title: Exogenous erythropoietin administration attenuates intermittent hypoxia-induced cognitive deficits in a murine model of sleep apnea.
abstract: BACKGROUND
  In rodents, exposure to intermittent hypoxia (IH), a hallmark of obstructive sleep apnea (OSA), is associated with neurobehavioral impairments, increased apoptosis in the hippocampus and cortex, as well as increased oxidant stress and inflammation. Such findings are markedly attenuated in rodents exposed to sustained hypoxia 9SH) of similar magnitude. The hypoxia-sensitive gene erythropoietin (EPO) has emerged as a major endogenous neuroprotectant, and could be involved in IH-induced neuronal dysfunction.
  
  
  RESULTS
  IH induced only transiently increased expression of EPO mRNA in hippocampus, which was continued in (SH)-exposed mice. IH, but not SH, adversely affected two forms of spatial learning in the water maze, and increased markers of oxidative stress. However, on a standard place training task, mice treated with exogenously administered EPO displayed normal learning, and were protected from the spatial learning deficits observed in vehicle-treated (C) littermates exposed to IH. Moreover, anxiety levels were increased in IH as compared to normoxia, while no changes in anxiety emerged in EPO-treated mice. Additionally, C mice, but not EPO-treated IH-exposed mice had significantly elevated levels of NADPH oxidase expression, as well as increased MDA and 8-OHDG levels in cortical and hippocampal lysates.
  
  
  CONCLUSIONS
  The oxidative stress responses and neurobehavioral impairments induced by IH during sleep are mediated, at least in part, by imbalances between EPO expression and increased NADPH oxidase activity, and thus pharmacological agents targeting EPO expression in CNS may provide a therapeutic strategy in sleep-disordered breathing.
authors: Department of Pediatrics, Pritzker School of Medicine, Comer Children's Hospital, The University of Chicago, 5721 S, Maryland Avenue, Chicago, IL USA.
authors: Ehab A
authors: EA
authors: Dayyat
authors: Shelley X
authors: SX
authors: Zhang
authors: Yang
authors: Y
authors: Wang
authors: Zixi Jack
authors: ZJ
authors: Cheng
authors: David
authors: D
authors: Gozal
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000704:Analysis of Variance; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D004921:Erythropoietin / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D004924:Escape Reaction / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D000860:Hypoxia / Q000150:complications*; D007274:Injections, Intraperitoneal; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D019255:NADPH Oxidases / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D012891:Sleep Apnea Syndromes / Q000150:complications*; D013550:Swimming / Q000523:psychology; D013997:Time Factors
chemical_list: D004921:Erythropoietin; D008315:Malondialdehyde; D000080242:8-Hydroxy-2'-Deoxyguanosine; D019255:NADPH Oxidases; D010751:Phosphopyruvate Hydratase; D003849:Deoxyguanosine