In vivo evidence that erythropoietin protects neurons from ischemic damage.
Erythropoietin (EPO) produced by the kidney and the liver (in fetuses) stimulates erythropoiesis. In the central nervous system, neurons express EPO receptor (EPOR) and astrocytes produce EPO. EPO has been shown to protect primary cultured neurons from N-methyl-D-aspartate (NMDA) receptor-mediated glutamate toxicity. Here we report in vivo evidence that EPO protects neurons against ischemia-induced cell death. Infusion of EPO into the lateral ventricles of gerbils prevented ischemia-induced learning disability and rescued hippocampal CA1 neurons from lethal ischemic damage. The neuroprotective action of exogenous EPO was also confirmed by counting synapses in the hippocampal CA1 region. Infusion of soluble EPOR (an extracellular domain capable of binding with the ligand) into animals given a mild ischemic treatment that did not produce neuronal damage, caused neuronal degeneration and impaired learning ability, whereas infusion of the heat-denatured soluble EPOR was not detrimental, demonstrating that the endogenous brain EPO is crucial for neuronal survival. The presence of EPO in neuron cultures did not repress a NMDA receptor-mediated increase in intracellular Ca2+, but rescued the neurons from NO-induced death. Taken together EPO may exert its neuroprotective effect by reducing the NO-mediated formation of free radicals or antagonizing their toxicity.
Sakanaka
M
M
Department of Anatomy, Ehime University School of Medicine, Shigenobu, Ehime 791-0295, Japan.
Wen
T C
TC
Matsuda
S
S
Masuda
S
S
Morishita
E
E
Nagao
M
M
Sasaki
R
R
D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology*; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002552:Cerebral Ventricles / Q000187:drug effects / Q000473:pathology; D004921:Erythropoietin / Q000008:administration & dosage / Q000627:therapeutic use*; D005849:Gerbillinae; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D007263:Infusions, Parenteral; D002546:Ischemic Attack, Transient / Q000473:pathology* / Q000503:physiopathology / Q000523:psychology; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D009569:Nitric Oxide / Q000633:toxicity; D009599:Nitroprusside / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D017467:Receptors, Erythropoietin / Q000008:administration & dosage / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use
D017467:Receptors, Erythropoietin; D011994:Recombinant Proteins; D004921:Erythropoietin; D009599:Nitroprusside; D009569:Nitric Oxide