Neurotherapeutic potential of erythropoietin after ischemic injury of the central nervous system
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摘要
Erythropoietin(EPO) is one of the most successful biopharmaceuticals in history and is used for treating anemia of different origins. However, it became clear that EPO could also work in a neuroprotective, antiapoptotic, antioxidative, angiogenetic and neurotropic way. It causes stimulation of cells to delay cell apoptosis, especially in the central nervous system. In rodent models of focal cerebral ischemia, EPO showed an impressive reduction of infarct size by 30% and improvement of neurobehavioral outcome by nearly 40%. A large animal model dealing with ischemia and reperfusion of the spinal cord showed that EPO could reduce the risk of spinal cord injury significantly. In addition, some clinical studies tested whether EPO works in real live clinical settings. One of the most promising studies showed the innocuousness and improvements in follow-up, outcome scales and in infarct size, of EPO-use in humans suffering from ischemic stroke. Another study ended unfortunately in a negative outcome and an increased overall death rate in the EPO group. The most possible reason was the involvement of patients undergoing simultaneously systemic thrombolysis with recombinant tissue plasminogen activator. An experimental study on rats demonstrated that administration of EPO might exacerbate tissue plasminogen activator-induced brain hemorrhage without reducing the ischemic brain damage. This case shows clearly how useful animal models can be to check negative side effects of a treatment before going into clinical trials. Other groups looked in human trials at the effects of EPO on the outcome after ischemic stroke, relation to circulating endothelial progenitor cells, aneurysmal subarachnoid hemorrhage, traumatic brain injury, hemoglobin transfusion thresholds and elective first-time coronary artery bypass surgery. Most of the results were positive, but are based mostly on small group sizes. However, some of the most neglected facts when focusing on experimental setups of ischemia of the central nervous system are issues like age and comorbidities. It might be extremely worthy to consider these points for future projects, because EPO might influence all these factors.
Erythropoietin(EPO) is one of the most successful biopharmaceuticals in history and is used for treating anemia of different origins. However, it became clear that EPO could also work in a neuroprotective, antiapoptotic, antioxidative, angiogenetic and neurotropic way. It causes stimulation of cells to delay cell apoptosis, especially in the central nervous system. In rodent models of focal cerebral ischemia, EPO showed an impressive reduction of infarct size by 30% and improvement of neurobehavioral outcome by nearly 40%. A large animal model dealing with ischemia and reperfusion of the spinal cord showed that EPO could reduce the risk of spinal cord injury significantly. In addition, some clinical studies tested whether EPO works in real live clinical settings. One of the most promising studies showed the innocuousness and improvements in follow-up, outcome scales and in infarct size, of EPO-use in humans suffering from ischemic stroke. Another study ended unfortunately in a negative outcome and an increased overall death rate in the EPO group. The most possible reason was the involvement of patients undergoing simultaneously systemic thrombolysis with recombinant tissue plasminogen activator. An experimental study on rats demonstrated that administration of EPO might exacerbate tissue plasminogen activator-induced brain hemorrhage without reducing the ischemic brain damage. This case shows clearly how useful animal models can be to check negative side effects of a treatment before going into clinical trials. Other groups looked in human trials at the effects of EPO on the outcome after ischemic stroke, relation to circulating endothelial progenitor cells, aneurysmal subarachnoid hemorrhage, traumatic brain injury, hemoglobin transfusion thresholds and elective first-time coronary artery bypass surgery. Most of the results were positive, but are based mostly on small group sizes. However, some of the most neglected facts when focusing on experimental setups of ischemia of the central nervous system are issues like age and comorbidities. It might be extremely worthy to consider these points for future projects, because EPO might influence all these factors.
Erythropoietin(EPO) is one of the most successful biopharmaceuticals in history and is used for treating anemia of different origins. However, it became clear that EPO could also work in a neuroprotective, antiapoptotic, antioxidative, angiogenetic and neurotropic way. It causes stimulation of cells to delay cell apoptosis, especially in the central nervous system. In rodent models of focal cerebral ischemia, EPO showed an impressive reduction of infarct size by 30% and improvement of neurobehavioral outcome by nearly 40%. A large animal model dealing with ischemia and reperfusion of the spinal cord showed that EPO could reduce the risk of spinal cord injury significantly. In addition, some clinical studies tested whether EPO works in real live clinical settings. One of the most promising studies showed the innocuousness and improvements in follow-up, outcome scales and in infarct size, of EPO-use in humans suffering from ischemic stroke. Another study ended unfortunately in a negative outcome and an increased overall death rate in the EPO group. The most possible reason was the involvement of patients undergoing simultaneously systemic thrombolysis with recombinant tissue plasminogen activator. An experimental study on rats demonstrated that administration of EPO might exacerbate tissue plasminogen activator-induced brain hemorrhage without reducing the ischemic brain damage. This case shows clearly how useful animal models can be to check negative side effects of a treatment before going into clinical trials. Other groups looked in human trials at the effects of EPO on the outcome after ischemic stroke, relation to circulating endothelial progenitor cells, aneurysmal subarachnoid hemorrhage, traumatic brain injury, hemoglobin transfusion thresholds and elective first-time coronary artery bypass surgery. Most of the results were positive, but are based mostly on small group sizes. However, some of the most neglected facts when focusing on experimental setups of ischemia of the central nervous system are issues like age and comorbidities. It might be extremely worthy to consider these points for future projects, because EPO might influence all these factors.
