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In vivo Evidence that Erythropoietin Protects Neurons from Ischemic Damage
Masahiro Sakanaka, Tong-Chun Wen, Seiji Matsuda, Seiji Masuda, Emi Morishita, Masaya Nagao and Ryuzo Sasaki
Proceedings of the National Academy of Sciences of the United States of America
Vol. 95, No. 8 (Apr. 14, 1998), pp. 4635-4640
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/44949
Page Count: 6
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Erythropoietin (EPO) produced by the kidney and the liver (in fetuses) stimulates erythropoiesis. In the central nervous system, neurons express EPO receptor (EPOR) and astrocytes produce EPO. EPO has been shown to protect primary cultured neurons from N-methyl-D-aspartate (NMDA) receptor-mediated glutamate toxicity. Here we report in vivo evidence that EPO protects neurons against ischemia-induced cell death. Infusion of EPO into the lateral ventricles of gerbils prevented ischemia-induced learning disability and rescued hippocampal CA1 neurons from lethal ischemic damage. The neuroprotective action of exogenous EPO was also confirmed by counting synapses in the hippocampal CA1 region. Infusion of soluble EPOR (an extra-cellular domain capable of binding with the ligand) into animals given a mild ischemic treatment that did not produce neuronal damage, caused neuronal degeneration and impaired learning ability, whereas infusion of the heat-denatured soluble EPOR was not detrimental, demonstrating that the endogenous brain EPO is crucial for neuronal survival. The presence of EPO in neuron cultures did not repress a NMDA receptor-mediated increase in intracellular Ca2+, but rescued the neurons from NO-induced death. Taken together EPO may exert its neuroprotective effect by reducing the NO-mediated formation of free radicals or antagonizing their toxicity.
Proceedings of the National Academy of Sciences of the United States of America © 1998 National Academy of Sciences