Skip to main content

Advertisement

SpringerLink
Log in

Long-Term Moderate Dose Exogenous Erythropoietin Treatment Protects from Intermittent Hypoxia-Induced Spatial Learning Deficits and Hippocampal Oxidative Stress in Young Rats

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Exposure to intermittent hypoxia (IH) is associated with cognitive impairments and oxidative stress in brain regions involved in learning and memory. In earlier studies, erythropoietin (EPO) showed a neuroprotective effect in large doses. The aim of the present study was to explore the effect of smaller doses of EPO, such as those used in the treatment of anemia, on IH-induced cognitive deficits and hippocampal oxidative stress in young rats. The effect of concurrent EPO treatment (500 and 1,000 IU/kg/day ip) on spatial learning and memory deficits induced by long-term exposure to IH for 6 weeks was tested using the Morris water maze (MWM) test and the elevated plus maze (EPM) test. Moreover, the effect on hippocampal glutamate and oxidative stress were assessed. Exposure to IH induced a significant impairment of spatial learning and cognition of animals in both MWM and EPM performance parameters. Moreover, hippocampal glutamate and thiobarbituric acid reactive substances (TBARS) increased while antioxidant defenses (GSH and GSH-Px) decreased. EPO in the tested doses significantly reduced the IH-induced spatial learning deficits in both MWM and EPM tests and dose-dependently antagonized the effects of IH on hippocampal glutamate, TBARS, GSH levels, and GSH-Px activity. Treatment with EPO in moderate doses that used for anemia, concurrently with IH exposure can antagonize IH-induced spatial learning deficits and protect hippocampal neurons from IH-induced lipid peroxidation and oxidative stress-induced damage in young rats, possibly through multiple mechanisms involving a potential antioxidative effect.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

BBB:

Blood–brain barrier

CNS:

Central nervous system

DTNB:

Ellman’s reagent [5,5′-dithiobis (2-nitrobenzoic acid)]

EPM:

Elevated plus maze test

EPO:

Erythropoietin

GSH:

Intracellular reduced glutathione

GSH-Px:

Glutathione peroxidase

IH:

Intermittent hypoxia

MWM:

Morris water maze test

RA:

Room air

SDB:

Sleep-disordered breathing

TBARS:

Thiobarbituric acid reactive substance

References

  1. Chang S, Chae K (2010) Obstructive sleep apnea syndrome in children: epidemiology, pathophysiology, diagnosis and sequelae. Korean J Pediatr 53:863–871

    Article  PubMed Central  PubMed  Google Scholar 

  2. Arnaud C, Dematteis M, Pepin J, Baguet J, Lévy P (2009) Obstructive sleep apnea, immuno-inflammation, and atherosclerosis. Semin Immuno Pathol 31:113–125

    Article  CAS  Google Scholar 

  3. Li RC, Row BW, Gozal E, Kheirandish L, Fan Q, Brittian KR et al (2003) Cyclooxygenase 2 and intermittent hypoxia-induced spatial deficits in the rat. Am J Respir Crit Care Med 168:469–475

    Article  PubMed  Google Scholar 

  4. Shan X, Chi L, Ke Y, Luo C, Qian SY, Gozal D et al (2007) Manganese superoxide dismutase protects mouse cortical neurons from chronic intermittent hypoxia mediated oxidative damage. Neurobiol Dis 28(2):206–215

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Miskowiak KW, Vinberg M, Harmer CJ, Ehrenreich H, Knudsen GM, Macoveanu J et al (2010) Effects of erythropoietin on depressive symptoms and neurocognitive deficits in depression and bipolar disorder. Trials 11:97

    Article  PubMed Central  PubMed  Google Scholar 

  6. Köllensperger M, Krismer F, Pallua A, Stefanova N, Poewe W, Wenning GK (2011) Erythropoietin is neuroprotective in a transgenic mouse model of multiple system atrophy. Mov Disord 26(3):507–515

    Article  PubMed  Google Scholar 

  7. Wang L, Zhang Z, Wang Y, Zhang R, Chopp M (2004) Treatment of stroke with erythropoietin enhances neurogenesis and angiogenesis and improves neurological function in rats. Stroke 35:1732–1737

    Article  CAS  PubMed  Google Scholar 

  8. Leist M, Ghezzi P, Grasso G, Bianchi R, Villa P, Fratelli M et al (2004) Derivatives of erythropoietin that are tissue protective but not erythopoietic. Science 305:239–242

    Article  CAS  PubMed  Google Scholar 

  9. Brines ML, Ghezzi P, Keenan S, Agnello D, de Lanerolle NC, Cerami C et al (2000) Erythropoietin crosses the blood–brain barrier to protect against experimental brain injury. Proc Natl Acad Sci USA 97:10526–10531

