Erythropoietin prevents motor neuron apoptosis and neurologic disability in experimental spinal cord ischemic injury

Abstract

The cytokine erythropoietin (EPO) possesses potent neuroprotective activity against a variety of potential brain injuries, including transient ischemia and reperfusion. It is currently unknown whether EPO will also ameliorate spinal cord injury. Immunocytochemistry performed using human spinal cord sections showed abundant EPO receptor immunoreactivity of capillaries, especially in white matter, and motor neurons within the ventral horn. We used a transient global spinal ischemia model in rabbits to test whether exogenous EPO can cross the blood-spinal cord barrier and protect these motor neurons. Spinal cord ischemia was produced in rabbits by occlusion of the abdominal aorta for 20 min, followed by saline or recombinant human (rHu)-EPO (350, 800, or 1,000 units/kg of body weight) administered intravenously immediately after the onset of reperfusion. The functional neurological status of animals was better for rHu-EPO-treated animals 1 h after recovery from anesthesia, and improved dramatically over the next 48 h. In contrast, saline-treated animals exhibited a poorer neurological score at 1 h and did not significantly improve. Histopathological examination of the affected spinal cord revealed widespread motor neuron injury associated with positive terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling in control but not in rHu-EPO-treated animals. These observations suggest both an acute as well as a delayed beneficial action of rHu-EPO in ischemic spinal cord injury. Because rHu-EPO is currently used widely with an excellent safety profile, clinical trials evaluating its potential to prevent motor neuron apoptosis and the neurological deficits that occur as a consequence of ischemic injury are warranted.

A novel protective effect of erythropoietin in the infarcted heart

“…These studies demonstrate that a single dose of EPO (1,000-5,000 U/kg) administered around the time of MI or reperfusion can have a profound therapeutic effect independent of hematocrit. A single-dose effect of EPO also had protective effects against ischemic injury in neuronal models (3,14). Thus, we anticipate that cellular protection by EPO in ischemia will be a generalizable phenomenon…”

Neuroprotection by erythropoietin administration after experimental traumatic brain injury

“…Although the mechanisms by which EPO acts as neuroprotectant are still a matter of controversy, an increasing number of evidence suggests that EPOR activation following EPO binding inhibits neuronal apoptosis (Celik et al, 2002;Digicaylioglu and Lipton, 2001). Prevention of neuronal apoptosis involves the activation of JAK-2 and nuclear factor (NF)-kB signaling pathways (Digicaylioglu and Lipton, 2001).…”

“…Although peripherally administered recombinant human EPO (rHuEPO) has shown to penetrate the blood-brain barrier (BBB) and reduce brain injury following a variety of insults (Brines et al, 2000;Digicaylioglu and Lipton, 2001;Grasso et al, 2004), its potential neuroprotective efficacy in an in vivo model of experimental TBI has been scarcely investigated (Brines et al, 2000;Lu et al, 2005;Ozturk et al, 2005;Shein et al, 2005;Siren et al, 2006;Verdonck et al, 2007;Yatsiv et al, 2005). Evidence shows widespread efficacy of rHuEPO in injury models of spinal cord (Celik et al, 2002;Gorio et al, 2002;Grasso et al, 2006), subarachnoid hemorrhage (Buemi et al, 2002a,b;Catania et al, 2002;Grasso, 2001;Grasso et al, 2002a,b;Springborg et al, 2002), retina, and the heart damage (Calvillo et al, 2003;Junk et al, 2002).…”

“…Available evidence suggests that EPO acts in a coordinated fashion at multiple levels to limit the production of tissue-injuring molecules such as glutamate (Kawakami et al, 2001), reverse vasospasm (Grasso, 2001), attenuate apoptosis (Celik et al, 2002;Digicaylioglu and Lipton, 2001), modulate inflammation (Brines et al, 2000), and recruit stem cells (Shingo et al, 2001). Furthermore, a recent phase II clinical trial has demonstrated significant improvement in outcome of ischemic stroke patients administered rHuEPO intravenously within 8 h of the onset of symptoms (Ehrenreich et al, 2002).…”

Regulation of Inflammatory Cytokines for Spinal Cord Injury Repair Through Local Delivery of Therapeutic Agents

“…EPO is also a cytokine whose tissue‐protective activity has been extensively investigated in various injury models,86 including SCI. EPO was first reported to dramatically improve functional neurological status in a rabbit ischemia SCI model 11. This kind of functional recovery was also demonstrated in rat,17, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96 mouse,86, 97 pig,22 and other rabbit98 models.…”