Therapeutic window for nonerythropoietic carbamylated-erythropoietin to improve motor function following multiple infarct ischemic strokes in New Zealand white rabbits

TY - JOUR

T1 - Therapeutic window for nonerythropoietic carbamylated-erythropoietin to improve motor function following multiple infarct ischemic strokes in New Zealand white rabbits

AU - Lapchak, Paul A.

AU - Kirkeby, Agnete

AU - Zivin, Justin A.

AU - Sager, Thomas N.

PY - 2008/10/31

Y1 - 2008/10/31

N2 - Carbamylated erythropoietin (CEPO) is a novel neuroprotective agent that does not bind to the classical erythropoietin receptor or affect hematocrit. Since CEPO has not been systematically studied in a fully blinded and randomized manner in an embolic stroke model, we determined if CEPO would be useful to attenuate clinical deficits associated with multiple infarct ischemia using the rabbit small clot embolic stroke model (RSCEM). Rabbits were embolized and treated with vehicle or CEPO within 6 h of embolization and behavioral analysis was conducted 48 h after embolization. Using quantal analysis, we determined the quantity of blood clot (mg) in brain that produce neurologic dysfunction in 50% of the rabbits (P50), with intervention considered beneficial if it increased the P50 compared to controls. CEPO administered between 5 min and 3 h after embolization significantly (p < 0.05) improved behavioral function and increased the P50 value by 55-216%. However, CEPO administration did not improve behavior when administered 6 h following embolization. In conclusion, in the RSCEM, CEPO had a therapeutic window of at least 3 h, where it effectively improved clinical rating scores and motor function. Our results suggest that CEPO may be useful to treat acute ischemic stroke and supports the study of CEPO in stroke patients.

AB - Carbamylated erythropoietin (CEPO) is a novel neuroprotective agent that does not bind to the classical erythropoietin receptor or affect hematocrit. Since CEPO has not been systematically studied in a fully blinded and randomized manner in an embolic stroke model, we determined if CEPO would be useful to attenuate clinical deficits associated with multiple infarct ischemia using the rabbit small clot embolic stroke model (RSCEM). Rabbits were embolized and treated with vehicle or CEPO within 6 h of embolization and behavioral analysis was conducted 48 h after embolization. Using quantal analysis, we determined the quantity of blood clot (mg) in brain that produce neurologic dysfunction in 50% of the rabbits (P50), with intervention considered beneficial if it increased the P50 compared to controls. CEPO administered between 5 min and 3 h after embolization significantly (p < 0.05) improved behavioral function and increased the P50 value by 55-216%. However, CEPO administration did not improve behavior when administered 6 h following embolization. In conclusion, in the RSCEM, CEPO had a therapeutic window of at least 3 h, where it effectively improved clinical rating scores and motor function. Our results suggest that CEPO may be useful to treat acute ischemic stroke and supports the study of CEPO in stroke patients.

KW - Acute ischemic stroke

KW - Behavior

KW - Clinical deficits

KW - Embolism

KW - Neuroprotection

KW - Statistical population analysis

KW - Translational science

UR - http://www.scopus.com/inward/record.url?scp=53549109121&partnerID=8YFLogxK

U2 - 10.1016/j.brainres.2008.08.017

DO - 10.1016/j.brainres.2008.08.017

M3 - Journal article

C2 - 18761001

AN - SCOPUS:53549109121

SN - 0006-8993

VL - 1238

SP - 208

EP - 214

JO - Brain Research

JF - Brain Research

ER -