Erythropoietin and Its Derivates Modulate Mitochondrial Dysfunction after Diffuse Traumatic Brain Injury

Anne Millet, Pierre Bouzat, Thibaut Trouve-Buisson, Cécile Batandier, Karin Pernet-Gallay, Lucie Gaide-Chevronnay, Emmanuel L. Barbier, Thierry Debillon, Eric Fontaine, Jean François Payen

Research output: Contribution to journalReview article

Abstract

Inhibiting the opening of mitochondrial permeability transition pore (mPTP), thereby maintaining the mitochondrial membrane potential and calcium homeostasis, could reduce the induction of cell death. Although recombinant human erythropoietin (rhEpo) and carbamylated erythropoietin (Cepo) were shown to prevent apoptosis after traumatic brain injury (TBI), their impact on mPTP is yet unknown. Thirty minutes after diffuse TBI (impact-acceleration model), rats were intravenously administered a saline solution (TBI-saline), 5000 UI/kg rhEpo (TBI-rhEpo) or 50 μg/kg Cepo (TBI-Cepo). A fourth group received no TBI insult (sham-operated) (n = 11 rats per group). Post-traumatic brain edema was measured using magnetic resonance imaging. A first series of experiments was conducted 2 h after TBI (or equivalent) to investigate the mitochondrial function with the determination of thresholds for mPTP opening and ultrastructural mitochondrial changes. In addition, the intramitochondrial calcium content [Caim] was measured. In a second series of experiments, brain cell apoptosis was assessed at 24 h post-injury. TBI-rhEpo and TBI-Cepo groups had a reduced brain edema compared with TBI-saline. They had higher threshold for mPTP opening with succinate as substrate: 120 (120-150) (median, interquartiles) and 100 (100-120) versus 80 (60-90) nmol calcium/mg protein in TBI-saline, respectively (p < 0.05). Similar findings were shown with glutamate-malate as substrate. TBI-rhEpo and Cepo groups had less morphological mitochondrial disruption in astrocytes. The elevation in [Caim] after TBI was not changed by rhEpo and Cepo treatment. Finally, rhEpo and Cepo reduced caspase-3 expression at 24 h post-injury. These results indicate that rhEpo and Cepo could modulate mitochondrial dysfunction after TBI. The mechanisms involved are discussed.

Original languageEnglish (US)
Pages (from-to)1625-1633
Number of pages9
JournalJournal of Neurotrauma
Volume33
Issue number17
DOIs
StatePublished - Sep 1 2016
Externally publishedYes

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Erythropoietin
Brain Edema
Calcium
Traumatic Brain Injury
Diffuse Brain Injury
Apoptosis
carbamylated erythropoietin
Mitochondrial Membrane Potential
Wounds and Injuries
Succinic Acid
Sodium Chloride
Caspase 3
Astrocytes
Glutamic Acid
Homeostasis
Cell Death
Magnetic Resonance Imaging

Keywords

  • brain edema
  • erythropoietin
  • mitochondrial permeability
  • transition pore
  • traumatic brain injury

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Millet, A., Bouzat, P., Trouve-Buisson, T., Batandier, C., Pernet-Gallay, K., Gaide-Chevronnay, L., ... Payen, J. F. (2016). Erythropoietin and Its Derivates Modulate Mitochondrial Dysfunction after Diffuse Traumatic Brain Injury. Journal of Neurotrauma, 33(17), 1625-1633. https://doi.org/10.1089/neu.2015.4160

Erythropoietin and Its Derivates Modulate Mitochondrial Dysfunction after Diffuse Traumatic Brain Injury. / Millet, Anne; Bouzat, Pierre; Trouve-Buisson, Thibaut; Batandier, Cécile; Pernet-Gallay, Karin; Gaide-Chevronnay, Lucie; Barbier, Emmanuel L.; Debillon, Thierry; Fontaine, Eric; Payen, Jean François.

In: Journal of Neurotrauma, Vol. 33, No. 17, 01.09.2016, p. 1625-1633.

Research output: Contribution to journalReview article

Millet, A, Bouzat, P, Trouve-Buisson, T, Batandier, C, Pernet-Gallay, K, Gaide-Chevronnay, L, Barbier, EL, Debillon, T, Fontaine, E & Payen, JF 2016, 'Erythropoietin and Its Derivates Modulate Mitochondrial Dysfunction after Diffuse Traumatic Brain Injury', Journal of Neurotrauma, vol. 33, no. 17, pp. 1625-1633. https://doi.org/10.1089/neu.2015.4160
Millet A, Bouzat P, Trouve-Buisson T, Batandier C, Pernet-Gallay K, Gaide-Chevronnay L et al. Erythropoietin and Its Derivates Modulate Mitochondrial Dysfunction after Diffuse Traumatic Brain Injury. Journal of Neurotrauma. 2016 Sep 1;33(17):1625-1633. https://doi.org/10.1089/neu.2015.4160
Millet, Anne ; Bouzat, Pierre ; Trouve-Buisson, Thibaut ; Batandier, Cécile ; Pernet-Gallay, Karin ; Gaide-Chevronnay, Lucie ; Barbier, Emmanuel L. ; Debillon, Thierry ; Fontaine, Eric ; Payen, Jean François. / Erythropoietin and Its Derivates Modulate Mitochondrial Dysfunction after Diffuse Traumatic Brain Injury. In: Journal of Neurotrauma. 2016 ; Vol. 33, No. 17. pp. 1625-1633.
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