Erythropoiesis and neuroprotection: two sides of the same coin?
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For personal use. Only reproduce with permission from The Lancet Publishing Group. THE LANCET Neurology Vol 2 June 2003 http://neurology.thelancet.com 332 Reflection & Reaction Erythropoiesis and neuroprotection: two sides of the same coin? Ischaemic stroke is a major cause of death and disability. Several drugs have been developed that can limit ischaemic brain damage and improve outcome. However, although many agents are effective at preventing the excitatory cascade of events that lead to ischaemic neuronal death in experimental conditions, no neuro- protective agent has been shown conclusively to improve stroke outcome. Human erythropoietin (HuEPO), a glycoprotein growth factor, is the main regulator of erythropoiesis. The human EPO gene was cloned in the early 1980s: a recombinant form of erythropoietin (rHuEPO) was subsequently developed and its use in clinical practice has increased substantially. Over the past few years, rHuEPO has greatly improved the management of anaemia due to chronic renal failure and has substantially improved quality of life in patients undergoing dialysis. The recent detection of erythro- poietin and its receptor (EPO-R) in the brain and other organs, both in rodents and in human beings, has stimulated the search for other biological roles of these proteins. In the brain, and in other tissues, erythropoietin gene expression is regulated by hypoxia inducible factor-1 (HIF-1), which is in turn activated by various stressers, particularly hypoxia. 1 Erythropoietin protects against neurological injury in several exp- erimental models both in vitro and in vivo. 2 Erythropoietin may protect neurons from glutamate toxicity by activation of calcium channels, increasing the activity of antioxidant enzymes in neurons, modulation of angiogenesis in the ischaemic brain, and by antiapoptotic effects via the activation of janus kinase-2 (JAK2) and nuclear factor B (NF-B) signalling pathways. 3 Although experimental studies to investigate the neuroprotective effects of erythropoietin are ongoing, the first clinical trial of rHuEPO in 53 patients with acute stroke of the middle cerebral artery has been recently reported. 4 Ehrenreich and co-workers report a safety study, in which 13 patients were given rHuEPO intravenously for 3 days starting within 8 h of initial stroke symptoms, and a double-blind “proof of concept” study. In the latter part of the study, 40 patients received either rHuEPO or saline. Clinical outcome at 30 days was assessed by the Barthel index and the modified Rankin scale. Additional outcome measures were sequential MRI to measure lesion size and S100b serum-protein assay. The results showed that rHuEPO was safe and associated with a significantly better recovery at 1 month follow-up. Treatment with rHuEPO was associated with a faster normalisation of S100b in the serum and a more favourable outcome, as indicated by MRI data. Although this study was well designed and adequately done, these exciting results put erythropoietin at risk of being labelled a “miracle drug” before better information on its biological actions, underlying mechanisms, and therapeutic window can be assessed. Although this was a phase II trial, rHuEPO is not a new drug. Evidence of safety from clinical use for over 14 years could rapidly lead to phase III clinical trials based on wishful thinking. This wishful thinking is already in evidence in that phase I and II trials have been bypassed by a late “proof of concept” phase II trial. Although the recent study represents a basic premise for future clinical investigations, important issues still need to be addressed. First, the safety of rHuEPO in acute stroke should take priority over all other issues. All of the currently available information on the safety of rHuEPO in human beings comes from its use in other clinical disorders. Translation of such safety information from the treatment of anaemia to the treatment of patients with stroke is extremely dangerous because the interaction and influence of rHuEPO on physiological variables, as well as with other drugs commonly used in patients with stroke, are unknown. Moreover, although rHuEPO is generally well tolerated, its use can cause hypertension, hypertensive encephalopathy, accelerated athero- sclerosis, seizures, and thrombotic/ vascular events. 5 Second, the time window and duration of treatment is an important issue. After ischaemia, locally reduced flow is present in 100% of patients scanned within 9 h and drops to 30% within 4 days; however, viable tissue may persist up to 48 h after stroke onset. Consequently, there is a rationale for starting and continuing neuro- protective treatment for at least 48 h after stroke onset. However, neuro- protective treatment should perhaps be given for several days or weeks after the first clinical cerebrovascular event, because it is during this period that the risk of recurrence is highest. Therefore, erythropoietin should be given for the duration of the ischaemic cascade, which can be up to 6 days. In the light of these observations, further phase II studies must be carried out to determine the safety, optimum tolerated doses, therapeutic time window, and treatment duration of erythropoietin for this new clinical application. Giovanni Grasso Department of Neurosurgery, University of Messina, Messina, Italy. Email [email protected] References 1 Semenza GL. HIF-1: mediator of physiological and pathophysiological responses to hypoxia. J Appl Physiol 2000; 88: 1474–80. 2 Grasso G, Buemi M, Alafaci C, et al. Beneficial effects of systemic administration of recombinant human erythropoietin in rabbits subjected to subarachnoid hemorrhage. Proc Natl Acad Sci USA 2002; 99: 5627–31. 3 Digicaylioglu M, Lipton SA. Erythropoietin- mediated neuroprotection involves cross-talk between Jak2 and NF-kappaB signalling cascades. Nature 2001; 412: 641–47. 4 Ehrenreich H, Hasselblatt M, Dembowski C, et al. Erythropoietin therapy for acute stroke is both safe and beneficial. Mol Med 2002; 8: 495–505. 5 Amgen I. Epogen (epoetin alfa) prescribing information. In: Physicians’ Desk Reference, 54th edn. Montvale: Medical Economics Press, 2000. A new clinical application for erythropoietin? D Phillips/Science Photo Library Rights were not granted to include this image in electronic media. Please refer to the printed journal.
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Transcript of Erythropoiesis and neuroprotection: two sides of the same coin?
