hippocampal neurons in culture upon hypoxia: effect of erythropoietin. Neuroreport 11, 3485–3488.
Li, Y., Chen, J., and Chopp, M. (2002). Cell proliferation and differentiation from ependymal, subependymal and choroid plexus cells in response to stroke in rats. J Neurol Sci 193, 137–146.
Love, S. (2003). Apoptosis and brain ischaemia. Prog Neuropsychopharmacol Biol Psychiatry 27, 267–282.
Love, S., Barber, R., and Wilcock, G. K. (2000). Neuronal death in brain infarcts in man. Neuropathol Appl Neurobiol 26, 55–66.
Masuda, S., Nagao, M., Takahata, K., Konishi, Y., Gallyas, F., Jr., Tabira, T., and Sasaki, R. (1993). Functional erythropoietin receptor of the cells with neural characteristics. Comparison with receptor properties of erythroid cells. J Biol Chem 268, 11208–11216.
Masuda, S., Okano, M., Yamagishi, K., Nagao, M., Ueda, M., and Sasaki, R. (1994). A novel site of erythropoietin production. Oxygen-dependent production in cultured rat astrocytes. J Biol Chem 269, 19488–19493.
Morishita, E., Masuda, S., Nagao, M., Yasuda, Y., and Sasaki, R. (1997). Erythropoietin receptor is expressed in rat hippocampal and cerebral cortical neurons, and erythropoietin prevents in vitro glutamate-induced neuronal death. Neuroscience 76, 105–116.
Nagai, A., Nakagawa, E., Choi, H. B., Hatori, K., Kobayashi, S., and Kim, S. U. (2001). Erythropoietin and erythropoietin receptors in human CNS neurons, astrocytes, microglia, and oligodendrocytes grown in culture. J Neuropathol Exp Neurol 60, 386–392.
Prass, K., Scharff, A., Ruscher, K., Lowl, D., Muselmann, C., Victorov, I., Kapinya, K., Dirnagl, U., and Meisel, A. (2003). Hypoxia-induced stroke tolerance in the mouse is mediated by erythropoietin. Stroke 34, 1981–1986.
Renzi, M. J., Farrell, F. X., Bittner, A., Galindo, J. E., Morton, M., Trinh, H., and Jolliffe, L. K. (2002). Erythropoietin induces changes in gene expression in PC-12 cells. Brain Res Mol Brain Res 104, 86–95.
Ruscher, K., Freyer, D., Karsch, M., Isaev, N., Megow, D., Sawitzki, B., Priller, J., Dimagl, U., and Meisel, A. (2002). Erythropoietin is a paracrine mediator of ischemic tolerance in the brain: evidence from an in vitro model. J Neurosci 22, 10291–10301.
Sadamoto, Y., Igase, K., Sakanaka, M., Sato, K., Otsuka, H., Sakaki, S., Masuda, S., and Sasaki, R. (1998). Erythropoietin prevents place navigation disability and cortical infarction in rats with permanent occlusion of the middle cerebral artery. Biochem Biophys Res Commun 253, 26–32.
Sakanaka, M., Wen, T. C., Matsuda, S., Masuda, S., Morishita, E., Nagao, M., and Sasaki, R. (1998). In vivo evidence that erythropoietin protects neurons from ischemic damage. Proc Natl Acad Sci U S A 95, 4635–4640.
Siren, A. L., Fratelli, M., Brines, M, Goemans, C, Casagrande, S., Lewczuk, P., Keenan, S., Gleiter, C, Pasquali, C., Capobianco, A., et al. (2001a). Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress. Proc Natl Acad Sci U S A 98, 4044–4049.
Siren, A. L., Knerlich, F., Poser, W., Gleiter, C. H., Bruck, W., and Ehrenreich, H. (2001b). Erythropoietin and erythropoietin receptor in human ischemic/hypoxic brain. Acta Neuropathol (Berl) 101, 271–276.
Stoll, G., Jander, S., and Schroeter, M. (2002). Detrimental and beneficial effects of injury-induced inflammation and cytokine expression in the nervous system. Adv Exp Med Biol 513, 87–113.
Stroemer, R. P., Kent, T. A., and Hulsebosch, C. E. (1998). Enhanced neocortical neural sprouting, synaptogenesis, and behavioral recovery with D-amphetamine therapy after neocortical infarction in rats. Stroke 29, 2381–2393; discussion 2393–2385.
Sugawara, T., and Chan, P. H. (2003). Reactive oxygen radicals and pathogenesis of neuronal death after cerebral ischemia. Antioxid Redox Signal 5, 597–607.
Tramontano, A. F., Muniyappa, R., Black, A. D., Blendea, M. C., Cohen, I., Deng, L., Sowers, J. R., Cutaia, M. V., and El-Sherif, N. (2003). Erythropoietin protects cardiac myocytes from hypoxia-induced apoptosis through an Akt-dependent pathway. Biochem Biophys Res Commun 308, 990–994.
Villa, P., Bigini, P., Mennini, T., Agnello, D., Laragione, T., Cagnotto, A., Viviani, B., Marinovich, M., Cerami, A., Coleman, T. R., et al. (2003). Erythropoietin selectively attenuates cytokine production and inflammation in cerebral ischemia by targeting neuronal apoptosis. J Exp Med 198, 971–975.
Wang, L., Zhang, Z., Wang, Y., Zhang, R., and Chopp, M. (2004). Treatment of stroke with erythropoietin enhances neurogenesis and angiogenesis and improves neurological function in rats. Stroke 35, 1732–1737.
Wen, T. C, Sadamoto, Y., Tanaka, J., Zhu, P. X., Nakata, K., Ma, Y. J., Hata, R., and Sakanaka, M. (2002). Erythropoietin protects neurons against chemical hypoxia and cerebral ischemic injury by up-regulating Bcl-xL expression. J Neurosci Res 67, 795–803.
Zhang, B., Wang, R. Z., Yao, Y., Liu, Z. H., Lian, Z. G., Zou, Y. J., and Wei, Y. K. (2004). Proliferation and differentiation of neural stem cells in adult rats after cerebral infarction. Chin Med Sci J 19, 73–77.
Zhang, R., Wang, L., Zhang, L., Chen, J., Zhu, Z., Zhang, Z., and Chopp, M. (2003). Nitric oxide enhances angiogenesis via the synthesis of vascular endothelial growth factor and cGMP after stroke in the rat. Circ Res 92, 308–313.
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Renzi, M.J., Jolliffe, L.K., Farrell, F.X., Rhodes, K.J. (2006). Erythropoietin for the Treatment of Acute Ischemic Stroke: Preclinical Rationale. In: Höke, A. (eds) Erythropoietin and the Nervous System. Springer, Boston, MA . https://doi.org/10.1007/978-0-387-30011-5_6
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DOI: https://doi.org/10.1007/978-0-387-30011-5_6
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