Authors
1 Physiology Research Center, Kashan University of Medical Sciences, Kashan, Iran
2 Department of Anatomical Sciences, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
3 Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
4 Department of Basic Sciences, Payame Noor University, Shahin Shahr Branch, Iran
5 Physiology; Applied Physiology Research Center and Biosensor Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
Abstract
Background: Alzheimer's disease (AD) is a prevalent disorder with severe learning and memory defects. Because it has been demonstrated that erythropoietin (EPO) has positive effects on the central nervous system, the aim of this study was to evaluate the effect of EPO on neuronal proliferation in dentate gyrus of hippocampal formation in a well-defined model for AD.
Materials and Methods: A rat model of sporadic dementia of Alzheimer's type was established by a bilateral intracerebroventricular injection of streptozotocin (ICV-STZ). Impairment of learning and memory was confirmed 2 weeks after ICV-STZ injection by passive avoidance learning test and then rats were divided into fourgroups:Control, control-EPO, Alzheimer and Alzheimer-EPO. EPO was injected intraperitoneally every other day with a dose of 5000 IU/kg and, finally, the rats were anesthetized and decapitated for immunohistochemical study and neurogenesis investigation (by Ki67 method) in dentate gyrus of hippocampal formation.
Results: The results driven from the histological study showed that EPO significantly increases neuronal proliferation in dentate gyrus of hippocampus in the Alzheimer-EPO group compared with the control, control-EPO and Alzheimer groups; however, there were no differences between the other groups.
Conclusion: Our results show that even though EPO in intact animals doesnot change neurogenesis in dentate gyrus, it can nonetheless significantly increase neurogenesis if there is an underlying disorder like neurodegenerative diseases.
Keywords
1. | Herring A, Ambrée O, Tomm M, Habermann H, Sachser N, Paulus W, et al. Environmental enrichment enhances cellular plasticity in transgenic mice with Alzheimer-like pathology. Exp Neurol 2009;216:184-92. |
2. | Bothwell M, Giniger E. Alzheimer's disease: Neurodevelopment converges with neurodegeneration. Cell 2000;102:271-3. |
3. | Lasne F, de Ceaurriz J. Recombinant erythropoietin in urine-An artificial hormone taken to boost athletic performance can now be detected. Nature 2000;405:635. [PUBMED] |
4. | Kumral A, Uysal N, Tugyan K, Sonmez A, Yilmaz O, Gokmen N, et al. Erythropoietin improves long-term spatial memory deficits and brain injury following neonatal hypoxia-ischemia in rats. Behav Brain Res 2004;153:77-86. [PUBMED] |
5. | Squadrito F, Altavilla D, Squadrito G, Campo GM, Arlotta M, Quartarone C, et al. Recombinant human erythropoietin inhibits iNOS activity and reverts vascular dysfunction in splanchnic artery occlusion shock. Br J Pharmacol 1999;127:482-8. [PUBMED] |
6. | Li F, Chong ZZ, Maiese K. Erythropoietin on a tightrope: balancing neuronal and vascular protection between intrinsic and extrinsic pathways. Neurosignals 2004;13:265-89. |
7. | Maiese K, Li F, Chong ZZ. New avenues of exploration for erythropoietin. JAMA 2005;293:90-5. [PUBMED] |
8. | Fisher JW. Erythropoietin: Physiology and pharmacology update. Exp Biol Med(Maywood) 2003;228:1-14. |
9. | Grasso G, Sfacteria A, Meli F, Fodale V, Buemi M, Iacopino DG. Neuroprotection by erythropoietin administration after experimental traumatic brain injury. Brain Res 2007;1182:99-105. [PUBMED] |
10. | Wu Y, Shang Y, Sun SG, Liu RG, Yang WQ. Protective effect of erythropoietin against 1-methyl-4-phenylpyridinium-induced neurodegenaration in PC12 cells. Neurosci Bull 2007;23:156-64. |
11. | Lu D, Mahmood A, Qu C, Goussev A, Schallert T, Chopp M. Erythropoietin enhances neurogenesis and restores spatial memory in rats after traumatic brain injury. J Neurotrauma 2005;22:1011-7. |
12. | Zhu L, Wang HD, Yu XG, Jin W, Qiao L, Lu TJ, et al. Erythropoietin prevents zinc accumulation and neuronal death after traumatic brain injury in rat hippocampus: in vitroandin vivostudies. Brain Res 2009;1289:96-105. [PUBMED] |
13. | Kawakami M, Sekiguchi M, Sato K, Kozaki S, Takahashi M. Erythropoietin receptor-mediated inhibition of exocytotic glutamate release confers neuroprotection during chemical ischemia. J Biol Chem 2001;276:39469-75. [PUBMED] |
14. | Nakata S, Matsumura I, Tanaka H, Ezoe S, Satoh Y, Ishikawa J, et al. NF-kappaB family proteins participate in multiple steps of hematopoiesis through elimination of reactive oxygen species. J Biol Chem 2004;279:55578-86. [PUBMED] |
15. | Ma R, Xiong N, Huang C, Tang Q, Hu B, Xiang J, et al. Erythropoietin protects PC12 cells from beta-amyloid(25-35)-induced apoptosis via PI3K/Akt signaling pathway. Neuropharmacology 2009;56:1027-34. [PUBMED] |