For personal use. Only reproduce with permission from The Lancet Publishing Group.
THE LANCET Neurology Vol 2 June 2003 http://neurology.thelancet.com332
Reflection & Reaction
Erythropoiesis and neuroprotection: two sides of the same coin?Ischaemic stroke is a major cause ofdeath and disability. Several drugs havebeen developed that can limitischaemic brain damage and improveoutcome. However, although manyagents are effective at preventing theexcitatory cascade of events that lead to ischaemic neuronal death inexperimental conditions, no neuro-protective agent has been shownconclusively to improve strokeoutcome.
Human erythropoietin (HuEPO), aglycoprotein growth factor, is the mainregulator of erythropoiesis. The humanEPO gene was cloned in the early 1980s:a recombinant form of erythropoietin(rHuEPO) was subsequently developedand its use in clinical practice hasincreased substantially. Over the past few years, rHuEPO has greatlyimproved the management of anaemiadue to chronic renal failure and hassubstantially improved quality of life inpatients undergoing dialysis.
The recent detection of erythro-poietin and its receptor (EPO-R) in thebrain and other organs, both in rodentsand in human beings, has stimulatedthe search for other biological roles ofthese proteins. In the brain, and inother tissues, erythropoietin geneexpression is regulated by hypoxiainducible factor-1 (HIF-1), which is inturn activated by various stressers,particularly hypoxia.1
Erythropoietin protects againstneurological injury in several exp-erimental models both in vitro and invivo.2 Erythropoietin may protectneurons from glutamate toxicity byactivation of calcium channels,increasing the activity of antioxidantenzymes in neurons, modulation ofangiogenesis in the ischaemic brain,and by antiapoptotic effects via theactivation of janus kinase-2 (JAK2) andnuclear factor �B (NF-�B) signallingpathways.3
Although experimental studies toinvestigate the neuroprotective effectsof erythropoietin are ongoing, the firstclinical trial of rHuEPO in 53 patientswith acute stroke of the middle cerebralartery has been recently reported.4
Ehrenreich and co-workers report asafety study, in which 13 patients were
given rHuEPO intravenously for 3 daysstarting within 8 h of initial strokesymptoms, and a double-blind “proofof concept” study. In the latter part ofthe study, 40 patients received eitherrHuEPO or saline. Clinical outcome at30 days was assessed by the Barthelindex and the modified Rankin scale.Additional outcome measures weresequential MRI to measure lesion sizeand S100b serum-protein assay. The
results showed that rHuEPO was safeand associated with a significantlybetter recovery at 1 month follow-up.Treatment with rHuEPO wasassociated with a faster normalisationof S100b in the serum and a morefavourable outcome, as indicated byMRI data.
Although this study was welldesigned and adequately done, theseexciting results put erythropoietin at risk of being labelled a “miracledrug” before better information on its biological actions, underlyingmechanisms, and therapeutic windowcan be assessed.
Although this was a phase II trial,rHuEPO is not a new drug. Evidence ofsafety from clinical use for over 14 yearscould rapidly lead to phase III clinicaltrials based on wishful thinking. Thiswishful thinking is already in evidencein that phase I and II trials have beenbypassed by a late “proof of concept”phase II trial. Although the recent studyrepresents a basic premise for futureclinical investigations, important issuesstill need to be addressed.
First, the safety of rHuEPO in acutestroke should take priority over allother issues. All of the currentlyavailable information on the safety ofrHuEPO in human beings comes fromits use in other clinical disorders.
Translation of such safety informationfrom the treatment of anaemia to thetreatment of patients with stroke isextremely dangerous because theinteraction and influence of rHuEPOon physiological variables, as well aswith other drugs commonly used inpatients with stroke, are unknown.Moreover, although rHuEPO isgenerally well tolerated, its use cancause hypertension, hypertensiveencephalopathy, accelerated athero-sclerosis, seizures, and thrombotic/vascular events.5
Second, the time window andduration of treatment is an importantissue. After ischaemia, locally reducedflow is present in 100% of patientsscanned within 9 h and drops to 30%within 4 days; however, viable tissuemay persist up to 48 h after strokeonset. Consequently, there is a rationalefor starting and continuing neuro-protective treatment for at least 48 hafter stroke onset. However, neuro-protective treatment should perhaps begiven for several days or weeks after thefirst clinical cerebrovascular event,because it is during this period that therisk of recurrence is highest. Therefore,erythropoietin should be given for theduration of the ischaemic cascade,which can be up to 6 days.
In the light of these observations,further phase II studies must be carriedout to determine the safety, optimumtolerated doses, therapeutic timewindow, and treatment duration oferythropoietin for this new clinicalapplication.
Giovanni GrassoDepartment of Neurosurgery, University ofMessina, Messina, Italy. Email [email protected]
References1 Semenza GL. HIF-1: mediator of physiological
and pathophysiological responses to hypoxia. J Appl Physiol 2000; 88: 1474–80.
2 Grasso G, Buemi M, Alafaci C, et al. Beneficialeffects of systemic administration of recombinanthuman erythropoietin in rabbits subjected tosubarachnoid hemorrhage. Proc Natl Acad Sci USA2002; 99: 5627–31.
3 Digicaylioglu M, Lipton SA. Erythropoietin-mediated neuroprotection involves cross-talkbetween Jak2 and NF-kappaB signalling cascades.Nature 2001; 412: 641–47.
4 Ehrenreich H, Hasselblatt M, Dembowski C, et al.Erythropoietin therapy for acute stroke is both safeand beneficial. Mol Med 2002; 8: 495–505.
5 Amgen I. Epogen (epoetin alfa) prescribinginformation. In: Physicians’ Desk Reference, 54thedn. Montvale: Medical Economics Press, 2000.
A new clinical application for erythropoietin?
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