Optimal neuroprotection by erythropoietin requires elevated expression of its receptor in neurons.
Erythropoietin receptor (EpoR) binding mediates neuroprotection by endogenous Epo or by exogenous recombinant human (rh)Epo. The level of EpoR gene expression may determine tissue responsiveness to Epo. Thus, harnessing the neuroprotective power of Epo requires an understanding of the Epo-EpoR system and its regulation. We tested the hypothesis that neuronal expression of EpoR is required to achieve optimal neuroprotection by Epo. The ventral limbic region (VLR) in the rat brain was used because we determined that its neurons express minimal EpoR under basal conditions, and they are highly sensitive to excitotoxic damage, such as occurs with pilocarpine-induced status epilepticus (Pilo-SE). We report that (i) EpoR expression is significantly elevated in nearly all VLR neurons when rats are subjected to 3 moderate hypoxic exposures, with each separated by a 4-day interval; (ii) synergistic induction of EpoR expression is achieved in the dorsal hippocampus and neocortex by the combination of hypoxia and exposure to an enriched environment, with minimal increased expression by either treatment alone; and (iii) rhEpo administered after Pilo-SE cannot rescue neurons in the VLR, unless neuronal induction of EpoR is elicited by hypoxia before Pilo-SE. This study thus demonstrates using environmental manipulations in normal rodents, the strict requirement for induction of EpoR expression in brain neurons to achieve optimal neuroprotection. Our results indicate that regulation of EpoR gene expression may facilitate the neuroprotective potential of rhEpo.
Sanchez
Pascal E
PE
University of Lyon, F-69003 Lyon, France.
Fares
Raafat P
RP
Risso
Jean-Jacques
JJ
Bonnet
Chantal
C
Bouvard
Sandrine
S
Le-Cavorsin
Marion
M
Georges
Béatrice
B
Moulin
Colette
C
Belmeguenai
Amor
A
Bodennec
Jacques
J
Morales
Anne
A
Pequignot
Jean-Marc
JM
Baulieu
Etienne-Emile
EE
Levine
Robert A
RA
Bezin
Laurent
L
D000818:Animals; D004797:Enzyme-Linked Immunosorbent Assay; D004921:Erythropoietin / Q000378:metabolism / Q000494:pharmacology*; D005786:Gene Expression Regulation; D000860:Hypoxia / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010862:Pilocarpine / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D017467:Receptors, Erythropoietin / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013226:Status Epilepticus / Q000139:chemically induced / Q000473:pathology
D018696:Neuroprotective Agents; D012333:RNA, Messenger; D017467:Receptors, Erythropoietin; D011994:Recombinant Proteins; D010862:Pilocarpine; D004921:Erythropoietin