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

Abstract

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 g/kg at 5 min after CII or a dose of 25 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 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 g/kg significantly reduced contusion volume from 39.1 Ϯ 6.7 to 8.1 Ϯ 3.1 and 11.2 Ϯ 6.0 mm 3 , respectively. In the time window study, darbEpo reduced contusion volume when given in a dose of 25 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.

Cerebral Vascular Injury in Traumatic Brain Injury

“…Microvascular injury is a near universal feature of preclinical TBI, and has been reported in nearly all animal models of TBI to date including impact acceleration (Baranova et al, 2008;Gao et al, 2010), fluid percussion injury (FPI) (Park et al, 2009;Wei et al, 2009), and controlled cortical impact (CCI)/ (Cherian et al, 2011;Schwarzmaier et al, 2010) models in rodents; FPI in cats as well as lateral head acceleration in baboons (Maxwell et al, 1988). The FPI model in rats shows a diffuse decrease in cerebral microvascular density in the ipsilateral hemisphere with preserved density in the contralateral hemisphere (Park et al, 2009).…”

Population Pharmacokinetics of Darbepoetin Alfa in Conjunction with Hypothermia for the Treatment of Neonatal Hypoxic-Ischemic Encephalopathy

“…Site-directed mutagenesis at five amino acid locations (Ala30Asn, His32Thr, Pro87Val, Trp88Asn, and Pro90Thr) added two additional N-linked carbohydrate chains, which extend the half-life [18–20]. Preclinical studies with darbepoetin alfa have shown that it crosses the blood-brain barrier and displays comparable neuroprotective activity when compared with erythropoietin [13, 21]. In animal models, weekly administration of darbepoetin alfa conferred histologic and behavioral neuroprotection after experimental intracerebral hemorrhage [14].…”

Darbepoetin administration to neonates undergoing cooling for encephalopathy: a safety and pharmacokinetic trial

“…Additionally, neuroimaging studies were improved with combined Epo/hypothermia treatment (9). Similar to the preclinical trials with Epo, Darbe administration following cortical impact injury in neonatal rats improved cerebrovascular function and reduced histological damage in a dose- and time-dependent manner (22). Weekly administration of Darbe conferred histological and behavioral neuroprotection after intracerebral hemorrhage in rats similar to that of Epo administration (8).…”