    Article  CAS  PubMed  Google Scholar 

  10. Banks WA, Jumbe NL, Farrell CL, Niehoff ML, Heatherington AC (2004) Passage of erythropoietic agents across the blood–brain barrier: a comparison of human and murine erythropoietin and the analog darbepoetin alfa. Eur J Pharmacol 505:93–101

    Article  CAS  PubMed  Google Scholar 

  11. Okazaki T, Ebihara S, Asada M, Yamanda S, Niu K, Arai H (2008) Erythropoietin promotes the growth of tumors lacking its receptor and decreases survival of tumor-bearing mice by enhancing angiogenesis. Neoplasia 10:932–939

    CAS  PubMed Central  PubMed  Google Scholar 

  12. Gombos Z, Danihel L, Repiska V, Acs G, Furth E (2011) Expression of erythropoietin and its receptor increases in colonic neoplastic progression: the role of hypoxia in tumorigenesis. Indian J Pathol Microbiol 54:273–278

    Article  PubMed  Google Scholar 

  13. Gozal E, Row BW, Schurr A, Gozal D (2001) Developmental differences in cortical and hippocampal vulnerability to intermittent hypoxia in the rat. Neurosci Lett 305:197–201

    Article  CAS  PubMed  Google Scholar 

  14. Morris R (1984) Developments of a water-maze procedure for studying spatial learning in the rat. J Neurosci Meth 11:47–60

    Article  CAS  Google Scholar 

  15. Sharma V, Nehru B, Munshi A, Jyothy A (2010) Antioxidant potential of curcumin against oxidative insult induced by pentylenetetrazol in epileptic rats. Methods Find Exp Clin Pharmacol 32:227–232

    Article  CAS  PubMed  Google Scholar 

  16. Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358

    Article  CAS  PubMed  Google Scholar 

  17. Griffith OW (1980) Determination of glutathione and glutathione disulfide using glutathione reductase and 2-vinylpyridine. Anal Biochem 106:207–212

    Article  CAS  PubMed  Google Scholar 

  18. Lund P (1986) L-glutamine and L-glutamate: UV-method with glutaminase and glutamate dehydrogenase. In: Bergmeyer HU (ed) Methods enzyme analys. VCH verlagesllschaft, Weinheim, pp 357–363

    Google Scholar 

  19. Paglia DE, Valentine WN (1967) Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med 70:158–169

    CAS  PubMed  Google Scholar 

  20. Lowry O, Rosenbrough N, Farr A, Randall R (1951) Protein measurement with the Folinphenol reagent. J Biol Chem 193:265–275

    CAS  PubMed  Google Scholar 

  21. Cai XH, Zhou YH, Zhang CX, Hu LG, Fan XF, Li CC et al (2010) Chronic intermittent hypoxia exposure induces memory impairment in growing rats. Acta Neurobiol Exp 70:279–287

    Google Scholar 

  22. Row B, Liu R, Xu W, Kheirandish L, Gozal D (2003) Intermittent hypoxia is associated with oxidative stress and spatial learning deficits in the rat. Am J Respir Crit Care Med 167:1548–1553

    Article  PubMed  Google Scholar 

  23. Kumar R, Singh J, Singh N (2010) Effects of Erythropoietin on memory deficits and brain oxidative stress in the mouse models of dementia. Korean J Physiol Pharmacol 14:345–352

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. van der Kooij MA, Groenendaal F, Kavelaars A, Heijnen CJ, van Bel F (2008) Neuroprotective properties and mechanisms of erythropoietin in in vitro and in vivo experimental models for hypoxia/ischemia. Brain Res Rev 59:22–33

    Article  PubMed  Google Scholar 

  25. Haiden N, Schwindt J, Cardona F, Berger A, Klebermass K, Wald M et al (2006) Effects of a combined therapy of erythropoietin, iron, folate, and vitamin B12 on the transfusion requirements of extremely low birth weight infants. Pediatrics 118:2004–2013

    Article  PubMed  Google Scholar 

  26. Kumral A, Tüzün F, Oner MG, Genç S, Duman N, Ozkan H (2011) Erythropoietin in neonatal brain protection: the past, the present and the future. Brain Dev 33:632–643

    Article  PubMed  Google Scholar 

  27. Parle M, Singh N (2004) Animal models of testing memory. Asia Pac J Pharmacol 16:101–120

    Google Scholar 

  28. Sharma AC, Kulkarni SK (1992) Evaluation of learning and memory mechanisms employing elevated plus-maze in rats and mice. Prog Neuropsychopharmacol Biol Psychiatry 16:117–125

