Prävention der ischämischen Querschnittlähmung durch ein carbamyliertes Fusionsprotein aus Erythropoetin und einem humanen Fc-Fragment bei Aortenokklusion am Schweinemodell

Abstract

During surgical replacement of the aorta, perfusion of the aorta is interrupted, leading to ischemia of the vulnerable spinal cord with possible postoperative paraplegia. The damage is even aggravated by reperfusion injury after restarting blood flow. Erythropoetin has been shown to be cytoprotective, particularly in cases of ischemia reperfusion sequences. We tested wether a new carbamylated fusion protein consisting of erythropoetin and a human Fc fragment (cEPO-Fc) improves the postoperative function of the lower extremities if administered twice, before ischemia as well as in the early reperfusion period. Therefore, a porcine model of 30 minutes of aortic occlusion and 10 hours of reperfusion was employed. Animals were randomly assigned to a placebo and a cEPO-Fc group (each n = 9). During reperfusion, anaesthesia was reduced at certain time points to graduate limb movement as reaction to a pain stimulus. Additionally, transcranial motor-evoked potentials were measured. Furthermore, blood samples were taken to measure for concentrations of interleukin 6, tumor necrosis factor alpha and 8-isoprostane. Finally, spinal cord samples were collected for detection of necrosis (Nissl stain) and apoptosis (TUNEL and Bax immunohistochemistry) as well as detection of DNA damage (comet assay). We found significantly better motoric reactions within the cEPO-Fc group after 10 hours of reperfusion and, in addition, the amplitudes of motor-evoked potentials were higher at the same time point. Moreover, the rate of necrotic motor neurons in our histologic samples was lower after treatment with cEPO-Fc. Finally, there was a decreased concentration of 8-isoprostane, indicating reduced oxidative stress. In conclusion, cEPO-Fc showed a marked protective effect in our model of spinal cord ischemia. More research is necessary to assess wether this protection can also be shown within individuals with multiple medical conditions and not only in young and healthy organisms.