Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
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ISSN 1899–5276 (print)
ISSN 2451-2680 (online)
Periodicity – monthly

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Advances in Clinical and Experimental Medicine

2017, vol. 26, nr 1, January-February, p. 23–29

doi: 10.17219/acem/61044

Publication type: original article

Language: English

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Neuroprotective effects of erythropoietin on Alzheimer’s dementia model in rats

Betul Cevik1,A,B,C,D,E,F, Volkan Solmaz2,A,B,C, Gurkan Yigitturk3,B,C, Turker Cavusoğlu3,B,C, Gonul Peker4,B,C, Oytun Erbas5,A,B,C,D,E,F

1 Department of Neurology, Faculty of Medicine, Gaziosmanpasa University, Tokat, Turkey

2 Department of Neurology, Turhal State Hospital, Tokat, Turkey

3 Department of Histology and Embryology, Ege University, Faculty of Medicine, Izmir, Turkey

4 Department of Physiology, Ege University, Faculty of Medicine, Izmir, Turkey

5 Department of Physiology, Istanbul Bilim University, Faculty of Medicine, Istanbul, Turkey


Background. Although Alzheimer’s disease (AD) is the most common age-related neurodegenerative disease and characterized by memory impairment, only symptomatic treatments are available.
Objectives. Because recombinant human erythropoietin (rhEPO) has various neuroprotective effects and improves cognitive function in animal models of neurodegenerative disorders, we investigated the therapeutic effects of rhEPO in an intracerebroventricular (ICV)-streptozotocin (STZ) animal model of sporadic-AD.
Material and Methods. A total of 24 Sprague-Dawley adult rats were divided into 4 groups of naive control (n = 6), sham-operated (n = 6), ICV-STZ + saline (n = 6) and ICV-STZ + rhEPO (n = 6). Twelve rats with Alzheimer’s disease, induced by STZ injection (3 mg/kg) into both lateral ventricles using a stereotaxic frame (bilaterally ICV-STZ), were divided into 2 groups 5 days after the STZ injection: one treated with rhEPO 5000 (IU/kg/day, i.p.) and the other with 0.9% NaCl (1 mL/kg/day, i.p.) for 2 weeks. The sham-operated rats received bilaterally ICV-0.9% NaCl. No surgical operation or treatment was given to the naive-control animals. On day 20, a passive avoidance learning (PAL) test was used followed by sacrification and removal of the brain tissue in all animals. Brain TNF-α and ChAT levels were determined, and neurons in the hippocampal CA1 and CA3 regions were counted by Cresyl violet staining.
Results. ICV-STZ was found to significantly shorten the latency time on the PAL, increase brain TNF-α level, and decrease brain ChAT activity and the number of neurons in the hippocampal CA1 and CA3 regions. On the other hand, rhEPO significantly attenuated all these detrimental effects induced by STZ.
Conclusion. RhEPO treatment significantly prevented the ICV-STZ-induced memory deficit by attenuating the hippocampal neuronal loss, neuroinflammation and cholinergic deficit in rats. This result suggests that rhEPO may be beneficial for treating AD.

Key words

Alzheimer’s disease, erythropoietin, streptozotocin, neuroprotection, hippocampus

References (30)

