Comparison of carbamylated erythropoietin-FC fusion protein and recombinant human erythropoietin during porcine aortic balloon occlusion-induced spinal cord ischemia/reperfusion injury

The balance of inflammation is critical to the repair of spinal cord injury (SCI), which is one of the most devastating traumas in human beings. Inflammatory cytokines, the direct mediators of local inflammation, have differential influences on the repair of the injured spinal cord. Some inflammatory cytokines are demonstrated beneficial to spinal cord repair in SCI models, while some detrimental. Various animal researches have revealed that local delivery of therapeutic agents efficiently regulates inflammatory cytokines and promotes repair from SCI. Quite a few clinical studies have also shown the promotion of repair from SCI through regulation of inflammatory cytokines. However, local delivery of a single agent affects only a part of the inflammatory cytokines that need to be regulated. Meanwhile, different individuals have differential profiles of inflammatory cytokines. Therefore, future studies may aim to develop personalized strategies of locally delivered therapeutic agent cocktails for effective and precise regulation of inflammation, and substantial functional recovery from SCI.

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“…It reduced microglial infiltration,28 and levels of TNF‐α,18, 26 8‐isoprostane,22 thrombospondin‐1 and transforming growth factor‐beta (TGF‐β) 27…”

Section: Roles Of Inflammatory Cytokines In Sci Repairmentioning

confidence: 99%

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

et al. 2018

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“…Erythropoietin (EPO) − a hormone best known for its effect on red blood cell production − has been shown to protect organs and tissues from ischemia and reperfusion injury including the heart [3]–[7], brain [8], [9], spinal cord [10], [11], kidney [12]–[14], liver [13]–[15], and skin [16], [17]. We have reported beneficial effects of EPO for resuscitation from cardiac arrest in animal models [18]–[20] and in human victims of sudden cardiac arrest [21].…”

Section: Introductionmentioning

confidence: 99%

“…This hypothesis was supported by rat models of HS in which pretreatment with EPO improved survival associated with lesser reductions in mean aortic pressure and lesser increases in lactic acid, tumor necrosis factor (TNF)-α, and interleukin (IL)-6 [14] along with lesser injury to the liver and kidneys [13], [14], and by studies – also in rats – showing that EPO given during HS attenuated intestinal mucosal injury and bacterial translocation [22] along with maintaining intestinal microcirculatory blood flow [23]. Although – to the best of our knowledge – the effects of EPO during HS have not been investigated in large animal models (i.e., swine, sheep, and dog), EPO has been shown to exert tissue protection in swine models of liver [15] and spinal cord [11] ischemia.…”

Section: Introductionmentioning

confidence: 99%

Effects of Intraosseous Erythropoietin during Hemorrhagic Shock in Swine

et al. 2014

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ObjectiveTo determine whether erythropoietin given during hemorrhagic shock (HS) ameliorates organ injury while improving resuscitation and survival.MethodsThree series of 24 pigs each were studied. In an initial series, 50% of the blood volume (BV) was removed in 30 minutes and normal saline (threefold the blood removed) started at minute 90 infusing each third in 30, 60, and 150 minutes with shed blood reinfused at minute 330 (HS-50BV). In a second series, the same HS-50BV protocol was used but removing an additional 15% of BV from minute 30 to 60 (HS-65BV). In a final series, blood was removed as in HS-65BV and intraosseous vasopressin given from minute 30 (0.04 U/kg min−1) until start of shed blood reinfusion at minute 150 (HS-65BV+VP). Normal saline was reduced to half the blood removed and given from minute 90 to 120 in half of the animals. In each series, animals were randomized 1∶1 to receive erythropoietin (1,200 U/kg) or control solution intraosseously after removing 10% of the BV.ResultsIn HS-50BV, O2 consumption remained near baseline yielding minimal lactate increases, 88% resuscitability, and 60% survival at 72 hours. In HS-65BV, O2 consumption was reduced and lactate increased yielding 25% resuscitability. In HS-65BV+VP, vasopressin promoted hemodynamic stability yielding 92% resuscitability and 83% survival at 72 hours. Erythropoietin did not affect resuscitability or subsequent survival in any of the series but increased interleukin-10, attenuated lactate increases, and ameliorated organ injury based on lesser troponin I, AST, and ALT increases and lesser neurological deficits in the HS-65BV+VP series.ConclusionsErythropoietin given during HS in swine failed to alter resuscitability and 72 hour survival regardless of HS severity and concomitant treatment with fluids and vasopressin but attenuated acute organ injury. The studies also showed the efficacy of vasopressin and restrictive fluid resuscitation for hemodynamic stabilization and survival.

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“…In this issue of Intensive Care Medicine, Simon et al [1] report that pretreatment with a carbamylated erythropoietin fusion protein (cEPO-FC) is as effective as recombinant human EPO (rhEPO) in ameliorating spinal cord injury in a well-established porcine model of acute spinal cord ischemia and reperfusion. This new fusion protein contains two rhEPO molecules connected by the Fc region of human IgG 1 .…”

mentioning

confidence: 99%

“…This new fusion protein contains two rhEPO molecules connected by the Fc region of human IgG 1 . Subsequent carbamylation of the EPO molecule is thought to improve the cytoprotective effects, while reducing side effects including hypertension and thrombosis [2].…”

mentioning

confidence: 99%

Erythropoietic neuroprotection: Holy Grail or potential to fail?

2011

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In this issue of Intensive Care Medicine, Simon et al. [1] report that pretreatment with a carbamylated erythropoietin fusion protein (cEPO-FC) is as effective as recombinant human EPO (rhEPO) in ameliorating spinal cord injury in a well-established porcine model of acute spinal cord ischemia and reperfusion. This new fusion protein contains two rhEPO molecules connected by the Fc region of human IgG 1 . Subsequent carbamylation of the EPO molecule is thought to improve the cytoprotective effects, while reducing side effects including hypertension and thrombosis [2]. EPO and EPO variantsSince the human EPO gene was cloned in 1985, several variants of the EPO molecule have been developed to improve its pharmacokinetic and pharmacodynamic characteristics and to separate its hemopoietic and neuroprotective properties [3]. Epoietin alpha and beta are rhEPOs and have minimal differences in their structure. A variety of EPO derivatives, including cEPO-FC, which target the erythropoietin receptor (EpoR), and mimetic compounds (such as EPO-peptide AB, helix B peptide and hematide) have been developed. Darbepoietin alpha is a hyperglycosylated analogue of EPO with a four-to fivefold lower erythropoietin receptor binding activity but a threefold longer serum half-life. Epoietin delta has been produced in a human cell line and has a human-type glycosylation pattern. CERA is a PEGylated form of epoietin beta with a long in vivo half-life. In addition, there are alternative means of enhancing endogenous EPO translation by preventing hypoxia-inducible factor-a degradation or GATA2 inhibition, thereby inducing endogenous EPO gene expression.

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Comparison of carbamylated erythropoietin-FC fusion protein and recombinant human erythropoietin during porcine aortic balloon occlusion-induced spinal cord ischemia/reperfusion injury

Abstract: In a porcine model of aortic balloon occlusion-induced spinal cord I/R injury, cEPO-FC and rhEPO comparably protected against ischemic spinal cord dysfunction and neuronal damage. This effect coincided with attenuated oxidative stress.

Cited by 32 publications

References 41 publications

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

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

Effects of Intraosseous Erythropoietin during Hemorrhagic Shock in Swine

Erythropoietic neuroprotection: Holy Grail or potential to fail?

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