Neuroprotective effects of erythropoietin on acute metabolic and pathological changes in experimentally induced neurotrauma.
OBJECTIVE
Head trauma is a dynamic process characterized by a cascade of metabolic and molecular events. Erythropoietin (EPO) has been shown to have neuroprotective effects in animal models of traumatic brain injury (TBI). Acute in vivo mechanisms and pathological changes associated with EPO following TBI are unknown. In this study the authors compare acute metabolic and pathological changes following TBI with and without systemically administered EPO.


METHODS
Right frontal lobe microdialysis cannulae and right parietal lobe percussion hubs were inserted into 16 Sprague-Dawley rats. After a 4- to 5-day recovery, TBI was induced via a DragonFly fluid-percussion device at 2.5-2.8 atm. Rats were randomized into 2 groups, which received 5000 U/kg EPO or normal saline intraperitoneally 30 minutes after TBI. Microdialysis samples for glucose, lactate, pyruvate, and glutamate were obtained every 25 minutes for 10 hours. Rats were killed, their brains processed for light microscopy, and sections stained with H & E.


RESULTS
Erythropoietin administered 30 minutes after TBI directly affects acute brain metabolism. Brains treated with EPO maintain higher levels of glucose 4-10 hours after TBI (p<0.01), lower levels of lactate 6-10 hours after TBI (p<0.01), and lower levels of pyruvate 7.5-10 hours after TBI (p<0.01) compared with saline-treated controls. Erythropoietin maintains aerobic metabolism after TBI. Systemic EPO administration reduces acute TBI-induced lesion volume (p<0.05).


CONCLUSIONS
Following TBI, neuron use initially increases, with subsequent depletion of extracellular glucose, resulting in increased levels of extracellular lactate and pyruvate. This energy requirement can result in cell death due to increased metabolic demands. These data suggest that the neuroprotective effect of EPO may be partially due to improved energy metabolism in the acute phase in this rat model of TBI.
Hartley
Chad E
CE
Department of Neurosurgery, Upstate Medical University, State University of New York, Syracuse, New York 13210, USA. chadhartley@centura.org
Varma
Madhu
M
Fischer
John P
JP
Riccardi
Richard
R
Strauss
Judith A
JA
Shah
Sejal
S
Zhang
Shengle
S
Yang
Zhong-Jin
ZJ
D000208:Acute Disease; D000818:Animals; D001930:Brain Injuries / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000187:drug effects; D004921:Erythropoietin / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D017551:Microdialysis; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019289:Pyruvic Acid / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D018696:Neuroprotective Agents; D004921:Erythropoietin; D019344:Lactic Acid; D018698:Glutamic Acid; D019289:Pyruvic Acid; D005947:Glucose