Carbamylated erythropoietin reduces radiosurgically-induced brain injury.
Gamma knife radiosurgery is an attractive noninvasive treatment of brain tumors and vascular malformations that minimizes collateral tissue damage. However, exposure of normal tissue to even low-dose radiation triggers a cascade of acute and chronic injury and potentially significant morbidity and mortality. Because many irradiated patients now survive for years, identifying methods to prevent radiotherapy-induced collateral tissue damage is a major focus of current research. Erythropoietin (EPO), a cytokine produced locally by many tissues in response to injury, antagonizes apoptosis, reduces inflammation, and promotes healing. Systemic administration of recombinant EPO, widely used for treatment of anemia, provides robust protection from numerous insults in a variety of tissues, including the brain. Although irradiation injury is likely sensitive to EPO, the hematopoietic activity of EPO is undesirable in this setting, increasing erythrocyte number and predisposing to thrombosis. To avoid these potential adverse effects, we developed carbamylated EPO (CEPO) which does not stimulate the bone marrow. In this study, we show that CEPO (50 microg kg(-1) intraperitoneally) improves functional outcome when administered to adult rats just before, and then once daily for 10 d after, a necrotizing dose of radiation (100 Gy) to the right striatum. Immediately following irradiation, use and reflex movements of the contralateral forelimb to vibrissae stimulation were abnormal but rapidly improved in animals receiving CEPO. Moreover, histological examination revealed that the extent of brain necrosis after 90 days was reduced by approximately 50%. These findings further extend the kinds of injury for which administration of a tissue-protective cytokine provides benefit.
Erbayraktar
Serhat
S
Dokuz Eylül School of Medicine, Izmir, Turkey.
de Lanerolle
Nihal
N
de Lotbinière
Alain
A
Knisely
Jonathan P S
JP
Erbayraktar
Zubeyde
Z
Yilmaz
Osman
O
Cerami
Anthony
A
Coleman
Thomas R
TR
Brines
Michael
M
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001930:Brain Injuries / Q000188:drug therapy* / Q000209:etiology* / Q000473:pathology; D004921:Erythropoietin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D005720:Gamma Rays; D008297:Male; D009336:Necrosis / Q000188:drug therapy / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016634:Radiosurgery / Q000295:instrumentation*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013238:Stereotaxic Techniques
D018696:Neuroprotective Agents; C488171:carbamylated erythropoietin; D004921:Erythropoietin