引文
Carnot P,Deflandre C(1906)Sur l'activite hemopoietique du serum au cours de la regeneration du sang.Compt Rend Acad Sci 143:348-386.
Ehrenreich H,Hasselblatt M,Dembowski C,Cepek L,Lewczuk P,Stiefel M,Rustenbeck H-H,Breiter N,Jacob S, Knerlich F,Bohn M,Poser W,Ruther E,Kochen M,Gefeller O,Gleiter C,Wessel TC,De Ryck M,Itri L,Prange H,et al.(2002)Erythropoietin therapy for acute stroke is both safe and beneficial.Mol Med 8:495-505.
Ehrenreich H,Weissenborn K,Prange H,Schneider D,Weimar C,Wartenberg K,Schellinger PD,Bohn M,Becker H,Wegrzyn M,Jahnig P,Herrmann M,Knauth M,Bahr M,Heide W,Wagner A,Schwab S,Reichmann H,Schwendemann G,Dengler R,et al.(2009)Recombinant human erythropoietin in the treatment of acute ischemic stroke.Stroke 40:e647-656.
Goldwasser E(1996)Erythropoietin:a somewhat personal history.Perspect Biol Med 40:18-32.
Haljan G,Maitland A,Buchan A,Arora RC,King M,Haigh J,Culleton B,Faris P, Zygun D(2009)The erythropoietin neuroprotective effect:assessment in CABG surgery(TENPEAKS):a randomized,double-blind,placebo controlled,proof-of-concept clinical trial.Stroke 40:2769-2775.
Jerndal M,Forsberg K,Sena ES,Macleod MR,O'Collins VE,Linden T,Nilsson M,Howells DW(2010)A systematic review and meta-analysis of erythropoietin in experimental stroke.J Cereb Blood Flow Metab 30:961-968.
Jia L,Chopp M,Zhang L,Lu M,Zhang Z(2010)Erythropoietin in combination of tissue plasminogen activator exacerbates brain hemorrhage when treatment is initiated 6 hours after stroke.Stroke41:2071-2076.
Juul SE,Yachnis AT,Rojiani AM,Christensen RD(1999)Immunohistochemical localization of erythropoietin and its receptor in the developing human brain.Pediatr Dev Pathol 2:148-158.
Lin FK,Suggs S,Lin CH,Browne JK,Smailing R,Egrie JC,Chen KK,Fox GM,Martin F,Stabinsky Z,et al.(1985)Cloning and expression of the human erythropoietin gene.Proc Natl Acad Sci U S A 82:7580-7584.
Maiese K,Li F,Chong ZZ(2004)Erythropoietin in the brain:can the promise to protect be fulfilled?Trends Pharmacol Sci 25:577-583.
Maiese K,Li F,Chong ZZ(2005)New avenues of exploration for erythropoietin.JAMA 293:90-95.
Nakano M,Satoh K,Fukumoto Y,Ito Y,Kagaya Y,Ishii N,Sugamura K,Shimokawa H(2007)Important role of erythropoietin receptor to promote VEGF expression and angiogenesis in peripheral ischemia in mice.Circ Res 100:662-669.
Popa-Wagner A,Glavan DG,Olaru A,Olaru DG,Margaritescu O,Tica O,Surugiu R,Sandu RE(2018)Present status and future challenges of new therapeutic targets in preclinical models of stroke in aged animals with/without Comorbidities.Int J Mol Sci 19:E3 56.
Robertson CS, Hannay HJ,Yamal JM,Gopinath S,Goodman JC,Tilley BC,Epo Severe TBI Trial Investigators,Baldwin A,Rivera Lara L,Saucedo-Crespo H,Ahmed O,Sadasivan S,Ponce L,Cruz-Navarro J,Shahin H,Aisiku IP,Doshi P,Valadka A,Neipert L,Waguspack JM,et al.(2014)Effect of erythropoietin and transfusion threshold on neurological recovery after traumatic brain injury:a randomized clinical trial.JAMA 312:36-47.
