Delayed administration of erythropoietin reducing hippocampal cell loss, enhancing angiogenesis and neurogenesis, and improving functional outcome following traumatic brain injury in rats: comparison of treatment with single and triple dose.
OBJECTIVE
This efficacy study was designed to investigate traumatic brain injury (TBI) in rats treated with delayed erythropoietin (EPO) administered in a single dose compared with a triple dose.


METHODS
Young adult male Wistar rats were randomly divided into the following groups: 1) sham group (6 animals); 2) TBI/saline group (6 animals); 3) TBI/EPOx1 group (6 animals); and 4) TBI/EPOx3 group (7 animals). Traumatic brain injury was induced by controlled cortical impact over the left parietal cortex. Erythropoietin (5000 U/kg) or saline was administered intraperitoneally on Day 1 (EPOx1 group) or on Days 1, 2, and 3 (EPOx3 group) postinjury. Neurological function was assessed using a modified neurological severity score, foot-fault, and Morris water maze tests. Animals were killed 35 days after injury and brain sections were stained for immunohistochemistry.


RESULTS
Compared with the saline treatment, EPO treatment in both the EPOx1 and EPOx3 groups significantly reduced hippocampal cell loss, enhanced angiogenesis and neurogenesis in the injured cortex and hippocampus, and significantly improved neurological functional outcome. The EPOx3 group exhibited significantly improved functional and histological outcomes compared with the EPOx1 group.


CONCLUSIONS
These data demonstrate that delayed posttraumatic administration of EPO significantly improved histological and long-term functional outcomes in rats after TBI. The triple doses of delayed EPO treatment produced better histological and functional outcomes in rats, although a single dose provided substantial benefits compared with saline treatment.
Xiong
Ye
Y
Department of Neurosurgery, Henry Ford Health System, Detroit, Michigan 48202, USA. nsxye@neuro.hfh.edu
Mahmood
Asim
A
Meng
Yuling
Y
Zhang
Yanlu
Y
Qu
Changsheng
C
Schallert
Timothy
T
Chopp
Michael
M
D000818:Animals; D001930:Brain Injuries / Q000188:drug therapy* / Q000503:physiopathology; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000008:administration & dosage* / Q000627:therapeutic use; D006624:Hippocampus / Q000098:blood supply / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D018919:Neovascularization, Physiologic / Q000187:drug effects; D055495:Neurogenesis / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D010296:Parietal Lobe / Q000098:blood supply / Q000187:drug effects* / Q000503:physiopathology; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function; D013997:Time Factors; D016896:Treatment Outcome
D018696:Neuroprotective Agents; D004921:Erythropoietin