title: Dose-dependent neurorestorative effects of delayed treatment of traumatic brain injury with recombinant human erythropoietin in rats.
abstract: OBJECTIVE
  Delayed (24 hours postinjury) treatment with erythropoietin (EPO) improves functional recovery following experimental traumatic brain injury (TBI). In this study, the authors tested whether therapeutic effects of delayed EPO treatment for TBI are dose dependent in an attempt to establish an optimal dose paradigm for the delayed EPO treatment.
  
  
  METHODS
  Experimental TBI was performed in anesthetized young adult male Wistar rats using a controlled cortical impact device. Sham animals underwent the same surgical procedure without injury. The animals (8 rats/group) received 3 intraperitoneal injections of EPO (0, 1000, 3000, 5000, or 7000 U/kg body weight, at 24, 48, and 72 hours) after TBI. Sensorimotor and cognitive functions were assessed using a modified neurological severity score and foot fault test, and Morris water maze tests, respectively. Animals were killed 35 days after injury, and the brain sections were stained for immunohistochemical analyses.
  
  
  RESULTS
  Compared with the saline treatment, EPO treatment at doses from 1000 to 7000 U/kg did not alter lesion volume but significantly reduced hippocampal neuron loss, enhanced angiogenesis and neurogenesis in the injured cortex and hippocampus, and significantly improved sensorimotor function and spatial learning. The animals receiving the medium dose of 5000 U/kg exhibited a significant improvement in histological and functional outcomes compared with the lower or higher EPO dose groups.
  
  
  CONCLUSIONS
  These data demonstrate that delayed (24 hours postinjury) treatment with EPO provides dose-dependent neurorestoration, which may contribute to improved functional recovery after TBI, implying that application of an optimal dose of EPO is likely to increase successful preclinical and clinical trials for treatment of TBI.
authors.affiliation: Department of Neurosurgery, Henry Ford Health System, Detroit, Michigan 48202, USA.
authors.forename: Yuling
authors.initials: Y
authors.lastname: Meng
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: Changsheng
authors.initials: C
authors.lastname: Qu
authors.forename: Michael
authors.initials: M
authors.lastname: Chopp
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects* / Q000293:injuries / Q000473:pathology / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004921:Erythropoietin / Q000494:pharmacology / Q000627:therapeutic use*; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function / Q000187:drug effects* / Q000502:physiology
chemical_list: D004921:Erythropoietin