Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress

Anna Leena Sirén, Maddalena Fratelli, Michael Brines, Christoph Goemans, Simona Casagrande, Piotr Lewczuk, Sonja Keenan, Christoph Gleiter, Claudio Pasquali, Annalisa Capobianco, Tiziana Mennini, Rolf Heumann, Anthony Cerami, Hannelore Ehrenreich, Pietro Ghezzi

Research output: Contribution to journalArticle

Abstract

Erythropoietin (EPO) promotes neuronal survival after hypoxia and other metabolic insults by largely unknown mechanisms. Apoptosis and necrosis have been proposed as mechanisms of cellular demise, and either could be the target of actions of EPO. This study evaluates whether antiapoptotic mechanisms can account for the neuroprotective actions of EPO. Systemic administration of EPO (5,000 units/kg of body weight, i.p.) after middle-cerebral artery occlusion in rats dramatically reduces the volume of infarction 24 h later, in concert with an almost complete reduction in the number of terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling of neurons within the ischemic penumbra. In both pure and mixed neuronal cultures, EPO (0.1-10 units/ml) also inhibits apoptosis induced by serum deprivation or kainic acid exposure. Protection requires pretreatment, consistent with the induction of a gene expression program, and is sustained for 3 days without the continued presence of EPO. EPO (0.3 units/ml) also protects hippocampal neurons against hypoxia-induced neuronal death through activation of extracellular signal-regulated kinases and protein kinase Akt-1/protein kinase B. The action of EPO is not limited to directly promoting cell survival, as EPO is trophic but not mitogenic in cultured neuronal cells. These data suggest that inhibition of neuronal apoptosis underlies short latency protective effects of EPO after cerebral ischemia and other brain injuries. The neurotrophic actions suggest there may be longer-latency effects as well. Evaluation of EPO, a compound established as clinically safe, as neuroprotective therapy in acute brain injury is further supported.

Original languageEnglish
Pages (from-to)4044-4049
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume98
Issue number7
DOIs
Publication statusPublished - Mar 27 2001

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Physiological Stress
Erythropoietin
Brain Ischemia
Apoptosis
Brain Injuries
Neurons
Proto-Oncogene Proteins c-akt
DNA Nucleotidylexotransferase
Kainic Acid
Middle Cerebral Artery Infarction
Extracellular Signal-Regulated MAP Kinases
Protein Kinases
Infarction
Cultured Cells
Cell Survival
Necrosis
Body Weight

ASJC Scopus subject areas

  • Genetics
  • General

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Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress. / Sirén, Anna Leena; Fratelli, Maddalena; Brines, Michael; Goemans, Christoph; Casagrande, Simona; Lewczuk, Piotr; Keenan, Sonja; Gleiter, Christoph; Pasquali, Claudio; Capobianco, Annalisa; Mennini, Tiziana; Heumann, Rolf; Cerami, Anthony; Ehrenreich, Hannelore; Ghezzi, Pietro.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 98, No. 7, 27.03.2001, p. 4044-4049.

Research output: Contribution to journalArticle

Sirén, 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', Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 7, pp. 4044-4049. https://doi.org/10.1073/pnas.051606598
Sirén, Anna Leena ; Fratelli, Maddalena ; Brines, Michael ; Goemans, Christoph ; Casagrande, Simona ; Lewczuk, Piotr ; Keenan, Sonja ; Gleiter, Christoph ; Pasquali, Claudio ; Capobianco, Annalisa ; Mennini, Tiziana ; Heumann, Rolf ; Cerami, Anthony ; Ehrenreich, Hannelore ; Ghezzi, Pietro. / Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress. In: Proceedings of the National Academy of Sciences of the United States of America. 2001 ; Vol. 98, No. 7. pp. 4044-4049.
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AU - Lewczuk, Piotr

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AU - Gleiter, Christoph

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AU - Capobianco, Annalisa

AU - Mennini, Tiziana

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N2 - Erythropoietin (EPO) promotes neuronal survival after hypoxia and other metabolic insults by largely unknown mechanisms. Apoptosis and necrosis have been proposed as mechanisms of cellular demise, and either could be the target of actions of EPO. This study evaluates whether antiapoptotic mechanisms can account for the neuroprotective actions of EPO. Systemic administration of EPO (5,000 units/kg of body weight, i.p.) after middle-cerebral artery occlusion in rats dramatically reduces the volume of infarction 24 h later, in concert with an almost complete reduction in the number of terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling of neurons within the ischemic penumbra. In both pure and mixed neuronal cultures, EPO (0.1-10 units/ml) also inhibits apoptosis induced by serum deprivation or kainic acid exposure. Protection requires pretreatment, consistent with the induction of a gene expression program, and is sustained for 3 days without the continued presence of EPO. EPO (0.3 units/ml) also protects hippocampal neurons against hypoxia-induced neuronal death through activation of extracellular signal-regulated kinases and protein kinase Akt-1/protein kinase B. The action of EPO is not limited to directly promoting cell survival, as EPO is trophic but not mitogenic in cultured neuronal cells. These data suggest that inhibition of neuronal apoptosis underlies short latency protective effects of EPO after cerebral ischemia and other brain injuries. The neurotrophic actions suggest there may be longer-latency effects as well. Evaluation of EPO, a compound established as clinically safe, as neuroprotective therapy in acute brain injury is further supported.

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