16. | Ishrat T, Khan MB, Hoda MN, Yousuf S, Ahmad M, Ansari MA, et al. Coenzyme Q10 modulates cognitive impairment against intracerebroventricular injection of streptozotocin in rats. Behav Brain Res 2006;171:9-16. [PUBMED] |
17. | Lannert H, Hoyer S. Intracerebroventricular administration of streptozotocin causes long-term diminutions in learning and memory abilities and in cerebral energy metabolism in adult rats. Behav Neurosci 1998;112:1199-208. [PUBMED] |
18. | Reisi P, Alaei H, Babri S, Sharifi MR, Mohaddes G. Effects of treadmill running on spatial learning and memory in streptozotocin-induced diabetic rats. Neurosci Lett 2009;455:79-83. [PUBMED] |
19. | Li G, Ma R, Huang C, Tang Q, Fu Q, Liu H, et al. Protective effect of erythropoietin on beta-amyloid-induced PC12 cell death through antioxidant mechanisms. Neurosci Lett 2008;442:143-7. [PUBMED] |
20. | Ishrat T, Hoda MN, Khan MB, Yousuf S, Ahmad M, Khan MM, et al. Amelioration of cognitive deficits and neurodegeneration by curcumin in rat model of sporadic dementia of Alzheimer's type (SDAT). Eur Neuropsychopharmacol 2009;19:636-47. [PUBMED] |
21. | Adamcio B, Sargin D, Stradomska A, Medrihan L, Gertler C, Theis F, et al. Erythropoietin enhances hippocampal long-term potentiation and memory. BMC Biol 2008;6:37. [PUBMED] |
22. | Chu K, Jung KH, Lee ST, Kim JH, Kang KM, Kim HK, et al. Erythropoietin reduces epileptogenic processes following status epilepticus. Epilepsia 2008;49:1723-32. [PUBMED] |
23. | El-Kordi A, Radyushkin K, Ehrenreich H. Erythropoietin improves operant conditioning and stability of cognitive performance in mice. BMC Biol 2009;7:37. [PUBMED] |
24. | van der Kooij MA, Groenendaal F, Kavelaars A, Heijnen CJ, van BF. Neuroprotective properties and mechanisms of erythropoietin in in vitro and in vivoexperimental models for hypoxia/ischemia. Brain Res Rev 2008;59:22-33. |
25. | Paxinos G, Watson C. The rat brain in stereotaxic coordinates. 5 th ed. Academic Press: San Diego;2005. |
26. | Shin EJ, Jeong JH, Bing G, Park ES, Chae JS, Yen TP, et al. Kainate-induced mitochondrial oxidative stress contributes to hippocampal degeneration in senescence-accelerated mice. Cell Signal 2008;20:645-58. [PUBMED] |
27. | Vendramini AA, de Lábio RW, Rasmussen LT, Dos Reis NM, Minett T, Bertolucci PH, et al. Interleukin-8-251T> A, Interleukin-1 alpha-889C> T and Apolipoprotein E polymorphisms in Alzheimer's disease. Genet Mol Biol 2011;34:1-5. |
28. | Zhou Y, Qu ZQ, Zeng YS, Lin YK, Li Y, Chung P, et al. Neuroprotective effect of preadministration with Ganoderma lucidum spore on rat hippocampus. Exp Toxicol Pathol 2011. |
29. | Wiese L, Hempel C, Penkowa M, Kirkby N, Kurtzhals JA. Recombinant human erythropoietin increases survival and reduces neuronal apoptosis in a murine model of cerebral malaria. Malar J 2008;7:3. |
30. | White LD, Barone S Jr. Qualitative and quantitative estimates of apoptosis from birth to senescence in the rat brain. Cell Death Differ 2001;8:345-56. |
31. | Biebl M, Cooper CM, Winkler J, Kuhn HG. Analysis of neurogenesis and programmed cell death reveals a self-renewing capacity in the adult rat brain. Neurosci Lett 2000;291:17-20. |
32. | Gould E, Vail N, Wagers M, Gross CG. Adult-generated hippocampal and neocortical neurons in macaques have a transient existence. Proc Natl Acad Sci USA 2001;98:10910-7. |
33. | Schlessinger AR, Cowan WM, Gottlieb DI. An autoradiographic study of the time of origin and the pattern of granule cell migration in the dentate gyrus of the rat. J Comp Neurol 1975;159:149-75. |
34. | Ferri P, Cecchini T, Ciaroni S, Ambrogini P, Cuppini R, Santi S, et al. Vitamin E affects cell death in adult rat dentate gyrus. J Neurocytol 2003;32:1155-64. |
35. | Osredkar D, Sall JW, Bickler PE, Ferriero DM. Erythropoietin promotes hippocampal neurogenesis inin vitromodels of neonatal stroke. Neurobiol Dis 2010;38:259-65. |
36. | Young D, Lawlor PA, Leone P, Dragunow M, During MJ. Environmental enrichment inhibits spontaneous apoptosis, prevents seizures and is neuroprotective. Nat Med 1999;5:448-53. |
37. | Ning B, Zhang A, Song H, Gong W, Ding Y, Guo S, et al. Recombinant human erythropoietin prevents motor neuron apoptosis in a rat model of cervical sub-acute spinal cord compression. Neurosci Lett 2011;490:57-62. |
38. | Viviani B, Bartesaghi S, Corsini E, Villa P, Ghezzi P, Garau A, et al. Erythropoietin protects primary hippocampal neurons increasing the expression of brain-derived neurotrophic factor. J Neurochem 2005;93:412-21. |
39. | Ghezzi P, Brines M. Erythropoietin as an antiapoptotic, tissue-protective cytokine. Cell Death Differ 2004;11:S37-44. |
40. | Kim SM, Song J, Kim S, Han C, Park MH, Koh Y, et al. Identification of peripheral inflammatory markers between normal control and Alzheimer's disease. BMC Neurol 2011;11:51. |