    Article  CAS  PubMed  Google Scholar 

  29. Ishii M, Iwamoto T, Nagai A, Sasao G, Iwasaki M, Kuwahira I (2010) Polycythemia and changes in erythropoietin concentration in rats exposed to intermittent hypoxia. Adv Exp Med Biol 662:121–126

    Article  CAS  PubMed  Google Scholar 

  30. Winnicki M, Shamsuzzaman A, Lanfranchi P, Accurso V, Olson E, Davison D, Somers VK (2004) Erythropoietin and obstructive sleep apnea. Am J Hypertens 17(9):783–786

    Article  CAS  PubMed  Google Scholar 

  31. Brugniaux JV, Pialoux V, Foster GE, Duggan CT, Eliasziw M, Hanly PJ et al (2011) Effects of intermittent hypoxia on erythropoietin, soluble erythropoietin receptor and ventilation in humans. Eur Respir J 37(4):880–887

    Article  CAS  PubMed  Google Scholar 

  32. Dayyat EA, Zhang SX, Wang Y, Cheng ZJ, Gozal D (2012) Exogenous erythropoietin administration attenuates intermittent hypoxia-induced cognitive deficits in a murine model of sleep apnea. BMC Neurosci 13:77

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Jelkmann W (2005) Effects of erythropoietin on brain function. Curr Pharm Biotechnol 6:65–79

    CAS  PubMed  Google Scholar 

  34. Parfenova H, Basuroy S, Bhattacharya S, Tcheranova D, Qu Y, Regan RF, Leffler CW (2006) Glutamate induces oxidative stress and apoptosis in cerebral vascular endothelial cells: contributions of HO-1and HO-2 to cytoprotection. Am J Physiol Cell Physiol 290:C1399–C1410

    Article  CAS  PubMed  Google Scholar 

  35. Xu X, Dai H, Shi Y (2009) Erythropoietin protects primary cultures of rat cortical neurons from hypoxia-induced toxicity through attenuating both glutamate release and NMDA receptor evoked neurotoxicity pathway. Pharmazie 64:210–232

    CAS  PubMed  Google Scholar 

  36. Hung MW, Tipoe GL, Poon AM, Reiter RJ, Fung ML (2008) Protective effect of melatonin against hippocampal injury of rats with intermittent hypoxia. J Pineal Res 44:214–221

    Article  CAS  PubMed  Google Scholar 

  37. Abdel-Wahab BA, Abd El-Aziz SM (2012) Ginkgo biloba protects against intermittent hypoxia-induced memory deficits and hippocampal DNA damage in rats. Phytomedicine 19:444–450

    Article  CAS  PubMed  Google Scholar 

  38. Lavie L, Vishnevsky A, Lavie P (2004) Evidence for lipid peroxidation in obstructive sleep apnea. Sleep 27:123–128

    PubMed  Google Scholar 

  39. Solaroglu I, Solaroglu A, Kaptanoglu E, Dede S, Haberal A, Beskonakli E et al (2003) Erythropoietin prevents ischemia-reperfusion from inducing oxidative damage in fetal rat brain. Childs Nerv Syst 19:19–22

    PubMed  Google Scholar 

  40. Toba H, Nakashima K, Oshima Y, Kojima Y, Tojo C, Nakano A et al (2010) Erythropoietin prevents vascular inflammation and oxidative stress in subtotal nephrectomized rat aorta beyond haematopoiesis. Clin Exp Pharmacol Physiol 37:1139–1146

    Article  CAS  PubMed  Google Scholar 

  41. Veasey SC, Davis C, Zhan G, Hsu YJ, Fenik P, Pratico D, Gow AJ (2004) Long-term intermittent hypoxia in mice: protracted hypersomnolence with oxidative injury to sleep-wake brain regions. Sleep 27:194–201

    PubMed  Google Scholar 

  42. Zhan G, Fenik P, Pratico D, Veasey SC (2005) Inducible nitric oxide synthase in long-term intermittent hypoxia: hypersomnolence and brain injury. Am J Respir Crit Care Med 171(12):1414–1420

    Article  PubMed  Google Scholar 

  43. Genc K, Genc S, Baskin H, Semin I (2006) Erythropoietin decreases cytotoxicity and nitric oxide formation induced by inflammatory stimuli in rat oligodendrocytes. Physiol Res 55(1):33–38

    CAS  PubMed  Google Scholar 

  44. Calapai G, Marciano MC, Corica F, Allegra A, Parisi A, Frisina N et al (2000) Erythropoietin protects against brain ischemic injury by inhibition of nitric oxide formation. Eur J Pharmacol 401(3):349–356

