title: Activation of migration of endogenous stem cells by erythropoietin as potential rescue for neurodegenerative diseases.
abstract: Neurodegenerative disorders such as Alzheimer's disease (AD) are characterized by progressive cognitive dysfunction and memory loss. There is deposition of amyloid plaques in the brain and subsequent neuronal loss. Neuroinflammation plays a key role in the pathogenesis of AD. There is still no effective curative therapy for these patients. One promising strategy involves the stimulation of endogenous stem cells. This study investigated the therapeutic effect of erythropoietin (EPO) in neurogenesis, and proved its manipulation of the endogenous mesenchymal stem cells in model of lipopolysaccharide (LPS)-induced neuroinflammation.
  
  
  METHODS
  Forty five adult male mice were divided equally into 3 groups: Group I (control), group II (LPS untreated group): mice were injected with single dose of lipopolysaccharide (LPS) 0.8 mg/kg intraperitoneally (ip) to induce neuroinflammation, group III (EPO treated group): in addition to (LPS) mice were further injected with EPO in dose of 40 μg/kg of body weight three times weekly for 5 consecutive weeks. Groups were tested for their locomotor activity and memory using open field test and Y-maze. Cerebral specimens were subjected to histological and morphometric studies. Glial fibrillary acidic protein (GFAP) and mesenchymal stem cell marker CD44 were assessed using immunostaining. Gene expression of brain derived neurotrophic factor (BDNF) was examined in brain tissue.
  
  
  RESULTS
  LPS decreased locomotor activity and percentage of correct choices in Y-maze test. Cerebral sections of LPS treated mice showed increased percentage area of dark nuclei and amyloid plaques. Multiple GFAP positive astrocytes were detected in affected cerebral sections. In addition, decrease BDNF gene expression was noted. On the other hand, EPO treated group, showed improvement in locomotor and cognitive function. Examination of the cerebral sections showed multiple neurons exhibiting less dark nuclei and less amyloid plaques in comparison to the untreated group. GFAP positive astrocytes were also reduced. Cerebral sections of the EPO treated group showed multiple branched and spindle CD44 positive cells inside and around blood vessels more than in LPS group. This immunostaining was negative in the control group. EPO administration increased BDNF gene expression.
  
  
  CONCLUSIONS
  This study proved that EPO provides excellent neuroprotective and neurotrophic effects in vivo model of LPS induced neuroinflammation. It enhances brain tissue regeneration via stimulation of endogenous mesenchymal stem cells proliferation and their migration to the site of inflammation. EPO also up regulates cerebral BDNF expression and production, which might contributes to EPO mediated neurogenesis. It also attenuates reactive gliosis thus reduces neuroinflammation. These encouraging results obtained with the use of EPO proved that it may be a promising candidate for future clinical application and treatment of neurodegenerative diseases.
authors.affiliation: Department of Physiology, Egypt; Faculty of Pharmacy & Biotechnology-German University in Cairo (GUC), Egypt. Electronic address: Mervat.khairallah@guc.edu.eg.
authors.forename: M I
authors.initials: MI
authors.lastname: Khairallah
authors.affiliation: Department of Physiology, Egypt; Faculty of Pharmacy & Biotechnology-German University in Cairo (GUC), Egypt; Faculty of Medicine, Cairo University, Egypt.
authors.forename: L A
authors.initials: LA
authors.lastname: Kassem
authors.affiliation: Department of Physiology, Egypt; Faculty of Pharmacy & Biotechnology-German University in Cairo (GUC), Egypt; Faculty of Medicine, Cairo University, Egypt.
authors.forename: N A
authors.initials: NA
authors.lastname: Yassin
authors.affiliation: Department of Physiology, Egypt; Faculty of Pharmacy & Biotechnology-German University in Cairo (GUC), Egypt; Faculty of Medicine, Cairo University, Egypt.
authors.forename: M A
authors.initials: MA
authors.lastname: Gamal el Din
authors.affiliation: Department of Histology, Egypt; Faculty of Medicine, Cairo University, Egypt.
authors.forename: M
authors.initials: M
authors.lastname: Zekri
authors.affiliation: Department of Histology, Egypt; Faculty of Medicine, Cairo University, Egypt.
authors.forename: M
authors.initials: M
authors.lastname: Attia
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects*; D004195:Disease Models, Animal; D004660:Encephalitis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology*; D004921:Erythropoietin / Q000627:therapeutic use*; D005786:Gene Expression Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D018960:Hyaluronan Receptors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008124:Locomotion / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D005904:Glial Fibrillary Acidic Protein; D018960:Hyaluronan Receptors; D008070:Lipopolysaccharides; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D004921:Erythropoietin
keywords: Alzheimer’s disease(AD); Brain derived neurotrophic factor (BDNF); Endogenous stem cells; Erythropoietin (EPO); Glial fibrillary acidic protein (GFAP)