Improved Cerebrovascular Function and Reduced Histological Damage with Darbepoietin Alfa Administration after Cortical Impact Injury in Rats

Darbepoetin alfa (darbEpo) is an erythropoietic glycoprotein that activates the erythropoietin receptor. The aim of our study was to determine whether darbEpo is neuroprotective in a cortical impact injury (CII) model and to determine the characteristics of dose response and time window. To better understand the vascular mechanism of darbEpo neuroprotection, the reactivity of cerebral blood flow (CBF) to L-arginine administration was also studied. Rats were given saline or darbEpo from 2.5 to 50 mu g/kg at 5 min after CII or a dose of 25 mu g/kg darbEpo at times ranging from 5 min to 24 h after CII. Histological assessment was determined 2 weeks after a severe CII. Other rats were given either darbEpo (25 mu g/kg) or saline daily for 3 days before injury. Five minutes after severe CII, they were given either L-arginine or D-arginine. Hemodynamic variables were monitored for 2 h after injury. In the dose-response study, darbEpo in doses of 25 and 50 mu g/kg significantly reduced contusion volume from 39.1 +/- 6.7 to 8.1 +/- 3.1 and 11.2 +/- 6.0 mm(3), respectively. In the time window study, darbEpo reduced contusion volume when given in a dose of 25 mu g/kg at 5 min to 6 h after the impact injury. In animals pretreated with darbEpo, the CBF response to L-arginine was significantly greater than in the animals pretreated with saline. These data demonstrate that darbEpo has neuroprotective effects in traumatic brain injury in a dose-and time-dependent manner and that vascular effects of darbEpo may have a role in neuroprotection.