Recombinant human erythropoietin counteracts secondary injury and markedly enhances neurological recovery from experimental spinal cord trauma

Abstract

Erythropoietin (EPO) functions as a tissue-protective cytokine in addition to its crucial hormonal role in red cell production. In the brain, for example, EPO and its receptor are locally produced, are modulated by metabolic stressors, and provide neuroprotective and antiinflammatory functions. We have previously shown that recombinant human EPO (rhEPO) administered within the systemic circulation enters the brain and is neuroprotective. At present, it is unknown whether rhEPO can also improve recovery after traumatic injury of the spinal cord. To evaluate whether rhEPO improves functional outcome if administered after cord injury, two rodent models were evaluated. First, a moderate compression of 0.6 N was produced by application of an aneursym clip at level T3 for 1 min. RhEPO (1,000 units per kg of body weight i.p.) administered immediately after release of compression was associated with partial recovery of motor function within 12 h after injury, which was nearly complete by 28 days. In contrast, saline-treated animals exhibited only poor recovery. In the second model used, rhEPO administration (5,000 units per kg of body weight i.p. given once 1 h after injury) also produced a superior recovery of function compared with saline-treated controls after a contusion of 1 N at level T9. In this model of more severe spinal cord injury, secondary inflammation was also markedly attenuated by rhEPO administration and associated with reduced cavitation within the cord. These observations suggest that rhEPO provides early recovery of function, especially after spinal cord compression, as well as longerlatency neuroprotective, antiinflammatory and antiapoptotic functions.T raumatic spinal cord injury (TSCI) occurs frequently and is devastating for the individual patient and costly to society by requiring substantial long-term health care expenditures. Currently, methylprednisolone administered at high dose within 8 h after injury is the only therapy with any recognized benefit (1), which, unfortunately, is relatively minor. Any new treatment of TSCI that allows for major recovery of function would be a significant advance in clinical care.Injury of the nervous system provokes a complex cascade of proinflammatory cytokines and other molecules that ultimately result in apoptosis and necrosis of neurons, oligodendrocytes, and endothelial cells (2-4). Recent studies have demonstrated that one general response of the brain to injury is the increased local production of the erythropoietin (EPO) and its receptor (5, 6). These proteins are members of the cytokine type I superfamily that provide beneficial effects including inhibition of apoptosis, reduction of inflammation, modulation of excitability (7-11), and mobilization and proliferation of neuronal stem cells (12). Prior study has shown that recombinant human EPO (rhEPO) administered directly into the brain dramatically reduces hypoxic or ischemic injury and conversely, that neutralization of endogenous EPO amplifies injury (8). We have extended these observations by sho...

Neuroprotection by erythropoietin administration after experimental traumatic brain injury

“…Furthermore, inflammatory cells are involved in the late damage that occurs to the oligodendrocytes that provide brain degeneration (Leinhase et al, 2006). rHuEPO appears to reduce the inflammatory infiltrate and in this manner likely reduces the contribution of late injury to the neurological deficit (Gorio et al, 2002). However, antiapoptotic action and reduced neuroinflammatory response by rHuEPO (Brines et al, 2000;Siren et al, 2001;Yatsiv et al, 2005) are based on mechanisms needing several hours, after the insult, to be effective.…”

“…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).…”

Neuroprotective effects and intracellular signaling pathways of erythropoietin in a rat model of multiple sclerosis

“…42 Epo acts as the main regulator of proliferation and differentiation of erythroid progenitor cells in the bone marrow. 13 Neuroprotective effects of systemically administered Epo have been shown in animal models of focal cerebral ischemia, traumatic brain injury, subarachnoid hemorrhage, and spinal cord injury, 19,[43][44][45] but the relevance of the underlying molecular mechanisms in vivo remained still unclear. Additionally, Epo treatment rescued RGCs from apoptosis in a retinal ischemia model and improved RGC function determined by ERG recordings.…”

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

“…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.…”