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Pathways Erythropoietin mediated neuroprotection through NF-kB
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Description: Description: Erythropoietin (Epo) is most commonly known as the cytokine secreted by the kidneys that stimulates red blood cell production and is used as a drug for the treatment of anemias. Epo is also secreted in the brain in response to hypoxia, such as ischemic stroke. Epo production in the brain is stimulated by the hypoxia-inducible transcription factor HIF-1 (see HIF pathway). Administration of Epo to the brain in rodents before hypoxic stress or other neuronal stresses is neuroprotective, preventing neuronal apoptosis. The erythropoietin receptor (EpoR) is known to associate with JAK kinases that phosphorylate and activate the STAT family of transcription factors (See Epo pathway). The neuroprotection by Epo involves cross-talk between Epo receptor and anti-apoptotic pathways through activation of NF-kB by the JAK2 kinase (see NF-kB pathway). Epo stimulates JAK2 phosphorylation of I-kB, releasing NF-kB to translocate into the nucleus and activate transcription of neuroprotective genes. Neuroprotective genes activated by NF-kB include the anti-oxidant enzyme manganese superoxide dismutase and calbindin-D(28k). The erythropoietin receptor is also essential for proper brain development in mice. The absence of EpoR causes high levels of neuronal apoptosis in the developing mouse brain, further confirming the important role of Epo as a neuroprotective agent.
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references: references: Dawson, T.M. (2002) Preconditioning-mediated neuroprotection through erythropoietin? Lancet 359(9301), 96-7

Digicaylioglu, M. and Lipton, S.A. (2001) Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-kappaB signalling cascades. Nature 412(6847), 641-7

Mattson, M.P. et al. (2000) Roles of nuclear factor kappaB in neuronal survival and plasticity. J. Neurochem. 74(2), 443-56

Ravati, A et al. (2001) Preconditioning-induced neuroprotection is mediated by reactive oxygen species and activation of the transcription factor nuclear factor-kappaB. J Neurochem 78(4), 909-19

Siren, A.L., Ehrenreich, H. (2001) Erythropoietin--a novel concept for neuroprotection. Eur Arch Psychiatry Clin Neurosci 251(4), 179-84

Yu, X., et al. (2002) Erythropoietin receptor signalling is required for normal brain development. Development 129(2), 505-16

Zaman K. et al. (1999) Protection from oxidative stress-induced apoptosis in cortical neuronal cultures by iron chelators is associated with enhanced DNA binding of hypoxia-inducible factor-1 and ATF-1/CREB and increased expression of glycolytic enzymes, p21(waf1/cip1), and erythropoietin. J Neurosci 19(22), 9821-30

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