title: Protective action of erythropoietin on neuronal damage induced by activated microglia.
abstract: Inflammation is a physiological defense response, but may also represent a potential pathological process in neurological diseases. In this regard, microglia have a crucial role in either progression or amelioration of degenerative neuronal damage. Because of the role of hypoxia in pro-inflammatory mechanisms in the nervous system, and the potential anti-inflammatory protective effect of erythropoietin (Epo), we focused our investigation on the role of this factor on activation of microglia and neuroprotection. Activation of microglial cells (EOC-2) was achieved by chemical hypoxia induced by cobalt chloride (CoCl2 ) and characterized by increased levels of nitrite, tumor necrosis factor-α and reactive oxygen species production, as well as up-regulation of inducible nitric oxide synthase expression. Under these conditions, cell proliferation data and proliferating cell nuclear antigen (PCNA) staining demonstrated a mitogenic effect of chemical hypoxia. Even though pre-treatment with Epo did not prevent nitrite production, inducible nitric oxide synthase protein expression or tumor necrosis factor-α secretion, it prevented the oxidative stress induced by CoCl2 as well as cell proliferation. Neuronal cells (SH-SY5Y) cultured in the presence of conditioned medium from activated EOC-2 cells or macrophages (RAW 264.7) developed significant apoptosis, an effect that was abolished by Epo via Epo/Epo receptor activation. The results show that even though Epo did not exert a direct anti-inflammatory effect on microglia activation, it did increase the resistance of neurons to subsequent damage from pro-inflammatory agents. In addition to its anti-apoptotic ability, the Epo antioxidant effect may have an indirect influence on neuronal survival by modulation of the pro-inflammatory environment.
authors: Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, IQUIBICEN-CONICET (Instituto de Química Biológica, Facultad de Ciencias Exactas y Naturales-Consejo Nacional de Investigaciones Científicas y Técnicas), Buenos Aires, Argentina.
authors: Shirley D
authors: SD
authors: Wenker
authors: María E
authors: ME
authors: Chamorro
authors: Daniela C
authors: DC
authors: Vittori
authors: Alcira B
authors: AB
authors: Nesse
mesh_terms: D000818:Animals; D015687:Cell Hypoxia / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003035:Cobalt / Q000494:pharmacology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004921:Erythropoietin / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D020258:Neurotoxicity Syndromes / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D017467:Receptors, Erythropoietin / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D017077:Culture Media, Conditioned; D018696:Neuroprotective Agents; D009573:Nitrites; D018809:Proliferating Cell Nuclear Antigen; D017382:Reactive Oxygen Species; D017467:Receptors, Erythropoietin; D014409:Tumor Necrosis Factor-alpha; D004921:Erythropoietin; D003035:Cobalt; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C018021:cobaltous chloride