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

Laboratory investigation

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  • 1 Departments of Neurosurgery and
  • 2 Neurology, Henry Ford Health System, Detroit;
  • 3 Department of Physics, Oakland University, Rochester, Michigan; and
  • 4 Department of Psychology and Institute for Neuroscience, University of Texas at Austin, Texas
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Object

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/EPO×1 group (6 animals); and 4) TBI/EPO×3 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 (EPO×1 group) or on Days 1, 2, and 3 (EPO×3 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 EPO×1 and EPO×3 groups significantly reduced hippocampal cell loss, enhanced angiogenesis and neurogenesis in the injured cortex and hippocampus, and significantly improved neurological functional outcome. The EPO×3 group exhibited significantly improved functional and histological outcomes compared with the EPO×1 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.

Abbreviations used in this paper: BrdU = 5-bromo-2′-deoxyuridine; BSA = bovine serum albumin; CCI = controlled cortical impact; EPO = erythropoietin; HCT = hematocrit; MCID = microcomputer imaging device; mNSS = modified neurological severity score; MWM = Morris water maze; PBS = phosphate-buffered saline; SVZ = subventricular zone; TBI = traumatic brain injury; vWF = von Willebrand factor.

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Contributor Notes

Address correspondence to: Ye Xiong, M.D., Ph.D., Department of Neurosurgery, Henry Ford Health System, E&R Building, Room #3096, 2799 West Grand Boulevard, Detroit, Michigan 48202. email: nsxye@neuro.hfh.edu.

Please include this information when citing this paper: published online October 9, 2009; DOI: 10.3171/2009.9.JNS09844.

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