Reduced brain edema and functional deficits after treatment of diffuse traumatic brain injury by carbamylated erythropoietin derivative

Pierre Bouzat, Gilles Francony, Sébastien Thomas, Samuel Valable, Franck Mauconduit, Marie Cécile Fevre, Emmanuel L. Barbier, Myriam Bernaudin, Hana Lahrech, Jean Francois Payen

Research output: Contribution to journalArticle

Abstract

Objective: To investigate the effects of carbamylated erythropoietin, a modified erythropoietin lacking erythropoietic activity, on brain edema and functional recovery in a model of diffuse traumatic brain injury. Design: Adult male Wistar rats. Setting: Neurosciences and physiology laboratories. Interventions: Thirty minutes after diffuse traumatic brain injury (impact-acceleration model), rats were intravenously administered with either a saline solution (traumatic brain injury-saline) or carbamylated erythropoietin (50 μg/kg; traumatic brain injury-carbamylated erythropoietin). A third group received no traumatic brain injury insult (sham-operated). Measurements and Main Results: Three series of experiments were conducted to investigate: 1) the effect of carbamylated erythropoietin on brain edema before and 1 hr after traumatic brain injury using diffusion-weighted magnetic resonance imaging and measurements of apparent diffusion coefficient (n = 10 rats per group), and the phosphorylation level of brain extracellular-regulated kinase-1/-2 was also determined to indicate the presence of an activated cell signaling pathway; 2) the time course of brain edema using magnetic resonance imaging between 4 and 6 hrs postinjury and the gravimetric technique at 6 hrs (n = 10 rats per group); and 3) motor and cognitive function over 10 days post traumatic brain injury, testing acute somatomotor reflexes, adhesive paper removal, and two-way active avoidance (n = 8 rats per group). Compared to traumatic brain injury-saline rats, rats receiving traumatic brain injury-carbamylated erythropoietin showed a significant reduction in brain edema formation at 1 hr that was sustained until 6 hrs when results were comparable with sham-operated rats. This antiedematous effect of carbamylated erythropoietin was possibly mediated through an early inhibition of extracellular-regulated kinase-1/-2 phosphorylation. Compared to traumatic brain injury-saline rats, traumatic brain injury-carbamylated erythropoietin rats showed improved functional recovery of the acute somatomotor reflexes post traumatic brain injury, took less time to remove adhesive from the forelimbs, and showed higher percentages of correct avoidance responses. Conclusion: Our findings indicate that early posttraumatic administration of carbamylated erythropoietin reduces brain edema development until at least 6 hrs postinjury and improves neurologic recovery. Carbamylated erythropoietin can thus be considered as a potential agent in the treatment of traumatic brain injury-induced diffuse edema.

Original languageEnglish (US)
Pages (from-to)2099-2105
Number of pages7
JournalCritical Care Medicine
Volume39
Issue number9
DOIs
StatePublished - Sep 2011
Externally publishedYes

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Brain Edema
Therapeutics
Adhesives
Traumatic Brain Injury
Diffuse Brain Injury
carbamylated erythropoietin
Reflex
Phosphotransferases
Phosphorylation
Diffusion Magnetic Resonance Imaging
Forelimb
Neurosciences
Erythropoietin
Sodium Chloride
Cognition
Nervous System
Wistar Rats
Edema
Magnetic Resonance Imaging

Keywords

  • brain edema
  • carbamylated erythropoietin
  • erythropoietin
  • magnetic resonance diffusion-weighted imaging
  • magnetic resonance imaging
  • neurological outcome
  • traumatic brain injury

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

Cite this

Reduced brain edema and functional deficits after treatment of diffuse traumatic brain injury by carbamylated erythropoietin derivative. / Bouzat, Pierre; Francony, Gilles; Thomas, Sébastien; Valable, Samuel; Mauconduit, Franck; Fevre, Marie Cécile; Barbier, Emmanuel L.; Bernaudin, Myriam; Lahrech, Hana; Payen, Jean Francois.

In: Critical Care Medicine, Vol. 39, No. 9, 09.2011, p. 2099-2105.

Research output: Contribution to journalArticle

Bouzat, P, Francony, G, Thomas, S, Valable, S, Mauconduit, F, Fevre, MC, Barbier, EL, Bernaudin, M, Lahrech, H & Payen, JF 2011, 'Reduced brain edema and functional deficits after treatment of diffuse traumatic brain injury by carbamylated erythropoietin derivative', Critical Care Medicine, vol. 39, no. 9, pp. 2099-2105. https://doi.org/10.1097/CCM.0b013e31821cb7b2
Bouzat, Pierre ; Francony, Gilles ; Thomas, Sébastien ; Valable, Samuel ; Mauconduit, Franck ; Fevre, Marie Cécile ; Barbier, Emmanuel L. ; Bernaudin, Myriam ; Lahrech, Hana ; Payen, Jean Francois. / Reduced brain edema and functional deficits after treatment of diffuse traumatic brain injury by carbamylated erythropoietin derivative. In: Critical Care Medicine. 2011 ; Vol. 39, No. 9. pp. 2099-2105.
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AU - Mauconduit, Franck

AU - Fevre, Marie Cécile

AU - Barbier, Emmanuel L.

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KW - magnetic resonance diffusion-weighted imaging

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