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 language | English |
|---|---|
| Pages (from-to) | 4044-4049 |
| Number of pages | 6 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 98 |
| Issue number | 7 |
| DOIs | |
| Publication status | Published - Mar 27 2001 |
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ASJC Scopus subject areas
- Genetics
- General
Cite this
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 journal › Article
}
TY - JOUR
T1 - Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress
AU - Sirén, Anna Leena
AU - Fratelli, Maddalena
AU - Brines, Michael
AU - Goemans, Christoph
AU - Casagrande, Simona
AU - Lewczuk, Piotr
AU - Keenan, Sonja
AU - Gleiter, Christoph
AU - Pasquali, Claudio
AU - Capobianco, Annalisa
AU - Mennini, Tiziana
AU - Heumann, Rolf
AU - Cerami, Anthony
AU - Ehrenreich, Hannelore
AU - Ghezzi, Pietro
PY - 2001/3/27
Y1 - 2001/3/27
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0035957426&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0035957426&partnerID=8YFLogxK
U2 - 10.1073/pnas.051606598
DO - 10.1073/pnas.051606598
M3 - Article
C2 - 11259643
AN - SCOPUS:0035957426
VL - 98
SP - 4044
EP - 4049
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 7
ER -