Schriebl K,Trummer E,Lattenmayer C,Weik R,Kunert R,Muller D,Katinger H,Vorauer-Uhl K(2006)Biochemical characterization of rhEpo-Fc fusion protein expressed in CHO cells.Protein Expr Purif49:265-275.
Simon F,Scheuerle A,Groger M,Vcelar B,McCook O,Moller P,Georgieff M,Calzia E,Radermacher P,Schelzig H(2011)Comparison of carbamylated erythropoietin-FC fusion protein and recombinant human erythropoietin during porcine aortic balloon occlusion-induced spinal cord ischemia/reperfusion injury.Intensive Care Med37:1525-1533.
Siren AL,Fratelli M,Brines M,Goemans C,Casagrande S,Lewczuk P,Keenan S,Gleiter C,Pasquali C,Capobianco A,Mennini T,Heumann R,Cerami A,Ehrenreich H,Ghezzi P(2001)Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress.Proc Natl Acad Sci U S A 98:4044-4049.
Springborg JB,Moller C,Gideon P, Jorgensen OS,Juhler M,Olsen NV(2007)Erythropoietin in patients with aneurysmal subarachnoid haemorrhage:a double blind randomised clinical trial.Acta Neurochir(Wien)149:1089-1101.
Tsai TH,Lu CH,Wallace CG,Chang WN,Chen SF,Huang CR,Tsai NW,Lan MY,Sung PH,Liu CF,Yip HK(2015)Erythropoietin improves long-term neurological outcome in acute ischemic stroke patients:a randomized,prospective,placebo-controlled clinical trial.Crit Care 19:49.
Tseng MY,Hutchinson PJ,Richards HK,Czosnyka M,Pickard JD,Erber WN,Brown S, Kirkpatrick PJ(2009)Acute systemic erythropoietin therapy to reduce delayed ischemic deficits following aneurysmal subarachnoid hemorrhage:a PhaseⅡrandomized,double-blind,placebo-controlled trial.Clinical article.J Neurosurg 111:1 71-180.
Villa P,Bigini P,Mennini T,Agnello D,Laragione T,Cagnotto A,Viviani B,Marinovich M,Cerami A,Coleman TR,Brines M,Ghezzi P(2003)Erythropoietin selectively attenuates cytokine production and inflammation in cerebral ischemia by targeting neuronal apoptosis.J Exp Med 198:971-975.
Yip HK,Tsai TH,Lin HS,Chen SF,Sun CK,Leu S,Yuen CM,Tan TY,Lan MY,Liou CW,Lu CH,Chang WN(2011)Effect of erythropoietin on level of circulating endothelial progenitor cells and outcome in patients after acute ischemic stroke.Crit Care 15:R40.
Ehrenreich H,Hasselblatt M,Dembowski C,Cepek L,Lewczuk P,Stiefel M,Rustenbeck H-H,Breiter N,Jacob S, Knerlich F,Bohn M,Poser W,Ruther E,Kochen M,Gefeller O,Gleiter C,Wessel TC,De Ryck M,Itri L,Prange H,et al.(2002)Erythropoietin therapy for acute stroke is both safe and beneficial.Mol Med 8:495-505.
Ehrenreich H,Weissenborn K,Prange H,Schneider D,Weimar C,Wartenberg K,Schellinger PD,Bohn M,Becker H,Wegrzyn M,Jahnig P,Herrmann M,Knauth M,Bahr M,Heide W,Wagner A,Schwab S,Reichmann H,Schwendemann G,Dengler R,et al.(2009)Recombinant human erythropoietin in the treatment of acute ischemic stroke.Stroke 40:e647-656.
Goldwasser E(1996)Erythropoietin:a somewhat personal history.Perspect Biol Med 40:18-32.
Haljan G,Maitland A,Buchan A,Arora RC,King M,Haigh J,Culleton B,Faris P, Zygun D(2009)The erythropoietin neuroprotective effect:assessment in CABG surgery(TENPEAKS):a randomized,double-blind,placebo controlled,proof-of-concept clinical trial.Stroke 40:2769-2775.
Jerndal M,Forsberg K,Sena ES,Macleod MR,O'Collins VE,Linden T,Nilsson M,Howells DW(2010)A systematic review and meta-analysis of erythropoietin in experimental stroke.J Cereb Blood Flow Metab 30:961-968.
Jia L,Chopp M,Zhang L,Lu M,Zhang Z(2010)Erythropoietin in combination of tissue plasminogen activator exacerbates brain hemorrhage when treatment is initiated 6 hours after stroke.Stroke41:2071-2076.
