The impact of erythropoietin on short-term changes in phosphorylation of brain protein kinases in a rat model of traumatic brain injury.
We found that recombinant human erythropoietin (rhEPO) reduced significantly the development of brain edema in a rat model of diffuse traumatic brain injury (TBI) (impact-acceleration model). In this study, we investigated the molecular and intracellular changes potentially involved in these immediate effects. Brain tissue nitric oxide (NO) synthesis, phosphorylation level of two protein kinases (extracellular-regulated kinase (ERK)-1/-2 and Akt), and brain water content were measured 1 (H1) and 2 h (H2) after insult. Posttraumatic administration of rhEPO (5,000 IU/kg body weight, intravenously, 30 mins after injury) reduced TBI-induced upregulation of ERK phosphorylation, although it increased Akt phosphorylation at H1. These early molecular changes were associated with a reduction in brain NO synthesis at H1 and with an attenuation of brain edema at H2. Intraventricular administration of the ERK-1/-2 inhibitor, U0126, or the Akt inhibitor, LY294002, before injury showed that ERK was required for brain edema formation, and that rhEPO-induced reduction of edema could involve the ERK pathway. These results were obtained in the absence of any evidence of blood-brain barrier damage on contrast-enhanced magnetic resonance images. The findings of our study indicate that the anti edematous effect of rhEPO could be mediated through an early inhibition of ERK phosphorylation after diffuse TBI.
Valable
Samuel
S
INSERM, U836, Grenoble, Cedex, France.
Francony
Gilles
G
Bouzat
Pierre
P
Fevre
Marie-Cécile
MC
Mahious
Nouara
N
Bouet
Valentine
V
Farion
Régine
R
Barbier
Emmanuel
E
Lahrech
Hana
H
Remy
Chantal
C
Petit
Edwige
E
Segebarth
Christoph
C
Bernaudin
Myriam
M
Payen
Jean-François
JF
D000818:Animals; D001812:Blood-Brain Barrier / Q000473:pathology; D015153:Blotting, Western; D001929:Brain Edema / Q000209:etiology / Q000517:prevention & control*; D001930:Brain Injuries / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000494:pharmacology*; D006801:Humans; D008297:Male; D010766:Phosphorylation; D011494:Protein Kinases / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins
D011994:Recombinant Proteins; D004921:Erythropoietin; D011494:Protein Kinases