In vivo evidence that erythropoietin protects neurons from ischemic damage

Abstract

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 extracellular 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 heatdenatured 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 Ca 2؉ , 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.Mammals respond to oxygen deficiency in many different ways (1). One strategy for survival of the individual cells under hypoxic conditions is the induction of glycolytic enzymes, facilitating ATP production by glycolysis rather than mitochondrial oxidative phosphorylation. In response to the systemic oxygen deficiency due to anemia or decreasedenvironmental oxygen concentration, erythropoietin (EPO) production is stimulated. EPO is a glycoprotein that stimulates differentiation and proliferation of erythroid precursor cells, and hypoxic induction of EPO production increases red blood cells, leading to better oxygen supply to tissues (2, 3). The action of EPO is mediated by binding to the specific receptor that belongs to a new family of cytokine receptors that have no tyrosine kinase domain (4). EPO regulating erythropoiesis is mainly produced by the kidney in adults and by the liver at fetal stages (2, 3).Stimulation of red blood cell formation was thought to be the sole physiological function of EPO, but a different function in the central nervous system has been proposed (5-7). Neuronal cell lines such as PC12 and SN6 express EPO receptor (EPOR), and binding of EPO to PC12 cells increases the intracellular concentration of monoamines (8). Immunochemical staining with anti-EPOR antibody showed that EPOR is expressed in murine hippocampal and cerebral cortical areas, and also in primary cultured hippocampal and cortical neurons (6, 9). With the use of radioiodinated EPO, specific EPO binding sites were found in some defined areas of the murine brain including the hippocampus and cerebral cortex (10). Because the blood-brain barrier prevents neurons fr...

Protective effect of erythropoietin against 1-methyl-4-phenylpyridinium-induced neurodegenaration in PC12 cells

“…10 U/mL) did not show stronger protective effects. Several studies have confirmed this particular dose-response behavior of EPO in vivo [17,18] , which might have relevance to the design of the upcoming clinical trials. As the recent human stroke study has demonstrated, EPO has beneficial effect on neurons in the context of cerebral ischemia [19] .…”

Targeting Astrocytes for Stroke Therapy

“…Erythropoietin reduces neuronal death with OGD, 86 glutamate toxicity, 91 and NO-induced cell death. 92 Astrocytes contribute to the EPO-mediated neuroprotection, as demonstrated by experiments in which conditioned media taken from hypoxic astrocyte cultures is protective to neurons exposed to OGD. 39 To reduce ischemic damage in the brain, neuroprotectants would need to reduce cell death of both neurons and astrocytes.…”

Erythropoietin Prevents Haloperidol Treatment-Induced Neuronal Apoptosis through Regulation of BDNF

“…Interestingly, recombinant human EPO (rhEPO) treatment has recently been reported to have such effects (ie to increase the expression of BDNF in the brain; Zhang et al, 2006). Furthermore, several studies have shown that rhEPO is a potent neuroprotective agent against neural dysfunction resulting from a variety of neural insults that involve increased apoptosis (Sakanaka et al, 1998;Siren et al, 2001a;Dzietko et al, 2004;Spandou et al, 2004).…”