  1. Grand JH, Caspar S, Macdonald SW. Clinical features and multidisciplinary approaches to dementia care. J Multidiscip Healthc. 2011;4:125–147.
  2. Montgomery SL, Bowers WJ. Tumor necrosis factor-alpha and the roles it plays in homeostatic and degenerative processes within the central nervous system. J Neuroimmune Pharmacol. 2012;7:42–49.
  3. Assaraf MI, Diaz Z, Liberman A, et al. Brain erythropoietin receptor expression in Alzheimer disease and mild cognitive impairment. J Neuropathol Exp Neurol. 2007;66:389–398.
  4. Khairallah MI, Kassem LA. Alzheimer’s disease: Current status of etiopathogenesis and therapeutic strategies. Pak J Biol Sci. 2011;14: 257–272.
  5. Lee ST, Chu K, Park JE, Jung KH, Jeon D, Lim JY, Kim M, JK. Erythropoietin improves memory function with reducing endothelial dysfunction and amyloid-beta burden in Alzheimer’s disease models. J Neurochem. 2012;120:115–124.
  6. Byts N, Sirén AL. Erythropoietin: A multimodal neuroprotective agent. Exp Transl Stroke Med. 2009;1:4.
  7. Miskowiak KW, Vinberg M, Harmer CJ, Ehrenreich H, Kessing LV. Erythropoietin: A candidate treatment for mood symptoms and memory dysfunction in depression. Psychopharmacology (Berl). 2012;219:687–698.
  8. Hamidi G, Arabpour Z, Shabrang M, Rashidi B, et al. Erythropoietin improves spatial learning and memory in streptozotocin model of dementia. Pathophysiology. 2013;20:153–158.
  9. Sargin D, Friedrichs H, El-Kordi A, Ehrenreich H. Erythropoietin as neuroprotective and neuroregenerative treatment strategy: comprehensive overview of 12 years of preclinical and clinical research. Best Pract Res Clin Anaesthesiol. 2010;24:573–594.
  10. Kowalczyk M, Banach M, Mikhailidis DP, Rysz J. Erythropoietin update 2011. Med Sci Monit. 2011;17:240–247.
  11. Subirós N, Del Barco DG, Coro-Antich RM. Erythropoietin: Still on the neuroprotection road. Ther Adv Neurol Disord. 2012;5:161–173.
  12. Mehla J, Pahuja M, Gupta YK. Streptozotocin-induced sporadic Alzheimer’s disease: selection of appropriate dose. J Alzheimers Dis. 2013;33:17–21.
  13. Salkovic-Petrisic M, Knezovic A, Hoyer S, Riederer P. What have we learned from the streptozotocin-induced animal model of sporadic Alzheimer’s disease, about the therapeutic strategies in Alzheimer’s research. J Neural Transm. 2013;120:233–252.
  14. Paxinos G, Watson C. The Rat Brain in Stereotaxic Coordinates, Spiral Bound, Academic Press, New York 1998, 4th ed.
  15. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976;72:248–254.
  16. Clark I, Atwood C, Bowen R, Paz-Filho G, Vissel B. Tumor necrosis factor-induced cerebral insulin resistance in Alzheimer’s disease links numerous treatment rationales. Pharmacol Rev. 2012;64:1004–1026.
  17. Pinton S, da Rocha JT, Gai BM, Nogueira CW. Sporadic dementia of Alzheimer’s type induced by streptozotocin promotes anxiogenic behavior in mice. Behav Brain Res. 2011;223:1–6.
  18. Arabpoor Z, Hamidi G, Rashidi B, et al. Erythropoietin improves neuronal proliferation in dentate gyrus of hippocampal formation in an animal model of Alzheimer’s disease. Adv Biomed Res. 2012;1:50.
  19. Adamcio B, Sargin D, Stradomska A, Medrihan L, Gertler C, Theis F. Erythropoietin enhances hippocampal long-term potentiation and memory. BMC Biol. 2008;6:37.
  20. Wüstenberg T, Begemann M, Bartels C, et al. Recombinant human erythropoietin delays loss of gray matter in chronic schizophrenia. Mol Psychiatry. 2011;16:26–36.
  21. Ehrenreich H, Fischer B, Norra C, et al. Exploring recombinant human erythropoietin in chronic progressive multiple sclerosis. Brain. 2007;130:2577–2588.
  22. Bierer R, Peceny MC, Hartenberger CH, Ohls RK. Erythropoietin concentrations and neurodevelopmental outcome in preterm infants. Pediatrics. 2006;118:635–640.
  23. Haljan G, Maitland A, Buchan A, et al. The erythropoietin neuroprotective effect: assessment in CABG surgery (TENPEAKS): A randomized, double-blind, placebo controlled, proof-of-concept clinical trial. Stroke. 2009;40:2769–2775.
  24. Francis PT, Palmer AM, Snape M, Wilcock GK. The cholinergic hypothesis of Alzheimer’s disease: A review of progress. J Neurol Neurosurg Psychiatry. 1999;66:137–147.
  25. Khairallah MI, Kassem LA, Yassin NA, et al. The hematopoietic growth factor “erythropoietin” enhances the therapeutic effect of mesenchymal stem cells in Alzheimer’s disease. Pak J Biol Sci. 2014; 17:9–21.
  26. Kumar R, Jaggi AS, Singh N. Effects of erythropoietin on memory deficits and brain oxidative stress in the mouse models of dementia. Korean J Physiol Pharmacol. 2010;14:345–352.
  27. Maurice T, Mustafa MH, Desrumaux C, et al. Intranasal formulation of erythropoietin (EPO) showed potent protective activity against amyloid toxicity in the Aβ₂₅–₃₅ non-transgenic mouse model of Alzheimer’s disease. J Psychopharmacol. 2013;27:1044–1057.
  28. Noh MY, Cho KA, Kim H, Kim SM, Kim SH. Erythropoietin modulates the immune-inflammatory response of a SOD1(G93A) transgenic mouse model of amyotrophic lateral sclerosis (ALS). Neurosci Lett. 2014;574:53–58.
  29. Villa P, Bigini P, Mennini, T et al. Erythropoietin selectively attenuates cytokine production and inflammation in cerebral ischemia by targeting neuronal apoptosis. J Exp Med. 2003;198:971–975.
  30. Diederich K, Schäbitz WR, Minnerup J. Seeing old friends from a different angle: novel properties of hematopoietic growth factors in the healthy and diseased brain. Hippocampus. 2012;22:1051–1057.