title: Erythropoietin promotes neurovascular remodeling and long-term functional recovery in rats following traumatic brain injury.
abstract: Erythropoietin (EPO) improves functional recovery after traumatic brain injury (TBI). This study was designed to investigate long-term (3 months) effects of EPO on brain remodeling and functional recovery in rats after TBI. Young male Wistar rats were subjected to unilateral controlled cortical impact injury. TBI rats were divided into the following groups: (1) saline group (n=7); (2) EPO-6h group (n=8); and (3) EPO-24h group (n=8). EPO (5000 U/kg in saline) was administered intraperitoneally at 6h, and 1 and 2 days (EPO-6h group) or at 1, 2, and 3 days (EPO-24h group) postinjury. Neurological function was assessed using a modified neurological severity score, footfault and Morris water maze tests. Animals were sacrificed at 3 months after injury and brain sections were stained for immunohistochemical analyses. Compared to the saline, EPO-6h treatment significantly reduced cortical lesion volume, while EPO-24h therapy did not affect the lesion volume (P<0.05). Both the EPO-6h and EPO-24h treatments significantly reduced hippocampal cell loss (P<0.05), promoted angiogenesis (P<0.05) and increased endogenous cellular proliferation (BrdU-positive cells) in the injury boundary zone and hippocampus (P<0.05) compared to saline controls. Significantly enhanced neurogenesis (BrdU/NeuN-positive cells) was seen in the dentate gyrus of both EPO groups compared to the saline group. Both EPO treatments significantly improved long-term sensorimotor and cognitive functional recovery after TBI. In conclusion, the beneficial effects of posttraumatic EPO treatment on injured brain persisted for at least 3 months. The long-term improvement in functional outcome may in part be related to the neurovascular remodeling induced by EPO.
authors.affiliation: Department of Neurosurgery, Henry Ford Health System, Detroit, MI 48202, USA.
authors.forename: Ruizhuo
authors.initials: R
authors.lastname: Ning
authors.forename: Ye
authors.initials: Y
authors.lastname: Xiong
authors.forename: Asim
authors.initials: A
authors.lastname: Mahmood
authors.forename: Yanlu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yuling
authors.initials: Y
authors.lastname: Meng
authors.forename: Changsheng
authors.initials: C
authors.lastname: Qu
authors.forename: Michael
authors.initials: M
authors.lastname: Chopp
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001930:Brain Injuries / Q000188:drug therapy* / Q000503:physiopathology*; D001973:Bromodeoxyuridine / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000627:therapeutic use*; D020233:Gait Disorders, Neurologic / Q000188:drug therapy / Q000209:etiology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000209:etiology; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function / Q000187:drug effects*; D012720:Severity of Illness Index; D014841:von Willebrand Factor / Q000276:immunology / Q000378:metabolism
chemical_list: C029417:Von Willebrand antigen; D014841:von Willebrand Factor; D004921:Erythropoietin; D010751:Phosphopyruvate Hydratase; D001973:Bromodeoxyuridine