Juul SE,Yachnis AT,Rojiani AM,Christensen RD(1999)Immunohistochemical localization of erythropoietin and its receptor in the developing human brain.Pediatr Dev Pathol 2:148-158.
Lin FK,Suggs S,Lin CH,Browne JK,Smailing R,Egrie JC,Chen KK,Fox GM,Martin F,Stabinsky Z,et al.(1985)Cloning and expression of the human erythropoietin gene.Proc Natl Acad Sci U S A 82:7580-7584.
Maiese K,Li F,Chong ZZ(2004)Erythropoietin in the brain:can the promise to protect be fulfilled?Trends Pharmacol Sci 25:577-583.
Maiese K,Li F,Chong ZZ(2005)New avenues of exploration for erythropoietin.JAMA 293:90-95.
Nakano M,Satoh K,Fukumoto Y,Ito Y,Kagaya Y,Ishii N,Sugamura K,Shimokawa H(2007)Important role of erythropoietin receptor to promote VEGF expression and angiogenesis in peripheral ischemia in mice.Circ Res 100:662-669.
Popa-Wagner A,Glavan DG,Olaru A,Olaru DG,Margaritescu O,Tica O,Surugiu R,Sandu RE(2018)Present status and future challenges of new therapeutic targets in preclinical models of stroke in aged animals with/without Comorbidities.Int J Mol Sci 19:E3 56.
Robertson CS, Hannay HJ,Yamal JM,Gopinath S,Goodman JC,Tilley BC,Epo Severe TBI Trial Investigators,Baldwin A,Rivera Lara L,Saucedo-Crespo H,Ahmed O,Sadasivan S,Ponce L,Cruz-Navarro J,Shahin H,Aisiku IP,Doshi P,Valadka A,Neipert L,Waguspack JM,et al.(2014)Effect of erythropoietin and transfusion threshold on neurological recovery after traumatic brain injury:a randomized clinical trial.JAMA 312:36-47.
Schriebl K,Trummer E,Lattenmayer C,Weik R,Kunert R,Muller D,Katinger H,Vorauer-Uhl K(2006)Biochemical characterization of rhEpo-Fc fusion protein expressed in CHO cells.Protein Expr Purif49:265-275.
Simon F,Scheuerle A,Groger M,Vcelar B,McCook O,Moller P,Georgieff M,Calzia E,Radermacher P,Schelzig H(2011)Comparison of carbamylated erythropoietin-FC fusion protein and recombinant human erythropoietin during porcine aortic balloon occlusion-induced spinal cord ischemia/reperfusion injury.Intensive Care Med37:1525-1533.
Siren AL,Fratelli M,Brines M,Goemans C,Casagrande S,Lewczuk P,Keenan S,Gleiter C,Pasquali C,Capobianco A,Mennini T,Heumann R,Cerami A,Ehrenreich H,Ghezzi P(2001)Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress.Proc Natl Acad Sci U S A 98:4044-4049.
Springborg JB,Moller C,Gideon P, Jorgensen OS,Juhler M,Olsen NV(2007)Erythropoietin in patients with aneurysmal subarachnoid haemorrhage:a double blind randomised clinical trial.Acta Neurochir(Wien)149:1089-1101.
Tsai TH,Lu CH,Wallace CG,Chang WN,Chen SF,Huang CR,Tsai NW,Lan MY,Sung PH,Liu CF,Yip HK(2015)Erythropoietin improves long-term neurological outcome in acute ischemic stroke patients:a randomized,prospective,placebo-controlled clinical trial.Crit Care 19:49.
Tseng MY,Hutchinson PJ,Richards HK,Czosnyka M,Pickard JD,Erber WN,Brown S, Kirkpatrick PJ(2009)Acute systemic erythropoietin therapy to reduce delayed ischemic deficits following aneurysmal subarachnoid hemorrhage:a PhaseⅡrandomized,double-blind,placebo-controlled trial.Clinical article.J Neurosurg 111:1 71-180.
Villa P,Bigini P,Mennini T,Agnello D,Laragione T,Cagnotto A,Viviani B,Marinovich M,Cerami A,Coleman TR,Brines M,Ghezzi P(2003)Erythropoietin selectively attenuates cytokine production and inflammation in cerebral ischemia by targeting neuronal apoptosis.J Exp Med 198:971-975.
Yip HK,Tsai TH,Lin HS,Chen SF,Sun CK,Leu S,Yuen CM,Tan TY,Lan MY,Liou CW,Lu CH,Chang WN(2011)Effect of erythropoietin on level of circulating endothelial progenitor cells and outcome in patients after acute ischemic stroke.Crit Care 15:R40.