    Article  CAS  PubMed  Google Scholar 

  45. Pialoux V, Hanly PJ, Foster GE, Brugniaux JV, Beaudin AE, Hartmann SE et al (2009) Effects of exposure to intermittent hypoxia on oxidative stress and acute hypoxic ventilatory response in humans. Am J Respir Crit Care Med 180:1002–1009

    Article  CAS  PubMed  Google Scholar 

  46. Sims B, Clarke M, Njah W, Hopkins ES, Sontheimer H (2010) Erythropoietin-induced neuroprotection requires cystine glutamate exchanger activity. Brain Res 1321:88–95

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Kumral A, Gonenc S, Acikgoz O, Sonmez A, Genc K, Yilmaz O et al (2005) Erythropoietin increases glutathione peroxidase enzyme activity and decreases lipid peroxidation levels in hypoxic ischemic brain injury in neonatal rats. Biol Neonate 87:15–18

    Article  CAS  PubMed  Google Scholar 

  48. Zinchuk VV, Shul’ga EV, Guliaĭ IE (2010) Erythropoietin influence on oxygen transport function of blood and prooxidant/antioxidant balance in rabbits under lipopolysaccharide injection. Ross Fiziol Zh Im IM Sechenova 96(1):43–49

    CAS  Google Scholar 

  49. Kawachi K, Iso Y, Sato T, Wakabayashi K, Kobayashi Y, Takeyama Y, Suzuki H (2012) Effects of erythropoietin on angiogenesis after myocardial infarction in porcine. Heart Vessels 27:79–88

    Article  PubMed  Google Scholar 

  50. Ning R, Xiong Y, Mahmood A, Zhang Y, Meng Y, Qu C, Chopp M (2011) Erythropoietin promotes neurovascular remodeling and long-term functional recovery in rats following traumatic brain injury. Brain Res 1384:140–150

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Gozal D, Kheirandish-Gozal L, Bhattacharjee R, Spruyt S (2010) Neurocognitive and endothelial dysfunction are frequently concordant in children with OSA. Pediatrics 126:e1161–e1167

    Article  PubMed  Google Scholar 

  52. Hogan AM, Hill CM, Harrison D, Kirkham FJ (2008) Cerebral blood flow velocity and cognition in children before and after adenotonsillectomy. Pediatrics 122:75–82 (Erratum in. Pediatrics 122:689–690)

    Article  PubMed  Google Scholar 

  53. Yamamoto M, Koshimura K, Kawaquchi M, Sohmiya M, Murakami Y, Kato Y (2000) Stimulating effect of Erythropoietin on the release of dopamine and acetylcholine from the rat brain slice. Neurosci Lett 292:131–133

    Article  CAS  PubMed  Google Scholar 

  54. Viviani B, Bartesaghi S, Corsini E, Villa P, Ghezzi P, Garau A et al (2005) Erythropoietin protects primary hippocampal neurons by increasing the expression of brain-derived neurotrophic factor. J Neurochem 93:412–421

    Article  CAS  PubMed  Google Scholar 

  55. Tabira T, Konishi Y, Gallyas F (1995) Neurotrophic effect of hematopoietic cytokines on cholinergic and other neurons in vitro. Int J Dev Neurosci 13:241–252

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was financially supported by Najran University Program for Health and Medical Research Grants, Grant No. (NU 8/13). The work of this study was carried out in College of Medicine, Najran University, Najran, Saudi Arabia.

Conflict of interest

On behalf of the authors, no conflict of interest is found in this work.

Author information

Author notes

  1. Basel A. Abdel-Wahab

    Present address: Department of Pharmacology, College of Medicine, Najran University, Najran, Saudi Arabia

Authors and Affiliations

  1. Department of Pediatrics, College of Medicine, Najran University, Najran, Saudi Arabia

    Jobran M. Al-Qahtani

  2. Department of Pharmacology, College of Medicine, Assiut University, Assiut, Egypt

    Basel A. Abdel-Wahab

  3. Department of Physiology, College of Medicine, Najran University, Najran, Saudi Arabia

    Samy M. Abd El-Aziz

Authors
  1. Jobran M. Al-Qahtani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Basel A. Abdel-Wahab
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Samy M. Abd El-Aziz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Basel A. Abdel-Wahab.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Al-Qahtani, J.M., Abdel-Wahab, B.A. & Abd El-Aziz, S.M. Long-Term Moderate Dose Exogenous Erythropoietin Treatment Protects from Intermittent Hypoxia-Induced Spatial Learning Deficits and Hippocampal Oxidative Stress in Young Rats. Neurochem Res 39, 161–171 (2014). https://doi.org/10.1007/s11064-013-1201-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-013-1201-2

Keywords

Search

Navigation